Am J Physiol Endocrinol Metab 2009 Wang E271 88

Lipoprotein lipase: from gene to obesityHong Wang and Robert H. Eckel Am J Physiol Endocrinol Metab 297:E271-E288, 2009. First published 24 March 2009; doi: 10.1152/ajpendo.90920.2008 You might find this additional info useful... This article cites 292 articles, 157 of which you can access for free at: http://ajpendo.physiology.org/content/297/2/E271.full#ref-list-1 This article has been cited by 31 other HighWire-hosted articles: http://ajpendo.physiology.org/content/297/2/E271#cited-by Updated information and services including high resolution figures, can be found at: http://ajpendo.physiology.org/content/297/2/E271.full Additional material and information about American Journal of Physiology - Endocrinology and Metabolism can be found at: http://www.the-aps.org/publications/ajpendo Downloaded from http://ajpendo.physiology.org/ by guest on December 5, 2012 This information is current as of December 5, 2012. American Journal of Physiology - Endocrinology and Metabolism publishes results of original studies about endocrine and metabolic systems on any level of organization. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2009 the American Physiological Society. ISSN: 0193-1849, ESSN: 1522-1555. Visit our website at http://www.the-aps.org/. edu). Ultimately. fatty acids. 2009. Review Lipoprotein lipase: from gene to obesity Hong Wang and Robert H. 222. All of the enzymes in this family exhibit significant TG esterase activity and variable levels of phospholipase activity (203). although they exhibit sequence similarity. 151. e. Overall.90920.org 0193-1849/09 $8. The complementary DNA for human LPL shows that the gene E271 Address for reprint requests and other correspondence: R. cardiac and skeletal muscle. are protected from excessive weight gain. insulin resistance. insulin action. 99. LPL has been intensively examined in vivo and in vitro and in humans and many animal models. Nutrient states and hormonal levels all have divergent effects on the regulation of LPL. In this review we are going to focus on the LPL gene and protein and how alterations in LPL gene expression. doi:10. 153. First published March 24. 244). 254). Lipoprotein lipase: from gene to obesity. 2009. LPL is the rate-limiting enzyme for the hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins. tissue-specific substrate delivery and utilization. Mice with LPL deletion in skeletal muscle have reduced TG accumulation and increased insulin action on glucose transport in muscle. and very low-density lipoproteins (VLDL). Aurora. 129.g. respectively (54. producing chylomicron remnants and intermediate-density lipoproteins (IDLs). lipid metabolism.90920. Am J Physiol Endocrinol Metab 297: E271–E288. LPL molecules can act as ligands for lipoprotein receptors to facilitate lipoprotein uptake (13. enzyme activity.ajpendo. this leads to increased lipid partitioning to other tissues. 149. they are stored as neutral lipids in adipose tissue. The Drosophila yolk proteins. Metabolism and Diabetes. Colorado Submitted 14 November 2008. LPL can interact with lipoproteins to anchor them to the vessel wall and facilitate lipoprotein particle uptake (184. lack lipase activity and show no obvious functional similarity to LPL and other enzymes (99..00 Copyright © 2009 the American Physiological Society . http://www. 260). and a variety of proteins that interact with LPL to regulate its tissue-specific activity have also been identified. University of Colorado Denver Anschutz Medical Campus. 88. and body weight regulation. 154. fatty acids. The fact that the heart depends increasingly on glucose implies that free fatty acids are not a sufficient fuel for optimal cardiac function. endothelial lipase (EL). and the many aspects of obesity and other metabolic disorders that relate to energy balance. LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism. 2. 50. accepted in final form 23 March 2009 Wang H. Mail Stop 8106. 163. 192). energy balance Downloaded from http://ajpendo. CO 80045 (e-mail: Robert. insulin action. 2012 LIPOPROTEIN LIPASE (LPL) plays a major role in the metabolism and transport of lipids. P.org/ by guest on December 5. chylomicrons. 86). 2009. To examine this divergent regulation further. and posttranslational levels in a tissue-specific manner. LPL can mediate the selective uptake of lipoprotein-associated lipids and lipophilic vitamins without the concomitant uptake of the lipoprotein particles (8.Am J Physiol Endocrinol Metab 297: E271–E288. hypertriglyceridemia. tissue-specific expression and regulation. Besides its hydrolytic activity. pancreatic lipase (PL). Univ. 240. LPL is regulated at transcriptional. 162. or stored in skeletal and cardiac muscle or as cholesteryl ester and TG in macrophages. playing an important role in the kinetics of the majority of plasma lipoprotein particles (141. 257).—Lipoprotein lipase (LPL) is a multifunctional enzyme produced by many tissues. of Colorado Denver Anschutz Medical Campus. lipid partitioning. Box 6511. and 3 (YP1. islets. O. First published March 24. and macrophages. 223.physiology. and increase their metabolic rate in the cold. and obesity. Eckel RH. transgenic and knockout murine models of tissue-specific LPL expression have been developed. These distinct physiological activities of LPL together regulate the supply of fatty acids to various tissues for either storage or oxidation. LPL Gene and Protein LPL is a member of the TG lipase gene family of proteins that includes hepatic lipase (HL). and the Drosophila yolk proteins [email protected]. It is the enzyme responsible for the hydrolysis of core triglycerides (TGs) in chylomicrons and very low-density lipoproteins (VLDLs). and tissue-specific regulation contribute to the metabolic disorders of hypertriglyceridemia and obesity. 223. and YP3. Aurora. Mice with overexpression of LPL in skeletal muscle accumulate TG in muscle. LPL has also been shown to promote the exchange of lipids between lipoproteins. H. protein binding. The LPL gene is mapped to human chromosome 8p22 (251). YP2. oxidized. 240). 2009.1152/ajpendo. and monoacylglycerol are in part taken up by the tissues locally and processed differentially. develop insulin resistance. LPL-catalyzed reaction products. 167. doi:10.1152/ajpendo. posttranscriptional. Last. including adipose tissue. Furthermore. body weight regulation. Eckel Division of Endocrinology. Mice with LPL deletion in the heart develop hypertriglyceridemia and cardiac dysfunction. respectively) (36. Eckel. 3. due to the high sequence similarity among the lipase gene family members. 196). whereas bovine tissues contain an additional 1. and His241) responsible for lipolysis. chicken. and fish (5. the enzyme is highly expressed but appears to be sourced from delipidated adipocytes and not the mammary epithelium (114). LPL protein is organized into two structurally distinct domains. sterol regulatory element. Dissociation to the monomeric form results in a loss of enzyme activity (94. 71. 5Ј-untranslated region containing most of the transcriptional regulatory elements. However. In tissues with low LPL activity (lung. in contrast to the low levels of mRNA expression. and white and brown adipose tissues and spread along the vascular mesh. LPL is synthesized in the parenchymal cells of heart. and macrophages (124). resulting in exons of the same or nearly the same size. Rat tissues contain only the 3. 122). the LPL gene is mapped to a region of mouse chromosome 8 that is homologous to the region of human chromosome 8. Native LPL monomers are arranged in a head-totail subunit orientation to form the noncovalent active homodimer (281).org/ by guest on December 5. and the monomers tend to aggregate rather than reassociate (180). partially in association with milk fat droplets (113). stop codon. rat. LPL is expressed only transiently in the embryonic liver but not in adult liver. In mice. 217). kidney. and bovine species (206). However. 59.org Downloaded from http://ajpendo. the crystal structure of the enzyme protein has not been solved yet. In rodents. The organization of the LPL gene is very similar to the HL gene with all introns interrupting coding sequence in identical phases. The first exon encodes the 5Ј-untranslated region. particularly in the glomeruli. AJP-Endocrinol Metab • VOL in size (278). This property has been widely used to assess LPL activity in vivo and to release LPL from cell membranes for purification by heparin-sepharose affinity chromatography. sheep. the organization of the EL gene is distinctly different from both LPL and HL. but little LPL mRNA is detected in surrounding cells. lung. Patients who have an inherited defect of the apoC-II gene are hypertriglyceridemic (28. cDNA clones corresponding to the entire coding region of LPL have been isolated and sequenced from a number of species. where it is anchored by ion interaction with heparin sulfate proteoglycans (HSPG) and/or by glycosyl phosphatidylinositol (61). peroxisome proliferator-activated receptor responsive element.7-kb species. Lipoprotein lipase (LPL) gene structure and proximal promoter elements. SRE.4 kb Fig. and 3Ј-untranslated region that also contains some translational regulatory elements. Following synthesis. The amino-terminal domain contains the catalytic triad (Ser132. 148). as judged by the conservation of linked genetic markers (107). and the 10th exon encodes the long 3Ј-untranslated region of 1. There are two major species of mRNA in mouse and human tissues. the signal peptide plus the first two amino acids of the mature protein. brain. These mRNAs are a consequence of different polyadenylation sites on the 3Ј-untranslated end of the mRNA. 43. Genomic clones for LPL have also been isolated in chicken. including adipose tissue. 62). In the adult liver. pig. 26. LPL requires a specific cofactor. but it is well known that LPL can be released from the bound form into the circulation by the intravenous administration of heparin. Asp156. 180). 1). ox. strong immunoreactivity has been detected in the sinusoids.6-kb species. an amino-terminal domain and a smaller carboxylterminal domain with a flexible peptide connecting the two domains (279). baboon. suggesting that the liver takes up circulating LPL from blood (165. there is strong immunofluorescence at the vascular endothelium. and liver). In the kidney. skeletal muscle. guinea pig. skeletal muscle.6 and 3.physiology. including human. LPL mRNA is most abundant in heart but is present in a wide variety of adult rat and mouse tissues at very different levels. www. reflecting both functional and developmental divergence in the lipase gene family. most of the enzyme appears to be secreted. to be fully active (38. 2012 297 • AUGUST 2009 • . strongly suggesting that the enzymes have similar overall folding patterns (280). Most striking is a conservation of five disulfide bridges in all three enzymes. mouse.Review E272 LPL AND OBESITY encodes 448 amino acids (278). Comparison of the nucleotide and amino acid sequence with those of HL and PL reveals extensive homology among the enzymes. LPL enzyme activity has been identified in a wide variety of extrahepatic tissues and cells. apoC-II. PPRE. The 10 exons of the LPL gene are schematically diagrammed with notations of the start codon. The gene is composed of 10 exons spanning ϳ30 kb (Fig. guinea pig. 1. The mechanism of this transport is still not completely understood. information from the crystal structure of PL has been used in combination with other biochemical studies to provide a good understanding of the structurefunction relationship for LPL (280).948 nucleotides (123). The predicted amino acid sequence indicates that the mature mouse protein contains 447 amino acids with a molecular mass of 50. human.314 Da. heart. The amino acid sequence of LPL is shown to be extraordinarily conserved among mouse. Although a purification scheme has existed for LPL for years.ajpendo. This dissociation occurs rapidly under the physiological conditions in the absence of stabilizing molecules such as heparan sulfate or HSPG (174. spleen. and these two regions appear to act cooperatively to enable the activation of LPL by apoC-II (38. lactating mammary gland. In the mammary gland. The binding site for this physiological activator has been located to 11 amino acid residues in two different regions of the NH2-terminal domain of LPL. 268). and fish (42. 206). 189. rat. the enzyme is made by scattered cells such as macrophages in the lung and spleen and Kupffer cells in the liver (33). LPL is secreted and then transported to the luminal surface of vascular endothelial cells. The next eight exons encode the remaining 446 amino acids. The carboxyl-terminal domain contains the dominant heparinbinding domain and is thought to be important for binding lipoproteins. In the lactating mammary gland. apoC-II transgenic mice that overexpress human apoC-II also develop hypertriglyceridemia attributable to delayed clearance of TG-rich lipoproteins (245). the peroxisome proliferator-activated receptor (PPAR)-responsive element (237. At least two separate loci appear to control the tissuespecific expression of LPL activity in mice. Interacting proteins regulate the LPL activity by 1 or more of the 4 basic regulation mechanisms. CNS. A proximal octamer motif that interacts with the POU domain of Oct-1 (164. and hormones. white adipose tissue. There are several examples of translational regulation of LPL activity. Schemative representation of the complex mechanisms of tissuespecific LPL regulation. glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1.Review LPL AND OBESITY E273 Moreover.ajpendo. When mice transgenic for apoC-II are crossed with mice that are transgenic for the overexpression of LPL in skeletal muscle. A CCAAT box just upstream of the octamer sequence binds nuclear factor Y (45) and plays an important role in transcriptional regulation of the LPL gene. we will integrate all of the LPL regulatory mechanisms into a diagram (Fig. LPL is regulated at transcriptional. translational. vator and repressor complexes can exist and contribute to the tissue-specific regulation of LPL (224. One locus controlling LPL activity in the heart is associated with an alteration in LPL mRNA size. receptor-associated protein. WAT. 1) (83). Most of the cis-acting elements positively regulate the activity of the LPL promoter. posttranscriptional. energy homeostasis. Induction of LPL by certain fatty acids (arachidonic acid and eicosapentaenoic acid) and the inhibition of LPL expression by epinephrine are mediated by the interaction of a cytosolic protein with the 3Ј-untranslated sequence of the LPL mRNA in ways that affect translational efficiency (157. and posttranslational levels in a tissue-specific manner. posttranscriptional. Tissue-specific regulation of LPL provides a mechanism for localized control of the uptake of lipoprotein lipids that results in a physiologically appropriate distribution of lipids among tissues. we will dissect the complex mechanisms of LPL regulation by first reviewing the basic mechanisms of this regulation. Basic Mechanisms of LPL Regulation Transcriptional regulation. Interestingly. RAP. interferon-␭-responsive element (109). the tissue-specific regulation of LPL activity in response to energy requirements and hormonal changes usually involves complex mechanisms at multiple levels. This tissuespecific expression and regulation of LPL has been shown to have major metabolic consequences on macronutrient fuel partitioning. In adipose tissue. and posttranslational levels in a tissue-specific manner. and AP-1-like element (104. sterol regulatory element 2 (236). insulin action. a homozygous point mutation in the apoC-II gene leading to no detectable plasma apoC-II in infancy causes massive hyperchylomicronemia and a severe encephalopathy (277). The nuclear factor Y complex possesses histone acetyltransferase activity. along with the inhibitory effects of excess apoC-II. Hormonal and nutritional regulation can affect the regulatory roles of interacting proteins or directly modify the regulation of LPL. a dose-dependent reduction of plasma TGs is observed. Furthermore. Angptls. contributes to the hypertriglyceridemia observed in apoC-II transgenic mice. however. and posttranslational regulation. Then we will discuss the different levels of LPL regulation by interacting proteins. GPIHBP1. apolipoprotein A5. the oxysterol liver X receptor-responsive element (294). translational. www. silencing elements reducing promoter activity have been identified at regions Ϫ225 to Ϫ81 within the human LPL promoter (258) and from position Ϫ263 to position Ϫ241 in the chicken promoter (293). 2). 2. indicating alterations in the expression/activity of endogenous LPL in the heart. The impact of altered regulation of LPL on metabolic diseases will be discussed last in this review. Finally. providing a potential mechanism to regulate the tissue-specific transcription of the LPL gene by remodeling of chromatin (199). APOA5. The enzymatic activity of LPL is regulated in a complex manner in response to energy requirements and hormonal changes. the DNA sequences between regions Ϫ169 and Ϫ151 account for both enhancer and silencer activity. central nervous system. Finally. In the following sections of this review.physiology. 200) and the ␤-cell protein Oct-2 is particularly important to the basal transcription of LPL. translational. 258). Oct-1 can interact with the transcription factor IIB at this site and make it function as a TATA box (164). most likely due to the effect of lowering plasma TGs by overexpression of LPL in muscle (201). LMF1. the nuclear factor-1-like motif (239). The inhibition of LPL gene transcription by TNF␣ is mediated at least in part by blocking the nuclear factor Y-CCAAT interaction (161). The 5Ј regulatory region extends Յ4 kb from the transcription start site and contains a large number of specific cis-acting elements (reviewed in Ref. angiopoietin like.org/ by guest on December 5. 235). 286).org 297 • AUGUST 2009 • . The activity of the LPL promoter has been studied extensively using in vitro transfection assays. Interestingly. heart LPL activity in these mice is reduced by 30% (201). Briefly. and lipoprotein metabolism. This region has a functional peroxisome proliferator-activated receptor-responsive element site where both transcriptional actiAJP-Endocrinol Metab • VOL Downloaded from http://ajpendo. 262). 199). Increasing evidence suggests that LPL is regulated at transcriptional. The basic promoter elements of the LPL gene are located within 101 bp upstream of the transcription start site (Fig. these regulatory elements include CT element (284). A point mutation within this octamer sequence is associated with elevated serum TG levels in humans (285. nutrient state. Posttranscriptional. 2012 Fig. another locus controlling LPL activity appears to affect the translation and/or posttranslational expression of the enzyme (124). anterior protein-1 (AP-1) element. these data suggest that the decrease of LPL activity in the heart. Together. lipase maturation factor 1. especially in adipose tissue and cardiac muscle (14. Cellular trafficking also appears to be involved in the glucose-dependent. Three of the Angptls impact metabolism (172. inactive conformation destined for ER degradation (16). The mutation does not involve the structural genes of LPL or HL and does not affect the mRNAs or protein levels of either enzyme (219). lethal mutation specific to the tw73 haplotype on mouse chromosome 17. a process that might also be involved in the posttranslational regulation of LPL activity. 2012 Fig. There is an inactive intracellular LPL pool. Finally. When LPL reaches the luminal surface of the capillary endothelium (EC) where it functions. Cell biology and posttranslational modifications of LPL. The posttranslational steps in forming active LPL are shown here. 212). Angptl4 is expressed in adipose tissue. with an NH2-terminal coiled-coil domain and a COOH-terminal fibrinogen-like domain. Interestingly. LPL activity is reduced in cardiac muscle and lipoprotein TG utilization is reduced (290). The mechanism of how Angptls inhibit LPL activity has been studied in adipose tissue. it has been proposed that the involvement of a functional actin cytoskeleton is a prerequisite for glucocorticoid and insulin-dependent intracellular translocation of LPL to sites where the release by heparin is possible (65– 67). 188). LMF1 encodes a transmembrane protein that is localized to the ER with five transmembrane-spanning domains and a conserved domain of unknown function. Active LPL. insulin secretion-independent translocation of LPL from intracellular to extracellular sites in pancreatic ␤-cells (44). 136. The angiopoietin-like (Angptl) family proteins share a structural motif with the angiopoietins.org/ by guest on December 5. Alternatively. The gene containing the cld mutation is identified as Tmem112. Angptl3 and Angptl4 inhibit LPL activity and are associated with hypertriglyceridemia (127. inactive LPL. 146. 19). and its expression increases during fasting (287). Inhibition of protein kinase C␣ in adipocytes results in decreases in LPL synthesis by translational inhibition (208. ER. Mature functional LPL is a homodimer.Review E274 LPL AND OBESITY 177. Y439X. regardless of its cellular location. 250). LPL reaches a functional conformation in the ER. 194). One individual homozygous for a C/G mutation (nucleotide 1319 in NM_022773) in exon 9 of the LMF1 gene has been identified (193). proteoglycans and GPIHBP1 have been shown to bind both LPL and chylomicrons (CM) to facilitate the hydrolysis (see Posttranscriptional. This conserved domain is found in more than 50 proteins and comprises most of the COOHterminal part of LMF1. The Y439X subject is severely hypertriglyceridemic and has repeated episodes of pancreatitis. Combined lipase deficiency (cld) is a recessive. As expected. However. This mutation causes a premature termination codon. 249). resulting in a LMF1 truncation. and retained in the ER. Angptl3 and Angptl4 have also been shown to inhibit the functions of other members of the TG lipase gene family such as HL and EL (137. In addition. aggregated. The posttranslational steps (shown in Fig. LPL Regulation by Interactive Proteins Lipase maturation factor 1.ajpendo. 47. 3) in forming the active enzyme involve the dimerization and asparagine-linked glycosylation in the endoplasmic reticulum (ER) and transportation to the Golgi apparatus (14. LPL is translocated to the functional HSPGbinding sites on the luminal surface of the capillary endothelium where hydrolysis of TG-rich lipoproteins takes place (27). is highly aggregated. LPL is first delivered to secretory vesicles and then either to lysosomes for intracellular degradation or to the parenchymal cell surface where the enzyme binds to HSPG. that removes 127 residues from the COOH terminus conserved domain. there is a 93% decrease in LPL activity and a 50% decrease in HL activity in the plasma of this affected individual. The NH2-termiwww. secretory vesicle. Well-established transcriptional regulators of LPL such as PPAR␣ and PPAR␭ agonists have been proposed to act through posttranslational mechanisms to affect cellular LPL trafficking (37. 127). SV. Knockout of the gene for either Angptl3 or Angptl 4 in mice leads to increased levels of heparin-releasable LPL activity and decreased levels of plasma TGs (78. found only in the ER. and posttranslational regulation). 213). although synthesis of the LPL protein continues (20). G. Current evidence suggests that a gene separate from the lipase gene prevents the LPL enzyme from becoming activated. In cardiomyocytes. The cld mutation results in LPL and HL proteins that are inactive. Both HSPG and the VLDL receptor are important for the transcytosis of LPL across endothelial cells (170). 209 –211. 225). Mice carrying the cld mutation show severe hypertriglyceridemia secondary to decreases in LPL and HL activities. Angiopoietin-like proteins 3 and 4. translational. Calcium has been shown to trigger the folding of LPL into active dimmers (292). After sorting occurs in the trans-Golgi apparatus. It appears that the inactive pool of LPL is not a precursor to the active form but rather contains misfolded LPL molecules that are trapped in an irreversible. when Angptl4 is overexpressed only in the heart. 3. AJP-Endocrinol Metab • VOL 297 • AUGUST 2009 • . exhibits the expected dimer conformation. renamed as lipase maturation factor 1 (LMF1) (193. 80). indicating impairment in maturation of nascent LPL and HL polypeptides. the overexpression of either Angptl leads to decreases in LPL activity and increases in plasma TGs (127). Specifically. Golgi apparatus.org Downloaded from http://ajpendo.physiology. endoplasmic reticulum. However. 2012 297 • AUGUST 2009 • . Without proteoglycans. 10. Interestingly. Angptl3 apparently inhibits LPL activity by a mechanism different from Angptl4. AJP-Endocrinol Metab • VOL Despite the very low levels of APOA5 in plasma (ϳ25 ␮g/dl) (45a) compared with other apolipoproteins. 150). cells expressing a nonglycosylated GPIHBP1 lack the ability to bind LPL or chylomicrons (12). It appears that glycosylation is a common posttranslational mechanism shared by both GPIHBP1 and LPL. Normally. Apolipoprotein A5. Expression of GPIHBP1 in cultured cells confers the ability to bind LPL. RAP can also inhibit the LRP-mediated LPL degradation in adipocytes (171). Glycosylphosphatidylinositol-anchored high-density lipoproteinbinding protein 1. conversely. chylomicrons.physiology. nor does the amino acid substitution have any discernible effect on the binding of LPL. A proteoglycan-binding site exists in APOA5. A homozygous G56R mutation in GPIHBP1 has recently been identified in two siblings with type V hyperlipoproteinemia and relapsing pancreatitis resistant to standard therapy. APOA5 appears to act as a potent regulator of plasma TG levels in humans. Common APOA5 single-nucleotide polymorphisms have been strongly associated with elevated plasma TG levels and familial combined hyperlipidemia (126). Furthermore. By cross-breeding a human LPL transgenic line with APOA5-deficient mice and. Apolipoprotein A5 (APOA5) has emerged as a regulator of the lipolysis of TG-rich lipoproteins either by inhibiting hepatic VLDL production (9. In APOA5 transgenic mice. Enzyme kinetic analysis using purified recombinant proteins shows that Angptl3 reduces LPL catalytic activity but does not alter the self-inactivation rate of LPL. mouse GPIHBP1 is N-glycosylated at Asn76 within the Lys6 domain. the same tissues that express high levels of LPL. Consistent with this finding. This unusual inactivation mechanism occurs with less-than-equal molar ratios of Angptl4 to LPL and is strongly temperature dependent. Angptl3 and Angptl4 may play unique roles in modulation of lipid metabolism by inhibiting LPL activity through distinct mechanisms. In genetically engineered mice. In these tissues. but the exact mechanism is yet to be determined. the APOA5 transgene to an LPL-deficient background. or APOA5 in vitro (84). APOA5 represents a protein that regulates LPL activity by facilitating its interaction with substrates. RAP may function as a chaperone/escort protein to prevent premature interaction of LPL with binding partners such as LRP and HSPG in the secretory pathway. Human GPIHBP1 is also glycosylated. G56R heterozygotes in the family have mild fasting hypertriglyceridemia. Of note. Thus. APOA5 derived from various sources does not alter the LPL hydrolytic rate (142. overexpression of human APOA5 modulates TG levels only slightly when LPL is reduced (155). 274) or by activating intravascular TG hydrolysis by proteoglycan-bound LPL (155. This defect correlates with an increase in the concentration of inactive LPL in plasma. LPL activity is downregulated in adipose tissue during fasting and at the posttranslational level with no change in LPL mRNA or protein (53). This effect is even increased in the presence of LPL and is abolished by heparin (142). catabolism of chylomicrons and VLDL is accelerated due to a faster plasma hydrolysis of TGs by LPL. It appears that Angptl4 is a fasting-induced regulator of LPL activity in adipose tissue and functions as an unfolding molecular chaperone (255). The GPIHBP1 G56 residue is well conserved. indicating a possible role of RAP in the maturation of LPL (265). 155). Whether GPIHBP1 can simultaneously bind chylomicrons and LPL also remains to be answered. and APOA5 (11). RAP-deficient adipocytes secrete poorly assembled LPL that has defective binding to the plasma membrane (182). First identified as a glycosylphosphatidylinositol-linked protein that facilitated the binding of highdensity lipoproteins (HDL) to cultured cells (110). and a truncation mutation of APOA5 is associated with familial hyperchylomicronemia (144). GPIHBP1 harbors a strongly negatively charged acidic domain that can potentially bind to the positively charged domain of apolipoproteins contained in chylomicrons as well as the positively charged heparin-binding domain in LPL (179). APOA5 can lead to a dose-dependent increase of LPL-mediated hydrolysis (155).000 mg/dl. 256). GPIHBP1 is expressed highly in the heart and adipose tissue. The interaction between APOA5 and LPL seems to be direct and proteoglycan dependent. GPIHBP1deficient mice exhibit a striking accumulation of large chylomicrons in the plasma. Exactly how GPIHBP1 mediates LPL and chylomicron binding is still not clear. and the G56R mutation is predicted to have compromised function (272). In addition. In the presence of proteoglycans. Recent studies show that RAP binds to LPL with high affinity in both purified systems and cell extracts. APOA5 plasma levels are inversely correlated with plasma TGs. Its function is confined largely to the ER. and APOA5 can specifically increase the binding of chylomicrons and VLDL to proteoglycans. heparin is able to overcome the inhibitory effect of Angptl3 on LPL but not that of Angptl4 (246). Glycosylphosphatidylinositol-anchored highdensity lipoprotein-binding protein 1 (GPIHBP1) is a newly reidentified endothelial cell molecule that appears to play an important role in the LPL-mediated lipolytic processing of chylomicrons (289). even on a low-fat diet. However. Receptor-associated protein. www. still folded but with decreased affinity for heparin. Angptl4 mRNA abundance is inversely correlated with LPL activity during both the fed-to-fasted and fasted-to-fed transitions.org Downloaded from http://ajpendo. RAP overexpression in mice deficient in both the low-density lipoprotein receptor and low-density lipoprotein receptor-related protein (LRP) results in a defect in conversion of chylomicrons into smaller remnant particles and striking hypertriglyceridemia. Receptor-associated protein (RAP) is a recognized chaperone/escort protein for members of the low-density lipoprotein receptor gene family (128. 32).org/ by guest on December 5.Review LPL AND OBESITY E275 nal coiled-coil domain of Angptl4 can bind transiently to LPL and convert the enzyme from a catalytically active dimer to the inactive monomer. GPIHBP1 is located on the luminal face of the capillary endothelium. it has been determined that increased LPL activity completely normalized the hypertriglyceridemia of APOA5-deficient mice.ajpendo. chylomicrons. since RAP is an ER resident protein that is recycled by the KDEL receptor (31. resulting in milky plasma and plasma TG levels as high as 5. G56R substitution does not appear to affect the ability of GPIHBP1 to reach the cell surface. Mutating the N-glycosylation site in mouse GPIHBP1 results in an accumulation of GPIHBP1 in the ER and a markedly reduced amount of the protein on the cell surface. the levels of LPL protein mass are unchanged by treatment of primary cultures of rat adipocytes with catecholamines. 1 and 2 represent directional effect and magnitude of the effect of the “condition” on LPL in 2 sites. this effect has not been demonstrated in the mammary gland. CHO. lipoprotein lipase. plasma www. 85). However. Differential responses of adipose tissue and skeletal muscle LPL to nutritional and hormonal signals and in metabolic disease states Condition SC Adipose Tissue LPL Skeletal Muscle LPL Fasting Feeding High CHO High fat Exercise Insulin Catecholamines Thyroid hormone Estrogen Testosterone Obesity Diabetes 2 11 1 Variable 11 2 2 in rat. Life stage is also important to LPL gene expression and regulation.ajpendo.org Downloaded from http://ajpendo. LPL is expressed in the liver during fetal and early postnatal life. Growth hormone and sex steroid hormones such as testosterone and estrogen inhibit adipose tissue LPL activity and promote lipid mobilization (reviewed in Ref. Evidence also indicates that adipose tissue LPL is downregulated rapidly by fasting (173). 90). cold exposure stimulates LPL activity by a combination of transcriptional and translational/posttranslational mechanisms that involve ␤-adrenergic stimulation (34. 30% CHO) for 2 wk. Hypothyroid rats also have increases in LPL activity and mass in skeletal muscle (178). It appears that during fasting there is activation of a gene whose product converts newly synthesized LPL into a catalytically inactive form (19. suggesting a possible mechanism for thyroid hormone regulation of LPL activity in rodents.org/ by guest on December 5. Thyroid hormone also appears to mediate the regulatory effect of catecholamines on adipose tissue LPL (231).Review E276 Nutritional and Hormonal Regulation of LPL LPL is synthesized in a number of tissues and is regulated in a tissue-specific manner by nutrients and hormones (Table 1). Treatment of rodents or isolated adipocytes with catecholamines decreases LPL activity (51. In rats fasted for 1 day. Detailed mechanistic studies demonstrate that catecholamines alter the LPL translation rate with variable effects on the level of LPL mRNA or the rate of LPL transcription. the density of which is higher in visceral than subcutaneous adipose tissue. Feeding and fasting regulate LPL activity in a tissue-specific manner as well. and the rate of LPL gene transcription is not altered. In mature adipocytes or adipose tissue. Adipose tissue LPL activity is increased in rats that are deficient in thyroid hormone (79) but decreased in humans (202). 23) but increase heart and skeletal muscle LPL activities (181). carbohydrate. subcutaneous. On refeeding. SC adipose tissue and skeletal muscle. similar to what happens in adipose tissue. Similar data are available in humans as well (175). LPL activity is induced during late pregnancy and lactation (49. the fall in adipose tissue LPL is not accompanied by changes in LPL AND OBESITY Table 1. LPL mRNA levels are unaffected in these rats. in a study with 25 human subjects consuming either a high-carbohydrate diet [50% carbohydrate (CHO). is believed to be the major mechanism (282). 176). Of interest. an effect likely due to decreases in LPL degradation and secretion (177). 211. In sedentary obese men. nutritional regulation of LPL activity in white adipose tissue and muscle exists mostly at the posttranslational level. 215). the process is rapidly reversed and the activity reaches the fed level within 4 h (18). 243). Glucose also stimulates LPL synthetic rate and potentiates the stimulatory effect of insulin (117. 35. 64). Unlike insulin. In one report. 30% fat] for 2 wk or a high-fat diet (50% fat. However. AJP-Endocrinol Metab • VOL LPL mRNA or LPL mass (53. 1 in human 2 2 11 (/cell) 2 1 1 Ϯ 1 Ϯ 1 2 No change 2 1 1 Ϯ 2 2 LPL. The transition between active and inactive forms of LPL. insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms (2. In brown adipose tissue. the high-carbohydrate exposure increases the LPL response to feeding in both adipose tissue and skeletal muscle (288). Thyroid hormone and glucocorticoids also play roles in the extinction of the hepatic expression of LPL (191). In both rodents and humans. SC. Adipose tissue LPL activity is high in fed animals and low when animals are fasted. 2012 297 • AUGUST 2009 • . but the magnitude of the changes is less in mice (229). Both chronic and acute stress decrease LPL activity in white adipose tissue but increase the LPL activity through the effect of catecholamines in cardiac and skeletal muscle as well as in the adrenal glands (221).physiology. The heparin-releasable LPL activity in the heart increases severalfold with fasting. A significant difference between the two diets in the LPL meal response is observed only in adipose tissue (high carbohydrate Ͼ high fat). For example. 215. followed by the alternative diet for 2 wk. The mechanism for LPL regulation in the heart appears to be more complex. In the mammary gland. 20). Insulin has a major effect on LPL activity in adipose tissue during adipocyte differentiation by increasing LPL gene transcription (243). Addition of triiodothyronine to cultured adipocytes decreases LPL activity without affecting LPL mRNA levels. which is essential for LPL catalytic activity and secretion. More recent evidence indicates that prolactin works through prolactin receptors to reduce LPL activity in cultured human abdominal adipose tissue (138). Studies in thyroid hormone receptor (TR)-deficient mice reveal that thyroid hormone negatively regulates LPL inhibitor Angptl3 gene expression in a TR␤-dependent manner (77). but gene expression is then suppressed by a putative transcriptional regulatory mechanism (239). there is no effect of diet composition on insulin sensitivity. alterations in the distribution of LPL between the vascular endothelium and other sites within the heart explain some of the differences in the enzyme activity with fasting and feeding (227). The glucose stimulatory effect appears to be mostly through the glycosylation of LPL. 3. Glucose also increases adipose tissue LPL activity. glucose does not affect the level of LPL mRNA. but most studies have shown that the opposite is true in the heart and skeletal muscle. LPL activity in mice responds to the nutritional state in the same direction and by a similar mechanism as in rats. and it appears that the partially dedifferentiated and delipidated adipocytes rather than the epithelial cell are the source of the lipase (114). However. The effect of these hormones is believed to be mediated by the androgen receptor. This may relate to the fundamental differences in the regulation of TG uptake between males and females in different regions of adipose tissue. and adipose tissue. LPL in the heart.780 or by progesterone. and thus LPL is likely to be an important enzyme in cardiac lipid uptake and metabolism.7-fold higher postheparin plasma LPL activity with a 75% reduction in plasma TGs (248). Estrogen reduces the fat mass gain following ovariectomy in rodents. Not surprisingly. a twofold increase in liver TG content and insulin resistance is observed (119). LPLϪ/Ϫ pups are severely hypertriglyceridemic (ϳ20. the specific LPL activity is greater in OM compared with SC adipose tissue (228). The heart is a major site of LPL synthesis. Transgenic mice with generalized overexpression of human LPL have a fivefold higher LPL activity in adipose tissue and 1. In addition. with the SC depot being more sensitive to the effects of glucocorticoids in the presence of insulin. increases in LPL activity occur in the heart. This estrogen effect on LPL is blocked by the estrogen receptor antagonist ICI-182. whereas ultimate extinction of LPL activity is seen in the liver (40). 230. 252). and die within 24 h either from ischemia or from hypoglycemia as a result of the inability to process the lipid nutrients in milk.org Downloaded from http://ajpendo. Fasting LPL activity/fat cell correlates well with the fat cell size in females in all three areas. When permitted to suckle. 183). in postmenopausal women.org/ by guest on December 5. it has been demonstrated that an AP-1-like TGAATTC sequence located at (Ϫ1. and excessive hepatic steatosis (156). LPL activity in liver homogenates is increased significantly (147). Insulin increases the levels of LPL mRNA and LPL activity in abdominal SC but not OM adipose tissue. LPL is normally not made in the adult liver but is expressed in the liver of newborn animals. possibly due to increased insulin secretion as a result of reduced expression of LPL and TG content in islets (145). When LPL is overexpressed in the liver in mice. but the rescued mice are still hypertriglyceridemic with plasma TG levels of ϳ3. whereas glucocorticoids increase the LPL mRNA and LPL activity more in OM adipose tissue. Adenovirus-mediated expression of LPL can rescue LPLϪ/Ϫ pups. Overexpression of LPL protects against diet-induced hypertriglyceridemia and hypercholesterolemia in these mice. In mice. Fat cell size is greater in females than males in the thigh and gluteal regions but not in the abdomen. Mice with a generalized deletion of LPL (LPLϪ/Ϫ) have threefold higher plasma TGs and sevenfold higher VLDL AJP-Endocrinol Metab • VOL cholesterol levels at birth. cardiac muscle is the tissue with the greatest expression of LPL. a single dose of TNF␣ can cause a marked increase in LPL mRNA levels in the liver (63). a widely used class of lipid-modifying agents. Testosterone treatment of abdominally obese men also produces a decrease in visceral fat mass (216). The www. but mice develop severe cachexia during high-fat suckling and have elevated plasma TGs. In obese women. LPL can be expressed in the liver under specific physiological and artificial conditions.physiology.ajpendo. Although there is no classical estrogen response element in the LPL promoter. It is interesting to note that overexpression of a catalytically inactive LPL (G188E-LPL) also seems to improve the high-fat diet-induced systemic insulin resistance and hypertriglyceridemia in these mice (247). The detailed mechanism of how LPL is induced under these conditions is not well understood. However. 2012 297 • AUGUST 2009 • . LPL activity has been reported to increase as a function of fat cell size (22. studies carried out in LPLϩ/Ϫ mice indicate that inactive LPL can act in vivo to mediate VLDL removal from plasma and uptake into tissues in which it is expressed (154). In liver-only LPL mice. LPL mRNA as well as TG accumulation are decreased in 3T3-L1 adipocytes stably transfected with the estrogen receptor.000 mg/dl on a chow diet (254). 238. and the defect in insulin action and signaling in the liver is associated with increases in intracellular fatty acid-derived metabolites. the addition of 17␤-estradiol to hearts from ovariectomized females increases LPL mRNA. particularly in men (73). indicating an age-dependent excessive accumulation of body fat (41).or liver-specific overexpression of LPL. then cyanotic. In this section we will review the tissue-specific mechanism of LPL regulation and its impact on fuel partitioning and energy metabolism revealed by these studies. As the pups suckle. However.000 mg/dl) and have depleted tissue storage of TGs (275).850) is responsible for the reduction of LPL gene transcription by estrogen (104). 89. a potential estrogen response element sequence has been located in the first intron of the mouse LPL gene (140). increased plasma ketones and glucose. Mice with heterozygous LPL deficiency (LPLϩ/Ϫ) have somewhat lower levels of fasting plasma glucose with relative hyperinsulinemia. A positive correlation between LPL activity and glucocorticoid binding exists for both OM and SC depots in both men and women (190). but only in the abdomen and thigh in men (270). and sex differences seem to alter the relationship between LPL activity and fat cell size. can activate PPARs and stimulate LPL activity in the liver (75. The Tissue-Specific Regulation of LPL in Fuel Partitioning Genetic modification using mouse models has been widely employed to characterize the tissue-specific role of LPL in lipid metabolism and energy balance. increases in hepatic LPL activity impair the ability of insulin to suppress endogenous glucose production in the liver. an inverse relationship between plasma estradiol levels and adipose tissue and postheparin plasma LPL is seen (111). treatment with both estrogen and progestins increases the LPL activity in the adipose tissue and preferentially in the femoral depot (216). skeletal muscle. For example. and treatment with fibrates.Review LPL AND OBESITY E277 testosterone and bioavailable testosterone levels are inversely correlated with femoral and abdominal wall adipose tissue LPL (207). In addition. LPLϪ/Ϫ pups become pale. The mechanism underlying this estrogen-dependent effect may in part relate to LPL.856/Ϫ1. The effects of insulin and glucocorticoids on human adipose tissue LPL activity are both transcriptional and posttranslational. and fatty acids provide Ͼ70% of the energy needs for cardiac muscle. 57. In mice with sarcoma 180. 241). 76. In these mice. There are marked variations in the activity of LPL in adipose tissue depots in humans. When LPLϩ/Ϫ mice are crossed with mice with cardiac muscle. The fat mass/lean mass ratio difference in LPLϩ/Ϫ mice generally increases over time. However. 156). the hypertriglyceridemia is eliminated and adipose tissue development appears normal (134. Insulin and glucocorticoids have synergistic effects on LPL activity in both depots. The steady-state mRNA levels for LPL as well as LPL mass are lower in omental (OM) than subcutaneous (SC) adipose tissue (73. Before death. the neonatal death of LPL knockout mice can be rescued. LPL in the liver. In summary. Fasting decreases the free fatty acid turnover in these transgenic mice. When mice express a GPI transgene to anchor LPL to cell membranes. Skeletal muscle is a major site for LPL synthesis. Yet. the lipase protein localizes to the surface of cardiomyocytes and increases lipid uptake. Arguably the most productive lines of research related to the tissue-specific effects of LPL on lipid AJP-Endocrinol Metab • VOL fuel partitioning. the maintenance of normal fatty acid uptake in the setting of cardiac-specific LPL deletion indicates that fatty acids derived from lipoprotein TGs and not just albumin-associated fatty acids are important for cardiac lipid metabolism and gene regulation. Several possible mechanisms have been suggested. 283). the suppression of hepatic glucose production is also reduced in SMLPLϪ/Ϫ mice. and reduced HDL cholesterol levels. Mice that express human LPL exclusively in skeletal muscle have normal postheparin LPL activities. The hearts of these transgenic mice experience cardiac lipotoxicity and a dilated cardiomyopathy (133. Heart-specific LPLknockout mice display elevated plasma TG levels and decreased clearance of postprandial lipids despite normal postheparin plasma LPL activity (6). 133). In addition. have increases in muscle TG (116. During a steady-state insulin infusion. body weight regulation. 269).org Downloaded from http://ajpendo. diacylglycerol. excess lipoprotein-derived lipids appear to hinder cardiac bioenergetics and cardiac function. SMLPLϪ/Ϫ mice have normal glycemic responses to intraperitoneal glucose or insulin administration. but PPAR␥ coactivator-1␣ and IL-1␤ mRNAs are higher and stearoyl-CoA desaturase-1 and PPAR␥ mRNAs are reduced. Mice without cardiac LPL survive (6. [3H]deoxyglucose disposal is increased in skeletal muscle but reduced in white adipose tissue. mice transgenic for LPL overexpression in skeletal muscle are insulin resistant (70. mice maintain normal levels of plasma TGs and HDL cholesterol despite the lack of skeletal muscle and adipose tissue LPL and a reduced amount of postheparin LPL activity (134). 2012 297 • AUGUST 2009 • . indicating a lesser dependence on plasma free fatty acids during periods of nutrient deficiency (17). Mice with a skeletal muscle-specific deletion of LPL (SMLPLϪ/Ϫ) have recently been generated (271). At 9 –11 wk. 156). the results from rodent models of altered expression of LPL in heart emphasize the important role of cardiac LPL in TG-rich lipoprotein metabolism. One such process involves the effect of AMP-activated protein kinase on the recruitment of LPL to the coronary lumen (4). and insulin-stimulated phosphorylated Akt (Ser473) is twofold greater in SMLPLϪ/Ϫ mice without changes in IRS-1 tyrosine phosphorylation and PI 3-kinase activity.e. Skeletal muscle TG is reduced. when LPL is overexpressed. but the growth and body composition of these mice appear to be normal (135). Overall.Review E278 LPL AND OBESITY role of LPL in the energy metabolism in the heart has been explored extensively in mouse models. 119). These mice also display a remarkable switch to the more oxidative type IIa fibers over the more glycolytic type IIb fibers in the gastrocnemius and quadriceps muscles (115). the lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues. Hepatic TG content and liver X receptor.physiology. and perhaps LPL-derived lipids.org/ by guest on December 5. although the loss of LPL in the heart leads to defective plasma TG-rich lipoprotein metabolism and compensatory increases in cardiac glucose metabolism (6). brown adipose tissue. at the terminus of the euglycemic clamp. SMLPLϪ/Ϫ mice also have normal whole body glucose disposal. and chronically altering this balance leads to cardiac dysfunction. may play on substrate partitioning and insulin action. Acute LPL deletion in adult mice also leads to cardiac dysfunction. Neither nonesterified fatty acids nor the compensatory increase in cardiac glucose metabolism can entirely replace the fatty acids not provided by LPL in the heart. Male mice are also resistant to high-fat diet-induced obesity (116). the important role of skeletal muscle LPL in the regulation of body weight and energy homeostasis has recently been established. carbohydrate response element-binding protein. It appears that the heart needs an optimal balance of glucose and fatty acids to maintain normal biochemistry and physiology. ultimately leading to age-dependent and diet-inducible obesity and systemic insulin resistance. i. and this regulation is regulated by short-term changes in insulin rather than glucose (233). and heart.to 11-wk-old SMLPLϪ/Ϫ mice.. transgenic overexpression of LPL in skeletal muscle increases cold tolerance of mice by enhancing metabolic rate and fat oxidation. Cardiomyopathy also occurs in the hearts of patients with diabetes. This effect is mediated by the p38 mitogen-activated protein kinase-dependent actin cytoskeleton organization to facilitate the translocation of LPL to the myocyte surface (120). mice with tamoxifen-inducible cardiomyocyte-specific LPL deletion show that acute loss of LPL leads to rapid increases in plasma TGs and decreases in expression of carnitine palmitoyl transferase I and pyruvate dehydrogenase kinase 4 in cardiac muscle (168). heparin-releasable LPL activity is upregulated in the hearts of rats with diabetes in response to the increased need of fatty acids for energy. LPL deletion in skeletal muscle seems to reduce lipid storage and increase insulin signaling in skeletal muscle without changes in body composition. Moreover. Loss of LPL-derived fatty acids in these mice also leads to increased cardiac glucose metabolism and cardiac dysfunction characterized by decreased fractional shortening and interstitial and perivascular fibrosis (7. Moreoever. 119. When LPL is expressed only in the heart. and phosphoenolpyruvate carboxykinase mRNAs are unaffected in 9. to promote nonhydrolyzable core lipid uptake. and skeletal muscle is also the major tissue responsible for whole body insulin-stimulated glucose uptake/disposal. Another mechanism involves protein kinase D as an important regulator of cardiac LPL secretion after diabetes (121). and various mechanisms have been proposed. Moreover. reduced plasma TG levels. However. There is an intense interest in what role lipid.g.ajpendo. and ceramides (119).. Of interest. LPL apparently has additional roles in the heart. www. SMLPLϪ/Ϫ mice provide another important model to study in detail the role of muscle LPL on lipid fuel partitioning and body weight regulation and energy balance. as shown by decreases in ejection fraction and increases in atrial natriuretic factor mRNA. and have less carcass lipid. and insulin action have come from genetic modifications of the LPL gene in skeletal muscle. e. Very interestingly. Importantly. Decreases in insulin-stimulated glucose uptake in skeletal muscle and insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity are also associated with increases in intracellular fatty acid-derived metabolites. LPL in skeletal muscle. Of interest. fatty acyl-CoAs. Combined lipase deficiency (cld) is a recessively inherited disorder in mice associated with a deficiency of LPL and HL. The fld mutation is mapped to a locus that is distinct from loci encoding LPL and HL and those in cld/cld mice. human LPL mRNA is low compared with the large amounts of human LPL protein and LPL activity. already described in an earlier section of this review. LPL mRNA is found in dentate granule cells. Thus. the role of adipocyte-derived LPL in the lipid storage function of adipose tissue has been studied indirectly in mice with muscle-specific expression of LPL on an LPLϪ/Ϫ background. LPL also appears to serve as a transport protein for cholesterol and vitamin E to neurons. The gene that is responsible for the fld mutation is lipin1. They develop severe hypertriglyceridemia and die within 3 days after birth (242). However. 21. and regeneration of neuronal processes (15. and insulin resistance. Fatty liver dystrophy (fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and fatty liver during neonatal development. free fatty acids for lipid storage are preferentially provided by LPL-mediated hydrolysis of plasma TG-rich lipoproteins (101). The fatty liver in fld/fld mice spontaneously resolves between the ages of 14 and 18 days. evidence supports that adipocyte-derived LPL is required for efficient fatty acid uptake and storage (87). There are three naturally occurring mutations related to LPL in mice that affect lipid transport and metabolism that result in hypertriglyceridemia (219). and insulin resistance. these mice exhibit normal body weight. However. the murine hippocampus exhibits a marked induction of LPL mRNA and protein levels. hypertriglyceridemia. fatty liver. 2012 297 • AUGUST 2009 • .physiology. Mice that have adipose tissue-specific deletion have not yet been reported. reaching activities five times higher than in the adult brain (169). 69. at which point the animals develop a neuropathy associated with abnormal myelin formation in the peripheral nerve. LPL in brain and central nervous system. Pharmacological and molecular manipulations of hypothalamic nutrient sensing affect appetite. The role of LPL in this process remains hypothetical but worthy of consideration as a protein that senses changes in macronutrient and/or energy balance.org Downloaded from http://ajpendo. and contribute in a substantial manner to body weight regulation (96). Serum and hepatic TG levels are elevated fivefold in suckling fld/fld mice. where hippocampal neurons contribute to memory by rapidly assimilating information about the perceptual and behavioral structure of experience. 169). modest hyperinsulinemia. glycosylation. In similar transgenic mice expressing human LPL without the proximal 3Ј-untranslated region. Transgenic mice expressing human LPL in adipose tissue have a twofold increase in LPL activity in white adipose tissue (98).Review LPL AND OBESITY E279 LPL in adipose tissue. and free fatty acid levels. LPL is synthesized in the tissues of cld mice but is retained in the ER (48). LPL is distributed on the endothelial surfaces throughout the brain. In addition. Although adipose tissue can synthesize free fatty acids de novo. and the spinal cord of the rat. The cld mutation is believed to affect components in the ER that play roles in protein maturation (29). cultured model of adipocyte differentiation in 3T3-L1 preadipocytes. AJP-Endocrinol Metab • VOL The hippocampus is well recognized as the learning center of the brain. 108. Adult fld/fld mice have adipose tissue deficiency. plasticity. whereby a series of conditioned impulses potentiate the size of synaptic potentials. 108. However. 186). LPL activity is relatively high in the newborn brain and peaks between the 5th and the 10th day after birth. The hippocampal area has the highest LPL activity among all brain regions (15. This indicates that the mutation is associated with developmentally programmed tissue-specific defects in the neonatal expression of LPL and HL activities (132). The gene that is affected by the cld mutation has recently been identified as LMF1. These mice have normal LPL synthesis. closer examination of the adipose tissue composition indicates that LPL deficiency is compensated for by large increases in endogenous adipose tissue fatty acid synthesis to preserve normal lipid storage (276). 185. the absence of 3Јuntranslated region in transgenic mice results in a LPL protein that is readily expressed. LPL mRNA. protein. pyramidal cells in the cortex. LPL in Metabolic Disorders: Hypertriglyceridemia and Obesity Hypertriglyceridemia.ajpendo. 169. In these cross-bred mice. disrupt energy balance. LPL expression is absent in adipose tissue. and LPL expression increases in parallel with cellular TG accumulation as preadipocytes differentiate (243). LPL is thus considered a gatekeeper enzyme to play an important role in the initiation and/or development of obesity. appears to have even more LPL activity than each individual brain region (21). The hypothalamus plays a critical role in monitoring the nutritional status of the body and to initiate cogent behavioral and metabolic responses (130). glucose intolerance. and the active LPL is required for this process (187). It will be interesting to see whether LPL-derived lipids or other nonenzymatic functions of LPL contribute to nutrient sensing in the brain. and dimerization but have impaired posttranslational processing of the lipase at the steps of activation and secretion. In a much simpler. a genetically heterogeneous group of disorders characterized by loss of body fat. The 3Ј-untranslated region of the LPL gene has been shown to be critical for the inhibitory effect of constitutively expressed hormones such as catecholamines. in particular the caudal spinal cord. well-established.org/ by guest on December 5. and enzyme activity are also found at a lower level in the hypothalamus. protein. glucose. 267). LPL mRNA. plasma lipids. LPL is an important marker for adipocyte differentiation (24). Purkinje cells in the cerebellum. Mice carrying fld mutations have features of human lipodystrophy. LPL is present throughout all parts of the nervous system. indicating a potential role of LPL in the recycling and/or scavenging of lipids and cholesterol released from the degenerating nerve terminals (25). LPL expression is essential for promoting VLDL-stimulated differentiation of Neuro-2A cells (186). and enzyme activity are also found in the spinal cord and sciatic nerve (15. and white adipose tissue LPL activity is reduced ϳ15-fold until the onset of weaning. which encodes a novel nuclear protein that www. The process by which this occurs is called long-term potentiation. a process that may help the survival. and CA1–CA4 cells in the hippocampus. and these mice appear to have normal body weight gain and body composition. The lack of lipid accumulation in fld/fld adipose tissue can be attributed in part to a failure to induce LPL and enzymes involved in fatty acid synthesis (220). In the brain. In response to deafferentation. leading to a moderate overexpression of adipose LPL activity (98). it is important to point out that the preheparin LPL activity does not accurately reflect LPL in postheparin plasma (56).physiology. Most often. strongly suggesting that LPL is a structural component of postprandial TG-rich lipoproteins that facilitates hepatic TG-rich lipoprotein clearance from the circulation independent of its catalytic function. and impaired insulin sensitivity (103).Review E280 LPL AND OBESITY is expressed in high levels in adipose tissue and skeletal muscle (195). In recent years. W/Wv mice have low postheparin plasma LPL activity. and preheparin LPL mass is inversely related to the extent of the metabolic syndrome (159. Carriers for the Gly1883 Glu mutation have increases in plasma TGs. and the regulation of body weight and composition. and 6 of the LPL gene result in a LPL enzyme that is usually catalytically inactive and consequently being degraded within the cells. 232. 217). and IDLs. Lipin1 belongs to a family of related proteins that possess phosphatidate phosphatase type 1 activity (52). Adipose tissue fatty acid composition analysis reveals an increase in 16:1 and a decrease in 18:0. and Asp2503 Asn (81). Obesity is in epidemic proportions and demonstrates no signs of reduced incidence. and dyslipidemias (92. AJP-Endocrinol Metab • VOL About 20% of the patients with hypertriglyceridmia are carriers of common LPL gene mutations such as Asp93 Asn. W/Wv mice have a genetic defect that leads to a deficiency of mast cells (125). Of interest. 286).org/ by guest on December 5. storage. Two common LPL polymorphisms (HindIII: T3 G. lipin1 has been implicated as both a lipodystrophy and obesity gene (197) and potentially plays an important role in glucose metabolism and regulation of energy balance (143). fat mass is preserved by endogenous fatty acid biosynthesis (276). LPLdeficient patients still have normal adiposity. 158. The importance of the Asn2913 Ser gene variant to hypertriglyceridemia has been reviewed using metaanalysis (106). Thus. Lipid partitioning is important to insulin action. 131. but the tissue LPL activity is not changed in heart and adipose tissue. decreases in energy expenditure. postheparin plasma LPL activity remains the gold standard to address systemic LPL lipolytic capacity (102). and enhanced de novo fatty acid synthesis sufficient to maintain normal adiposity (266). higher fasting insulin levels. type I hyperlipoproteinemia is a rare autosomal recessive disease (1/1.000) characterized by little or no LPL activity and severe hypertriglyceridemia. The lack of transport of LPL to the endothelium substantially reduces LPL-dependent TG-rich lipoprotein catabolism. A similar adipose and plasma fatty acid composition has been found in normal and LPL-deficient cats wherein LPL deficiency also results in reductions in dietary fatty acid storage. Tyr2623 His) with familial LPL deficiency (226). 160. The contribution of lipin1 to the tissue-specific. 232). mechanisms must exist to defend the expanded fat mass. Preheparin LPL mass levels are not affected by aging and sex differences but are generally lower in the conditions in which TG catabolism is disturbed (273). 2012 297 • AUGUST 2009 • . However. 159. and the level is significantly lower in patients with type 2 diabetes (160). In humans. 18:2. LPL mass in preheparin serum (preheparin LPL mass) has been suggested as a biomarker of the metabolic syndrome. unsaturated fatty acid storage. VLDLs. a condition that is characterized by a combination of obesity. and modifications of energy partitioning. Furthermore. Patients with type I hyperlipoproteinemia can also have familial apoC-II deficiency or an inhibitor to LPL (30. multiple family members of a familial LPL deficiency patient showed compound heterozygosity for the known Gly1883 Glu missense mutation and a novel nonsense mutation Trp394X (105). 100. As previously stated in LPL Gene and Protein. in mice deficient in adipose tissue LPL. insulin resistance. This variant also predisposes to more severe dyslipidemia with increasing age and weight gain. This suggests that LPL may affect the receptor-mediated removal of these particles in vivo. Moreover. Interestingly. lipoprotein lipid partitioning is largely dependent on the enzymatic action www. 263). increases in energy intake. The mast cell deficiency in W/Wv mice leads to a reduction in connective tissue heparin (253) that contributes to defects in LPL transport (95). 55). preferential saturated vs. 5. A similar study conducted in transgenic mice that express inactive LPL exclusively in muscle reveals greater hepatic uptake (97). developmental regulation of LPL activity is worthy of further pursuit. Obesity. however. Most patients with LPL deficiency are compound heterozygotes. Trp863 Arg. it becomes increasingly important to understand how body weight and adipose tissue are regulated. patients with severe hypertriglyceridemia do not have LPL deficiency but the combination of a genetic cause of overproduction of VLDL plus an additional acquired disorder(s) of VLDL production and/or reduction in LPL activity (39. Gly1883 Glu. The latter nonsense mutation causes a truncated protein product that lacks the carboxyl-terminal 12% of the mature LPL with residues that are important for binding lipid substrates. energy balance. causing little or no postheparin LPL activity in the plasma of these patients (72. Seventy percent of the W/Wv mice show hypertriglyceridemia combined with hypercholesterolemia with variable increases in chylomicrons. Exemplary is a patient homozygous for two point mutations in the LPL gene (Asp93 Asn.org Downloaded from http://ajpendo. Pro2073 Leu. including the role of macronutrient partitioning. 273). Preheparin LPL mass reflects insulin sensitivity in the general population (92). Therefore. low levels of HDL cholesterol.000. and oxidation all contribute (1. Because weight loss is not only difficult to achieve but more difficult to sustain long term (46. lipemia retinalis. and 18:3 fatty acids (264). Several mutations occurring predominantly in exons 4. 234). affecting the stability of the LPL dimer and subsequently reduced heparin affinity. Asn2913 Ser. 166. In another very recent report. The Gly1883 Glu mutation is the most frequent among French Canadians (72) and is by far the most frequent mutation in patients with LPL deficiency and chylomicronemia in the general population (82). The normal physiology of lipid and lipoprotein fuel partitioning is controlled by the transport and uptake of adipose tissuederived free fatty acids and lipoprotein-derived TG fatty acids. 295). Following weight reduction. Ser4473 Ter: C3 G) have also been shown to be associated with low HDL cholesterol levels and hypertriglyceridemia in Asian Indians (204).ajpendo. decreases in HDL cholesterol. The reduction in essential fatty acids suggests that enhanced adipocyte lipogenesis is most likely responsible for maintaining normal lipid storage in these patients. and the variable presence of eruptive xanthomata. and pancreatitis when plasma TGs are not controlled by dietary fat restriction. preheparin LPL has been reported to be bound to postprandial TG-rich lipoproteins (such as remnants or IDLs) in humans when ex vivo lipolytic activity is inhibited (291. Clinical studies have implicated that low preheparin LPL mass may reflect systemic oxidative stress (232). 241).physiology. and the conservation of the Ϫ93G allele among different species suggests that it is the ancestral allele on which a transition to T and the Asp93 Asn mutation arises (60). REFERENCES 1. Variants in the promoter of the LPL gene have been associated with changes in lipid metabolism leading to obesity and type 2 diabetes. 2. In skeletal muscle. Park SY. However. D’armiento J. In skeletal muscle. 2006. Comp Biochem Physiol B Biochem Mol Biol 148: 151–159. 241. including energy balance. However. LPL is also produced in the brain and spinal cord. body weight regulation. 7. Although the predominant function of LPL is to hydrolyze the TG core of circulating TG-rich lipoproteins. Albalat A. 259). The ϪT93G SNP is also found in high frequency in the black South African population. Goldberg IJ. The ϪT93G promoter variant single nucleotide polymorphism (SNP) of the LPL gene has been found to be associated with obesity but not type 2 diabetes among an urban Asian Indian population. 1996. 2006. Gutierrez J. 2007. The metabolic “switch” AMPK regulates cardiac heparin-releasable lipoprotein lipase. Harney JW. LPL is regulated by posttranslational processing and not at the level of LPL gene transcription. Conclusions LPL is an important multifunctional enzyme produced by many tissues. Capilla E. Augustus AS. Together these tissuespecific changes in the regulation of LPL in reduced-obese subjects may play an important role in nutrient partitioning when energy intake exceeds energy expenditure. a process that is critical to cardiac physiology. Zechner R. Hirata K. Augustus A. Loss of lipoprotein lipase-derived fatty acids leads to increased cardiac glucose metabolism and heart dysfunction. Gen Comp Endocrinol 146: 226 –235. Regulation of lipoprotein lipase activity in rainbow trout (Oncorhynchus mykiss) tissues. Park TS. and heterozygous carriers have normal or minimal hypertriglyceridemia. It is thus important to consider that the nonhydrolytic functions of LPL. a divergent effect of sustained weight reduction on LPL is seen. Gutierrez J. LPL either fails to decrease or increases to a level above that present prior to weight reduction (22. Of even greater importance is the impact of sustained weight reduction on the tissuespecific expression of LPL. LPL in skeletal muscle is markedly decreased. 230. Etienne J. decreases in cardiac LPL are observed (22). 2004. prevail in the setting of LPL deficiency. Noh HL. Goldberg IJ. the enzyme protein may also be important in the uptake of lipoproAJP-Endocrinol Metab • VOL tein lipids in the absence of TG hydrolytic activity. 230. LPL is increased by insulin and meals but decreased by fasting. the responsiveness of LPL to insulin and feeding is diminished (93. tissuespecific substrate delivery and utilization. Saera-Vila A. In heart. whereas another promoter variant. Raisonnier A. it is well established that the genetics of LPL deficiency in humans is autosomal recessive and typically a result of missence mutations. This is important in that the amount of LPL in skeletal muscle in humans is inversely correlated with RQ (68). Brault D. insulin does not stimulate LPL. LPL functions at the endothelium but is synthesized in parenchymal cells. insulin action. but the function of LPL in the central nervous system has yet to be discerned. Sun J. following weight reduction. Navarro I. 259). However. 2012 297 • AUGUST 2009 • . which are relatively understudied. For the most part. 118. appears to be protective against both obesity and type 2 diabetes (205). in contrast to lower vertebrates. The mechanism of the tissue-specific regulation of LPL remains the most challenging topic in the field. In adipose tissue. Recent advances in obesity: adiposity signaling and fat metabolism in energy homeostasis. Human lipoprotein lipase last exon is not translated. Hamelin J. Overall. In obesity. Buchanan J. Arnault F.org Downloaded from http://ajpendo. 2005. and atherosclerosis. Sanchez-Gurmaches J. including possible effects in the central nervous system. LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism. Galibert F. a Ͼ70% decrease in skeletal muscle LPL occurs (58). J Biol Chem 279: 25050 – 25057. following weight reduction and stabilization of the reduced-obese state. Yagyu H. Moran TH. and the enzyme activity is variably reduced in obesity. Perez-Sanchez J. 5.ajpendo. 3. and the many aspects of metabolism. increases in the responsiveness of the enzyme are seen (57). An D. www. In adipose tissue of reduced obese rodents or humans. Vikramadithyan RK. Albalat A. 57. 6. Pulinilkunnil T. Tse C.org/ by guest on December 5. LPL in adipose tissue is increased when expressed per cell (22.Review LPL AND OBESITY E281 of LPL. an effect that can contribute to the increase in respiratory quotient (RQ) (74) and the decrease in fat utilization (214) that follow weight reduction. J Biol Chem 281: 8716 – 8723. 89. Insulin regulation of lipoprotein lipase (LPL) activity and expression in gilthead sea bream (Sparus aurata). Ultimately. 58. 198. Ghosh S. the LPL gene has a number of cis-acting elements that may confer tissue-specific regulation. Rodrigues B. and the amount of increase in RQ in reduced-obese subjects is predictive of resumption of the obese state (74). ϪG53C SNP in the LPL gene. Mouse models of tissue-specific LPL deletion and overexpression (summarized previously) have implicated a direct role of LPL in the regulation of body weight and composition. LPL is also important in HDL metabolism contributing to the transfer of surface lipid to small HDL after lipolysis. adipose tissue LPL is increased per cell but unresponsive to insulin and meals. Cardiacspecific knock-out of lipoprotein lipase alters plasma lipoprotein triglyceride metabolism and cardiac gene expression. however. 261). Limited mechanistic studies are available to facilitate the direct application of the knowledge we gain from mouse models to metabolic disorders in humans that relate to altered LPL expression. In human and rodent obesity. In reduced-obese fa/fa (Zucker) rats. Results from human studies also provide increasing evidence that LPL is an obesity gene. adipose tissue LPL is increased. Qi D. Noe L. 4. In humans. when weight-reduced subjects are given a meal or exposed to the hyperinsulinemia of a euglycemic clamp. The HindIII polymorphism is significantly associated with body mass index in obese people (112). as is the response of the enzyme to insulin and meals. however. LPL activity is either unchanged or modestly decreased after an overnight fast in obese subjects (22. the ability to selectively modify LPL in skeletal muscle and/or adipose tissue may favorably influence body weight and composition. like other metabolic responses to insulin in obesity. 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