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• W2162547981 abstract "Hepatic lipase (HL) is a lipolytic enzyme, synthesized by hepatocytes and found localized at the surface of liver sinusoid capillaries. In humans, the enzyme is mostly bound onto heparan-sulfate proteoglycans at the surface of hepatocytes and also of sinusoid endothelial cells. HL shares a number of functional domains with lipoprotein lipase and with other members of the lipase gene family. It is a secreted glycoprotein, and remodelling of the N-linked oligosaccharides appears to be crucial for the secretion process, rather than for the acquisition of the catalytic activity. HL is also present in adrenals and ovaries, where it might promote delivery of lipoprotein cholesterol for steroidogenesis. However, evidence of a local synthesis is still controversial. HL activity is fairly regulated according to the cell cholesterol content and to the hormonal status. Coordinate regulations have been reported for both HL and the scavenger-receptor B-I, suggesting complementary roles in cholesterol metabolism. However, genetic variants largely contribute to HL variability and their possible impact in the development of a dyslipidemic phenotype, or in a context of insulin-resistance, is discussed. Hepatic lipase (HL) is a lipolytic enzyme, synthesized by hepatocytes and found localized at the surface of liver sinusoid capillaries. In humans, the enzyme is mostly bound onto heparan-sulfate proteoglycans at the surface of hepatocytes and also of sinusoid endothelial cells. HL shares a number of functional domains with lipoprotein lipase and with other members of the lipase gene family. It is a secreted glycoprotein, and remodelling of the N-linked oligosaccharides appears to be crucial for the secretion process, rather than for the acquisition of the catalytic activity. HL is also present in adrenals and ovaries, where it might promote delivery of lipoprotein cholesterol for steroidogenesis. However, evidence of a local synthesis is still controversial. HL activity is fairly regulated according to the cell cholesterol content and to the hormonal status. Coordinate regulations have been reported for both HL and the scavenger-receptor B-I, suggesting complementary roles in cholesterol metabolism. However, genetic variants largely contribute to HL variability and their possible impact in the development of a dyslipidemic phenotype, or in a context of insulin-resistance, is discussed. Hepatic lipase (HL) is a lipolytic enzyme synthesized mostly by hepatocytes and found localized at the surface of liver sinusoidal capillaries. It can be considered as a lipase of the vascular compartment, together with lipoprotein lipase (LPL), with which it shares number of structural and functional similarities. HL exerts both triglyceride lipase and phospholipase A1 activities, and is involved at different steps of lipoprotein metabolism. During recent years, cellular and molecular biology approaches, as well as studies in transgenic animals, have been useful in elucidating the enzyme structure and functional domains, its metabolic roles, and the mechanisms regulating its expression. This article will focus on the structure/function relationship of HL, its synthesis, and the regulation of its expression in liver and steroidogenic tissues. The metabolic and patho-physiological roles of HL are developed in a joint review. The HL gene is located on chromosome 15 (q15–q22) in humans and on chromosome 9 in mice (1Cai S.J. Wong D.M. Chen S.H. Chan L. Structure of the human hepatic triglyceride lipase gene.Biochemistry. 1989; 28: 8966-8971Crossref PubMed Scopus (89) Google Scholar, 2Ameis D. Stahnke G. Kobayashi J. McLean J. Lee G. Buscher M. Schotz M.C. Will H. Isolation and characterization of the human hepatic lipase gene.J. Biol. Chem. 1990; 265: 6552-6555Abstract Full Text PDF PubMed Google Scholar, 3Warden C.H. Davis R.C. Yoon M.Y. Hui D.Y. Svenson K. Xia Y.R. Diep A. He K.Y. Lusis A.J. Chromosomal localization of lipolytic enzymes in the mouse: pancreatic lipase, colipase, hormone-sensitive lipase, hepatic lipase, and carboxyl ester lipase.J. Lipid Res. 1993; 34: 1451-1455Abstract Full Text PDF PubMed Google Scholar). It spans over 60 kb with eight introns and nine exons accounting for 1.6 kb (Fig. 1A). The organization of introns and exons is relatively close to that of the LPL gene and the exons are all of average size (118–234 bp) (1Cai S.J. Wong D.M. Chen S.H. Chan L. Structure of the human hepatic triglyceride lipase gene.Biochemistry. 1989; 28: 8966-8971Crossref PubMed Scopus (89) Google Scholar). Two transcription start sites were described 43 or 77 nucleotides upstream of the translation initiation codon (1Cai S.J. Wong D.M. Chen S.H. Chan L. Structure of the human hepatic triglyceride lipase gene.Biochemistry. 1989; 28: 8966-8971Crossref PubMed Scopus (89) Google Scholar, 2Ameis D. Stahnke G. Kobayashi J. McLean J. Lee G. Buscher M. Schotz M.C. Will H. Isolation and characterization of the human hepatic lipase gene.J. Biol. Chem. 1990; 265: 6552-6555Abstract Full Text PDF PubMed Google Scholar). The 5′-flanking region of the HL gene spans between nucleotides −1550 and +129 (2Ameis D. Stahnke G. Kobayashi J. McLean J. Lee G. Buscher M. Schotz M.C. Will H. Isolation and characterization of the human hepatic lipase gene.J. Biol. Chem. 1990; 265: 6552-6555Abstract Full Text PDF PubMed Google Scholar, 4Chang S.F. Scharf J.G. Will H. Structural and functional analysis of the promoter of the hepatic lipase gene.Eur. J. Biochem. 1997; 247: 148-159Crossref PubMed Scopus (15) Google Scholar). DNAase footprint analysis in presence of hepatic nuclear factors revealed eight zones of interaction in the proximal promoter (Nt −281 to Nt +129) (Fig. 1A). For instance, the A zone (between Nt −28 and Nt −75) contains an AGGTTAATTATTAAT motif frequently found in liver-expressed genes, and binds to the positive transcriptional factor HNF1 (5Hadzopoulou-Cladaras M. Cardot P. Identification of a cis-acting negative DNA element which modulates human hepatic triglyceride lipase gene expression.Biochemistry. 1993; 32: 9657-9667Crossref PubMed Scopus (33) Google Scholar) (Fig. 1B). In contrast, the domains E2, E3, and E4, present in the first exon, contain a negative regulatory element (5Hadzopoulou-Cladaras M. Cardot P. Identification of a cis-acting negative DNA element which modulates human hepatic triglyceride lipase gene expression.Biochemistry. 1993; 32: 9657-9667Crossref PubMed Scopus (33) Google Scholar). In addition, the 5′ nontranscribed region contains sequences corresponding to regulatory responsive elements (6Sensel M.G. Legrand-Lorans A. Wang M.E. Bensadoun A. Isolation and characterization of clones for the rat hepatic lipase gene upstream regulatory region.Biochim. Biophys. Acta. 1990; 1048: 297-302Crossref PubMed Scopus (24) Google Scholar) (see section 4). Interest for HL modulations was renewed by the discovery of functional genetic variants of HL, with high frequencies among populations (7Guerra R. Wang J. Grundy S.M. Cohen J.C. A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol.Proc. Natl. Acad. Sci. USA. 1997; 94: 4532-4537Crossref PubMed Scopus (223) Google Scholar). The proximal promoter of HL gene contains four polymorphic sites (Fig. 1B) in complete linkage desequilibrium: G-250A, C-514T, T-710C, and A-763G (7Guerra R. Wang J. Grundy S.M. Cohen J.C. A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol.Proc. Natl. Acad. Sci. USA. 1997; 94: 4532-4537Crossref PubMed Scopus (223) Google Scholar, 8Murtomaki S. Tahvanainen E. Antikainen M. Tiret L. Nicaud V. Jansen H. Ehnholm C. Hepatic lipase gene polymorphisms influence plasma HDL levels. Results from Finnish EARS participants. European Atherosclerosis Research Study.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1879-1884Crossref PubMed Scopus (74) Google Scholar), according to the nomenclature of Ameis et al. (2Ameis D. Stahnke G. Kobayashi J. McLean J. Lee G. Buscher M. Schotz M.C. Will H. Isolation and characterization of the human hepatic lipase gene.J. Biol. Chem. 1990; 265: 6552-6555Abstract Full Text PDF PubMed Google Scholar). The minor allele frequency ranges between 0.15 and 0.21 in Caucasians, but is about 50% in African Americans (9Nie L. Niu S. Vega G.L. Clark L.T. Tang A. Grundy S.M. Cohen J.C. Three polymorphisms associated with low hepatic lipase activity are common in African Americans.J. Lipid Res. 1998; 39: 1900-1903Abstract Full Text Full Text PDF PubMed Google Scholar). It is associated with a low post-heparin HL activity (9Nie L. Niu S. Vega G.L. Clark L.T. Tang A. Grundy S.M. Cohen J.C. Three polymorphisms associated with low hepatic lipase activity are common in African Americans.J. Lipid Res. 1998; 39: 1900-1903Abstract Full Text Full Text PDF PubMed Google Scholar, 10Jansen H. Verhoeven A.J. Weeks L. Kastelein J.J. Halley D.J. van den Ouweland A. Jukema J.W. Seidell J.C. Birkenhager J.C. Common C-to-T substitution at position −480 of the hepatic lipase promoter associated with a lowered lipase activity in coronary artery disease patients.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2837-2842Crossref PubMed Scopus (149) Google Scholar), with high HDL-cholesterol (HDL-C) and large HDL-particle size, and with the presence of large and buoyant LDL, all features that would confer a favorable phenotype. However, enrichment of all particles in TG is also observed. Functionally, the variant allele, as compared with wild-type, drives a decreased transcriptional activity of a promoter/reporter construct in murine hepatoma cells (11Deeb S.S. Peng R. The C-514T polymorphism in the human hepatic lipase gene promoter diminishes its activity.J. Lipid Res. 2000; 41: 155-158Abstract Full Text Full Text PDF PubMed Google Scholar). Rat and human cDNAs (1,569 bp) display strong homologies (12Martin G.A. Busch S.J. Meredith G.D. Cardin A.D. Blankenship D.T. Mao S.J. Rechtin A.E. Woods C.W. Racke M.M. Schafer M.P. Fitzgerald M.C. Burke D.W. Flanagan M.A. Jackson R.L. Isolation and cDNA sequence of human postheparin plasma hepatic triglyceride lipase.J. Biol. Chem. 1988; 263: 10907-10914Abstract Full Text PDF PubMed Google Scholar, 13Stahnke G. Sprengel R. Augustin J. Will H. Human hepatic triglyceride lipase: cDNA cloning, amino acid sequence and expression in a cultured cell line.Differentiation. 1987; 35: 45-52Crossref PubMed Scopus (64) Google Scholar) and contain two polyadenylation sites. However, only one mRNA of 1.7 kb has been detected in hepatic cells. The human HL protein consists of 499 amino acids including a leader-peptide of 22 residues (12Martin G.A. Busch S.J. Meredith G.D. Cardin A.D. Blankenship D.T. Mao S.J. Rechtin A.E. Woods C.W. Racke M.M. Schafer M.P. Fitzgerald M.C. Burke D.W. Flanagan M.A. Jackson R.L. Isolation and cDNA sequence of human postheparin plasma hepatic triglyceride lipase.J. Biol. Chem. 1988; 263: 10907-10914Abstract Full Text PDF PubMed Google Scholar) so that the secreted protein contains only 477 residues. The amino acid sequence reveals the presence of several functional domains; for instance, two hydrophobic segments of 10 amino acids involved in interactions with lipids. Each one segment contains a Serine residue (Ser146 and Ser267). In humans, Ser146 is at the center of a Gly-X-Ser-X-Gly consensus, which is part of a classical Ser-Asp-His catalytic triad found in the endothelial lipase, LPL, pancreatic lipase, and other esterases (13Stahnke G. Sprengel R. Augustin J. Will H. Human hepatic triglyceride lipase: cDNA cloning, amino acid sequence and expression in a cultured cell line.Differentiation. 1987; 35: 45-52Crossref PubMed Scopus (64) Google Scholar, 14Jaye M. Lynch K.J. Krawiec J. Marchadier D. Maugeais C. Doan K. South V. Amin D. Perrone M. Rader D.J. A novel endothelial-derived lipase that modulates HDL metabolism.Nat. Genet. 1999; 21: 424-428Crossref PubMed Scopus (425) Google Scholar) (Table 1). Site-directed mutagenesis showed that in the rat Ser147 is essential for the catalytic activity (15Davis R.C. Stahnke G. Wong H. Doolittle M.H. Ameis D. Will H. Schotz M.C. Hepatic lipase: site-directed mutagenesis of a serine residue important for catalytic activity.J. Biol. Chem. 1990; 265: 6291-6295Abstract Full Text PDF PubMed Google Scholar). At the center of the protein, 10 cysteine residues are present and the distances between them are conserved in the structures of LPL and pancreatic lipase, suggesting that the formation of disulphide bridges is important for the conformation and catalytic activity of these lipases. Human HL also contains four putative heparin-binding sites, with sequences like BBBXXB or BBXB (Table 1), where B is a basic residue, and which are likely involved in the binding to cell-surface heparan sulfates (13Stahnke G. Sprengel R. Augustin J. Will H. Human hepatic triglyceride lipase: cDNA cloning, amino acid sequence and expression in a cultured cell line.Differentiation. 1987; 35: 45-52Crossref PubMed Scopus (64) Google Scholar, 16Sendak R.A. Berryman D.E. Gellman G. Melford K. Bensadoun A. Binding of hepatic lipase to heparin. Identification of specific heparin-binding residues in two distinct positive charge clusters.J. Lipid Res. 2000; 41: 260-268Abstract Full Text Full Text PDF PubMed Google Scholar). Such consensus sequences were found in other proteins of the lipoprotein metabolism, like apoB-100, apoE endothelial lipase, and LPL. The fourth motif (Lys337-Arg443), located in the carboxy-terminus of human HL, is absent in murine HL (17Chang S.F. Netter H.J. Will H. Characterization of cDNA encoding the mouse hepatic triglyceride lipase and expression by in vitro translation.FEBS Lett. 1991; 289: 69-72Crossref PubMed Scopus (15) Google Scholar) and in other members of the lipase gene family. It is noteworthy that, in mice, HL is primarily free in the circulation and not bound to the cell surfaces (18Peterson J. Bengtsson-Olivecrona G. Olivecrona T. Mouse preheparin plasma contains high levels of hepatic lipase with low affinity for heparin.Biochim. Biophys. Acta. 1986; 878: 65-70Crossref PubMed Scopus (73) Google Scholar). However, conflicting results have been reported concerning the affinity of the mouse HL for heparin-like polysaccharides (19Masuno H. Okuda H. Hepatic triacylglycerol lipase in circulating blood of normal and tumor-bearing mice and its hydrolysis of very-low-density lipoprotein and synthetic acylglycerols.Biochim. Biophys. Acta. 1986; 879: 339-344Crossref PubMed Scopus (6) Google Scholar), as well as regarding the role of the fourth C-terminal cluster in the binding of HL onto liver heparan-sulphates (17Chang S.F. Netter H.J. Will H. Characterization of cDNA encoding the mouse hepatic triglyceride lipase and expression by in vitro translation.FEBS Lett. 1991; 289: 69-72Crossref PubMed Scopus (15) Google Scholar).TABLE 1.Structure similarities between hepatic lipase, other lipases, and apolipoproteinsActive SiteLipasesSerineAspartateHistidinehHLHLIGYS146LGAHVSGRITGLD172AAGPCSH257ERShELHLIGYS151LGAHVAGRITGLD175PAGPCEH256ERShLPLHLLGYS132LGAHAAGRITGLD156PAGPCSH241ERShPLHVIGHS153LGAHAAGRITGLD177PAEPCNH263LRSHeparin Binding DomainsConsensusXBBBXXBXXBBXBXhApoE144LRKRLLRDhApoB3364TRKRGLKL84LKKTKL2081VRKYRA2119TKKYRITrHL162GKRKIGRI294LKKTGRhHL163HKIGRITG294CKKGRChLPL145TNKKVNRI278CRKNRChEL293CRKNRCActive Site: Homology of the amino acids of the catalytic triad between human (h) hepatic lipase (HL), endothelial lipase (EL), lipoprotein lipase (LPL) and pancreatic lipase (PL).Heparin Binding Domains: Sequence similarities among basic regions in heparin binding domains of human (h) or rat (r) apoB, apoE, HL, LPL and EL. Open table in a new tab Active Site: Homology of the amino acids of the catalytic triad between human (h) hepatic lipase (HL), endothelial lipase (EL), lipoprotein lipase (LPL) and pancreatic lipase (PL). Heparin Binding Domains: Sequence similarities among basic regions in heparin binding domains of human (h) or rat (r) apoB, apoE, HL, LPL and EL. HL is a secreted glycoprotein and synthesized in the endoplasmic reticulum (ER). An NH2-terminal leader peptide is lost after crossing through the ER membrane. Kinetics of endogenously labeled enzyme and use of glycosidases or inhibitors have demonstrated that HL is first synthesized as a high mannose form (52–55 kDa in the rat), and further acquires sialic acid-containing complex oligosaccharides during transit through the Golgi cisternae (20Cisar L.A. Bensadoun A. Characterization of the intracellular processing and secretion of hepatic lipase in FU5AH rat hepatoma cells.Biochim. Biophys. Acta. 1987; 927: 305-314Crossref PubMed Scopus (18) Google Scholar). The mature HL (57–59 kDa, in the rat) is then rapidly secreted. The residence half-time of HL in hepatocyte is about 60 min (20Cisar L.A. Bensadoun A. Characterization of the intracellular processing and secretion of hepatic lipase in FU5AH rat hepatoma cells.Biochim. Biophys. Acta. 1987; 927: 305-314Crossref PubMed Scopus (18) Google Scholar). The rat enzyme contains two N-glycosylation sites. Mutation of either one impairs HL processing rather than the enzyme activity itself (21Stahnke G. Davis R.C. Doolittle M.H. Wong H. Schotz M.C. Will H. Effect of N-linked glycosylation on hepatic lipase activity.J. Lipid Res. 1991; 32: 477-484Abstract Full Text PDF PubMed Google Scholar). Trimming of the glucose residues off the high-mannose form appears to be a determining step for rat HL secretion (22Verhoeven A.J. Jansen H. Secretion of rat hepatic lipase is blocked by inhibition of oligosaccharide processing at the stage of glucosidase I.J. Lipid Res. 1990; 31: 1883-1893Abstract Full Text PDF PubMed Google Scholar). The human HL presents four glycosylation sites, which are all utilized at positions 20, 56, 340, and 375, and a molecular mass around 65 kDa (23Wolle J. Jansen H. Smith L.C. Chan L. Functional role of N-linked glycosylation in human hepatic lipase: asparagine-56 is important for both enzyme activity and secretion.J. Lipid Res. 1993; 34: 2169-2176Abstract Full Text PDF PubMed Google Scholar, 24Ben-Zeev O. Stahnke G. Liu G. Davis R.C. Doolittle M.H. Lipoprotein lipase and hepatic lipase: the role of asparagine-linked glycosylation in the expression of a functional enzyme.J. Lipid Res. 1994; 35: 1511-1523Abstract Full Text PDF PubMed Google Scholar). Site-directed mutagenesis indicated that Asn 56, a conserved site in the NH2-terminus, is crucial for the secretion of active HL (23Wolle J. Jansen H. Smith L.C. Chan L. Functional role of N-linked glycosylation in human hepatic lipase: asparagine-56 is important for both enzyme activity and secretion.J. Lipid Res. 1993; 34: 2169-2176Abstract Full Text PDF PubMed Google Scholar). Moreover, besides remodeling of the N-linked oligosaccharides, association of HL with calnexin, a chaperone protein, may increase the efficiency of HL export from the ER (25Boedeker J.C. Doolittle M. Santamarina-Fojo S. White A.L. Role of N-linked carbohydrate processing and calnexin in human hepatic lipase secretion.J. Lipid Res. 1999; 40: 1627-1635Abstract Full Text Full Text PDF PubMed Google Scholar). Different physico-chemical techniques have beeen used to determine the sub-unit structure of secreted active HL, all indicating a homodimer structure (26Hill J.S. Davis R.C. Yang D. Wen J. Philo J.S. Poon P.H. Phillips M.L. Kempner E.S. Wong H. Human hepatic lipase subunit structure determination.J. Biol. Chem. 1996; 271: 22931-22936Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Some mutations, described in the rare cases of familial HL-deficiency, are associated either with a loss of enzymatic activity, or with an impaired cellular processing. For instance, in a Canadian pedigree, the affected patients are compound heterozygotes, bearing both Ser267Phe and Thr383Met substitutions (27Hegele R.A. Little J.A. Connelly P.W. Compound heterozygosity for mutant hepatic lipase in familial hepatic lipase deficiency.Biochem. Biophys. Res. Commun. 1991; 179: 78-84Crossref PubMed Scopus (28) Google Scholar). The first mutation results in an inactive lipase and the second one in an impaired secretion. Earlier reports had described the binding of HL to heparin-sensitive sites of liver non-parenchymal cells, leading to the assumption that the enzyme was essentially present at the vascular endothelium (28Jansen H. VanBerkel T.J.C. Hülsmann W.C. Properties of binding of lipases to non-parenchymal rat liver cells.Biochim. Biophys. Acta. 1980; 619: 119-128Crossref PubMed Scopus (15) Google Scholar). However, HL immuno-localization experiments in rats or, in rabbits, overexpressing human HL have revealed that it is concentrated at the surface of hepatic sinusoids, and mostly located in the microvilii of parenchymal cells, with lesser amounts found at the sinusoid endothelium (29Sanan D.A. Fan J. Bensadoun A. Taylor J.M. Hepatic lipase is abundant on both hepatocyte and endothelial cell surfaces in the liver.J. Lipid Res. 1997; 38: 1002-1013Abstract Full Text PDF PubMed Google Scholar, 30Breedveld B. Schoonderwoerd K. Verhoeven A.J. Willemsen R. Jansen H. Hepatic lipase is localized at the parenchymal cell microvilli in rat liver.Biochem. J. 1997; 321: 425-430Crossref PubMed Scopus (35) Google Scholar). This predominant situation of the enzyme at the surface of hepatocytes is in good agreement with its role in the catabolism of lipoproteins by liver parenchymal cells. Finally, a heparin-releasable 70 kDa protein was identified in liver perfusates as a potential HL binding site (31Breedveld B. Schoonderwoerd K. Jansen H. Identification of a heparin-releasable hepatic lipase binding protein from rat liver.Biochem. J. 1998; 330: 785-789Crossref PubMed Scopus (5) Google Scholar). A lipase activity has been reported in rat adrenals and ovaries, sharing common properties with HL in terms of salt resistance and immuno-reactivity toward monoclonal antibodies raised against rat HL (32Persoon N.L. Sips H.J. Hulsmann W.C. Jansen H. Monoclonal antibodies against salt-resistant rat liver lipase. Cross-reactivity with lipases from rat adrenals and ovaries.Biochim. Biophys. Acta. 1986; 875: 286-292Crossref PubMed Scopus (15) Google Scholar). In adrenals, HL activity has been localized in blood vessels and could be induced by corticotrophin (33Jansen H. Schoonderwoerd K. Baggen M.G. De Greef W.J. The effect of corticotrophin on liver-type lipase activity in adrenals, liver and high-density lipoprotein subfractions in the rat.Biochim. Biophys. Acta. 1983; 753: 205-212Crossref PubMed Scopus (19) Google Scholar). In ovaries, HL has been mostly found in corpora lutea, while very little activity was detected in pre-ovulatory follicles (34Jansen H. de Greef W.J. Uilenbroek J.T. Localization of liver-type lipase in rat ovaries and its activity during the estrous cycle and lactation.Mol. Cell. Endocrinol. 1985; 42: 253-258Crossref PubMed Scopus (8) Google Scholar). HL activity was strongly correlated with the plasma levels of progesterone (34Jansen H. de Greef W.J. Uilenbroek J.T. Localization of liver-type lipase in rat ovaries and its activity during the estrous cycle and lactation.Mol. Cell. Endocrinol. 1985; 42: 253-258Crossref PubMed Scopus (8) Google Scholar). However, neither adrenal nor ovarian cells appeared to synthesize HL, as illustrated by the inability to detect mRNA transcripts by Northern blot, or to immuno-isolate labeled newly synthesized HL (35Hixenbaugh E.A. Sullivan T.R. Strauss III J.F. Laposata E.A. Komaromy M. Paavola L.G. Hepatic lipase in rat ovary; Ovaries cannot synthesize hepatic lipase but accumulate it from the circulation.J. Biol. Chem. 1989; 266: 4222-4230Abstract Full Text PDF Google Scholar). Thus, so far, the leading opinion is that the enzyme is primarily synthesized in hepatocytes, is further transported in the circulation, and can accumulate at heparin-sensitive sites in ovarian or adrenal blood vessels. Using a sensitive RT-PCR assay, Jansen and co-workers (36Verhoeven A.J. Carling D. Jansen H. Hepatic lipase gene is transcribed in rat adrenals into a truncated mRNA.J. Lipid Res. 1994; 35: 966-975Abstract Full Text PDF PubMed Google Scholar, 37Verhoeven A.J. Jansen H. Hepatic lipase mRNA is expressed in rat and human steroidogenic organs.Biochim. Biophys. Acta. 1994; 1211: 121-124Crossref PubMed Scopus (25) Google Scholar) have described the presence, in rat adrenals and ovaries, of a truncated mRNA, deleted of the first two exons. Accordingly, these steroidogenic cells were found to synthesize a 45 kDa catalytically inactive HL-like protein that remained intra-cellular (36Verhoeven A.J. Carling D. Jansen H. Hepatic lipase gene is transcribed in rat adrenals into a truncated mRNA.J. Lipid Res. 1994; 35: 966-975Abstract Full Text PDF PubMed Google Scholar, 37Verhoeven A.J. Jansen H. Hepatic lipase mRNA is expressed in rat and human steroidogenic organs.Biochim. Biophys. Acta. 1994; 1211: 121-124Crossref PubMed Scopus (25) Google Scholar). The ovarian transcript and the corresponding protein synthesis can be induced by gonadotrophin treatment, but this transient induction preceded the appearance of HL-activity (38Vieira-van Bruggen D. Verhoeven A.J. Heuveling M. Kalkman C. de Greef W.J. Jansen H. Hepatic lipase gene expression is transiently induced by gonadotropic hormones in rat ovaries.Mol. Cell. Endocrinol. 1997; 126: 35-40Crossref PubMed Scopus (8) Google Scholar). This and the fact that those shorter transcripts in adrenals are 40× less abundant than full-length mRNA in the liver, questions the physiological relevance of those truncated forms (36Verhoeven A.J. Carling D. Jansen H. Hepatic lipase gene is transcribed in rat adrenals into a truncated mRNA.J. Lipid Res. 1994; 35: 966-975Abstract Full Text PDF PubMed Google Scholar). As regards human ovarian cells, our group has recently detected HL transcripts and measured a HL-secreted activity in luteinizing hormone-stimulated human pre-ovulatory granulosa cells isolated during an in-vitro fertilization protocole (L. Mabile, unpublished observations). Several putative regulatory elements have been identified in the rat HL promoter, allowing the definition of partners potentially involved in the regulation of the enzyme expression. Among them, responsive elements for cholesterol (SRE), estrogens (ERE), thyroid hormones (TRE), and glucocorticoids (GRE), and for cAMP (6Sensel M.G. Legrand-Lorans A. Wang M.E. Bensadoun A. Isolation and characterization of clones for the rat hepatic lipase gene upstream regulatory region.Biochim. Biophys. Acta. 1990; 1048: 297-302Crossref PubMed Scopus (24) Google Scholar). In addition, another motif possibly responsive for glucose and/or insulin (proximal E-box), has been since described in humans (11Deeb S.S. Peng R. The C-514T polymorphism in the human hepatic lipase gene promoter diminishes its activity.J. Lipid Res. 2000; 41: 155-158Abstract Full Text Full Text PDF PubMed Google Scholar) (Fig. 1B). The major regulators of HL activity are summarized in Tables 2 and 3.TABLE 2.Physiological and pharmacological regulators of HL activity in liverRegulatory AgentsHL ActivityReferencesSex steroidsEstrogens−Androgens Glucocorticoids+ (39, 49–51)Corticotrophin−aOpposite (increased) effect in adrenal cells.(54–56)Corticosteroids (dexamethasone, triamcinolone) −Thyroid hormonesThyroxin (T4)+Triiodo-thyronin (T3) Catecholamines (adrenalin)+ −57, 58 (65)Leptin−bReported for mRNA levels; not determined for HL activity.(66)Heparin Diet++(71)Cholesterol−Saturated fatty acids−(72–74)N-3 fatty acids Drugs−Fibrates+(67, 75)Statins Genetic variant−−514T−(11)a Opposite (increased) effect in adrenal cells.b Reported for mRNA levels; not determined for HL activity. Open table in a new tab TABLE 3.Common and symmetrical regulations of hepatic lipase and of the Scavenger Receptor class B-type I in response to cholesterol and hormonesCell TypesSR-BIHLChol.rich-diethepatocytes−−Estrogenshepatocytes−−HL −/−hepatocytes++KOACTHadrenal cells++HCGovarian cells++ Open table in a new tab Several experimental evidences suggest that HL is regulated as a function of the cholesterol demand, as are various proteins of cell sterol homeostasis. In cultured hepatoma cells, an inverse relation has been described between the cell cholesterol content and the levels of HL mRNA and activity (39Ragab A. Rittner U. Danet C. Ragab J. Chap H. Perret B.P. Competitive PCR as a tool to study hepatic lipase regulation in Hep G2 cells.Bull. Mol. Biol. and Med. 1995; 20: 19-21Google Scholar). Accordingly, incubation with Mevinolin, a blocker of cholesterol synthesis, induced a stimulation of both HL and HMG-CoA reductase transcripts, an effect reversed by mevalonate (40Bush S.J. Barnhart R.L. Martin G.A. Flanagan M.A. Jackson R.L. Differential regulation of hepatic triglyceride lipase, and 3-hydroxy-3methyl glutaryl-CoA-reductase gene expression in a human hepatoma cell line, Hep G2.J. Biol. Chem. 1990; 265: 22474-22479Abstract Full Text PDF PubMed Google Scholar). The SRE-binding proteins are supposed to be involved in this regulatory process. Concordant arguments support the view that HL and the scavenger receptor BI (SR-BI) would exert coordinate functions in cell cholesterol supply. Indeed, both proteins display comparable tissue distributions, being particularly expressed in the liver and steroidogenic organs (41Acton S.L. Rigotti A. Landschulz K. Xu S. Hobbs H.H. Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor.Science. 1996; 271: 518-520Crossref PubMed Scopus (2001) Google Scholar). The multi-ligand receptor SR-BI has been involved in the selective uptake of HDL-cholesteryl esters" @default.
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• W2162547981 title "Hepatic lipase:structure/function relationship, synthesis,and regulation" @default.
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