Hormone-sensitive Lipase Deficiency in Mice Changes the Plasma Lipid Profile by Affecting the Tissue-specific Expression Pattern of Lipoprotein Lipase in Adipose Tissue and Muscle
2002; Elsevier BV; Volume: 277; Issue: 15 Linguagem: Inglês
10.1074/jbc.m108640200
ISSN1083-351X
AutoresGuenter Haemmerle, Robert Zimmermann, Juliane Gertrude Bogner‐Strauß, Dagmar Kratky, Monika Riederer, Gabriele Knipping, Rudolf Zechner,
Tópico(s)Adipose Tissue and Metabolism
ResumoHormone-sensitive lipase (HSL) is believed to play an important role in the mobilization of fatty acids from triglycerides (TG), diglycerides, and cholesteryl esters in various tissues. Because HSL-mediated lipolysis of TG in adipose tissue (AT) directly feeds non-esterified fatty acids (NEFA) into the vascular system, the enzyme is expected to affect many metabolic processes including the metabolism of plasma lipids and lipoproteins. In the present study we examined these metabolic changes in induced mutant mouse lines that lack HSL expression (HSL-ko mice). During fasting, when HSL is normally strongly induced in AT, HSL-ko animals exhibited markedly decreased plasma concentrations of NEFA (−40%) and TG (−63%), whereas total cholesterol and HDL cholesterol levels were increased (+34%). Except for the increased HDL cholesterol concentrations, these differences were not observed in fed animals, in which HSL activity is generally low. Decreased plasma TG levels in fasted HSL-ko mice were mainly caused by decreased hepatic very low density lipid lipoprotein (VLDL) synthesis as a result of decreased NEFA transport from the periphery to the liver. Reduced NEFA transport was also indicated by a depletion of hepatic TG stores (−90%) and strongly decreased ketone body concentrations in plasma (−80%). Decreased plasma NEFA and TG levels in fasted HSL-ko mice were associated with increased fractional catabolic rates of VLDL-TG and an induction of the tissue-specific lipoprotein lipase (LPL) activity in cardiac muscle, skeletal muscle, and white AT. In brown AT, LPL activity was decreased. Both increased VLDL fractional catabolic rates and increased LPL activity in muscle were unable to provide the heart with sufficient NEFA, which led to decreased tissue TG levels in cardiac muscle. Our results demonstrate that HSL deficiency markedly affects the metabolism of TG-rich lipoproteins by the coordinate down-regulation of VLDL synthesis and up-regulation of LPL in muscle and white adipose tissue. These changes result in an “anti-atherogenic” lipoprotein profile. Hormone-sensitive lipase (HSL) is believed to play an important role in the mobilization of fatty acids from triglycerides (TG), diglycerides, and cholesteryl esters in various tissues. Because HSL-mediated lipolysis of TG in adipose tissue (AT) directly feeds non-esterified fatty acids (NEFA) into the vascular system, the enzyme is expected to affect many metabolic processes including the metabolism of plasma lipids and lipoproteins. In the present study we examined these metabolic changes in induced mutant mouse lines that lack HSL expression (HSL-ko mice). During fasting, when HSL is normally strongly induced in AT, HSL-ko animals exhibited markedly decreased plasma concentrations of NEFA (−40%) and TG (−63%), whereas total cholesterol and HDL cholesterol levels were increased (+34%). Except for the increased HDL cholesterol concentrations, these differences were not observed in fed animals, in which HSL activity is generally low. Decreased plasma TG levels in fasted HSL-ko mice were mainly caused by decreased hepatic very low density lipid lipoprotein (VLDL) synthesis as a result of decreased NEFA transport from the periphery to the liver. Reduced NEFA transport was also indicated by a depletion of hepatic TG stores (−90%) and strongly decreased ketone body concentrations in plasma (−80%). Decreased plasma NEFA and TG levels in fasted HSL-ko mice were associated with increased fractional catabolic rates of VLDL-TG and an induction of the tissue-specific lipoprotein lipase (LPL) activity in cardiac muscle, skeletal muscle, and white AT. In brown AT, LPL activity was decreased. Both increased VLDL fractional catabolic rates and increased LPL activity in muscle were unable to provide the heart with sufficient NEFA, which led to decreased tissue TG levels in cardiac muscle. Our results demonstrate that HSL deficiency markedly affects the metabolism of TG-rich lipoproteins by the coordinate down-regulation of VLDL synthesis and up-regulation of LPL in muscle and white adipose tissue. These changes result in an “anti-atherogenic” lipoprotein profile. white adipose tissue hormone-sensitive lipase triglycerides adipose tissue brown adipose tissue non-esterified fatty acids knock-out wild type lipoprotein lipase total cholesterol high density lipoprotein very low density lipoprotein fractional catabolic rate absolute catabolic rate phospholipid fast protein liquid chromatography wild type In mammals, white adipose tissue (WAT)1 is the most important storage organ of TG. The mobilization of TG during fasting or periods of increased energy demand, and the release of non-esterified fatty acids (NEFA) is an essential process that supplies non-adipose organs with substrates for energy conversion (1.Sztalryd C. Kraemer F.B. Am. J. Physiol. 1994; 266: 179-185Crossref PubMed Google Scholar, 2.Langfort J. Ploug T. Ihlemann J. Enevoldsen L.H. Stallknecht B. Saldo M. Kjaer M. Holm C. Galbo H. Adv. Exp. Med. Biol. 1998; 441: 219-228Crossref PubMed Scopus (46) Google Scholar). NEFA absorbed by skeletal and cardiac muscle are predominantly used for oxidation and energy production. In the liver, NEFA are also used for oxidation but, in addition, are utilized for several other metabolic processes. NEFA can be stored as hepatic TG droplets, used for the synthesis of ketone bodies, or incorporated into VLDL (3.Bulow J. Simonsen L. Wiggins D. Humphreys S.M. Frayn K.N. Powell D. Gibbons G.F. J. Lipid Res. 1999; 40: 2034-2043Abstract Full Text Full Text PDF PubMed Google Scholar, 4.Gibbons G.F. Islam K. Pease R.J. Biochim. Biophys. Acta. 2000; 1483: 37-57Crossref PubMed Scopus (247) Google Scholar). Once formed, VLDL particles are secreted from the liver into the vascular system where they are lipolyzed by endothelial cell associated lipoprotein lipase (LPL) (5.Goldberg I. Curr. Opin. Lipidol. 1996; 7: 184-192Crossref Scopus (1) Google Scholar, 6.Olivecrona T. Bengtsson-Olivecrona G. Borensztajn J. Lipoprotein Lipase. Evener, Chicago1987: 15-25Google Scholar). This process supplies peripheral tissues such as AT with NEFA, thereby closing an inter-tissue cycle of fatty acid transport.An important enzyme for the mobilization of TG and NEFA production in AT is hormone-sensitive lipase (HSL). This multifunctional neutral lipase hydrolyzes TG, diglycerides, cholesteryl esters, retinyl esters (7.Belfrage P. Jergil B. Stralfors P. Tornqvist H. FEBS Lett. 1977; 75: 259-264Crossref PubMed Scopus (61) Google Scholar, 8.Yeaman S.J. Biochim. Biophys. Acta. 1990; 1052: 128-132Crossref PubMed Scopus (181) Google Scholar, 9.Khoo J.C. Reue K. Steinberg D. Schotz M.C. J. Lipid Res. 1993; 34: 1969-1974Abstract Full Text PDF PubMed Google Scholar, 10.Wei S. Lai K. Patel S. Piantedosi R. Shen H. Colantuoni V. Kraemer F.B. Blaner W.S. J. Biol. Chem. 1997; 272: 14159-14165Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar), and possibly other, yet unidentified, substrates. Although the highest levels of expression are found in WAT and brown adipose tissue (BAT), the enzyme is also found in many other tissues including muscle (2.Langfort J. Ploug T. Ihlemann J. Enevoldsen L.H. Stallknecht B. Saldo M. Kjaer M. Holm C. Galbo H. Adv. Exp. Med. Biol. 1998; 441: 219-228Crossref PubMed Scopus (46) Google Scholar), macrophages (11.Contreras J.A. Holm C. Martin A. Gaspar M.L. Lasuncion M.A. Isr. J. Med. Sci. 1994; 30: 778-781PubMed Google Scholar), testis (12.Holm C. Belfrage P. Fredrikson G. Biochem. Biophys. Res. Commun. 1987; 148: 99-105Crossref PubMed Scopus (132) Google Scholar), and pancreas (13.Mulder H. Holst L.S. Svensson H. Degerman E. Sundler F. Ahren B. Rorsman P. Holm C. Diabetes. 1999; 48: 228-232Crossref PubMed Scopus (96) Google Scholar). In the postprandial state, HSL activity accounts for most of the detectable lipolysis in human WAT and thus determines whole-body lipid fuel availability (14.Frayn K.N. Shadid S. Hamlani R. Humphreys S.M. Clark M.L. Fielding B.A. Boland O. Coppack S.W. Am. J. Physiol. 1994; 266: 308-317PubMed Google Scholar, 15.Frayn K.N. Humphreys S.M. Coppack S.W. Proc. Nutr. Soc. 1995; 54: 177-189Crossref PubMed Scopus (33) Google Scholar). In WAT, the enzyme activity is activated by hormones such as catecholamines. Stimulation of adenylyl cyclase activity (16.Yip R.G. Goodman H.M. Endocrinology. 1999; 140: 1219-1227Crossref PubMed Google Scholar, 17.Elks M.L. Manganiello V.C. Endocrinology. 1985; 116: 2119-2121Crossref PubMed Scopus (54) Google Scholar, 18.Goldberg D.I. Khoo J.C. J. Biol. Chem. 1985; 260: 5879-5882Abstract Full Text PDF PubMed Google Scholar, 19.Oscai L.B. Caruso R.A. Wergeles A.C. Palmer W.K. J. Appl. Physiol. 1981; 50: 250-254Crossref PubMed Scopus (12) Google Scholar, 20.Shepherd R.E. Noble E.G. Klug G.A. Gollnick P.D. J. Appl. Physiol. 1981; 50: 143-148Crossref PubMed Scopus (40) Google Scholar) results in a rise in the intracellular cAMP levels that activate protein kinase A (21.McKnight G.S. Cummings D.E. Amieux P.S. Sikorski M.A. Brandon E.P. Planas J.V. Motamed K. Idzerda R.L. Recent Prog. Horm. Res. 1998; 53: 139-159PubMed Google Scholar). Protein kinase A-mediated phosphorylation of HSL promotes the formation of a stable complex between HSL and lipotransin (22.Syu L.J. Saltiel A.R. Mol. Cell. 1999; 4: 109-115Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar), which translocates the enzyme from the cytosol to the lipid droplet. In response to hormone signals, lipotransin-mediated ATP hydrolysis causes HSL to dissociate and thus gain access to the lipid surface. Insulin, the major antilipolytic hormone, inhibits HSL through phosphodiesterase-3-dependent cAMP degradation and interference with the lipotransin-mediated enzyme translocation.Recently, the rate-limiting function of HSL in the catabolism of WAT TG was challenged by studies in HSL knock-out (ko) mice (23.Osuga J. Ishibashi S. Oka T. Yagyu H. Tozawa R. Fujimoto A. Shionoiri F. Yahagi N. Kraemer F.B. Tsutsumi O. Yamada N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 787-792Crossref PubMed Scopus (497) Google Scholar). HSL deficiency was compatible with normal body weight and fat mass, suggesting that at least one alternative lipase must exist in WAT to compensate for the hydrolysis of TG in the absence of HSL. Nonetheless, HSL-ko mice exhibited increased mass of BAT and marked changes in the lipid composition of WAT, BAT, and other tissues of the body (23.Osuga J. Ishibashi S. Oka T. Yagyu H. Tozawa R. Fujimoto A. Shionoiri F. Yahagi N. Kraemer F.B. Tsutsumi O. Yamada N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 787-792Crossref PubMed Scopus (497) Google Scholar, 24.Haemmerle G. Zimmermann R. Hayn M. Theussl C. Waeg G. Wagner E. Sattler W. Magin T.M. Wagner E.F. Zechner R. J. Biol. Chem. 2002; 277: 4806-4815Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar). Additionally, in vitro lipolysis studies with isolated WAT revealed decreased NEFA and glycerol release when HSL was absent, thus arguing for a crucial role of HSL in the catabolism of TG and diglycerides and the subsequent release of NEFA (24.Haemmerle G. Zimmermann R. Hayn M. Theussl C. Waeg G. Wagner E. Sattler W. Magin T.M. Wagner E.F. Zechner R. J. Biol. Chem. 2002; 277: 4806-4815Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar). As a result, the plasma levels of NEFA are decreased in fasting HSL-deficient mice (23.Osuga J. Ishibashi S. Oka T. Yagyu H. Tozawa R. Fujimoto A. Shionoiri F. Yahagi N. Kraemer F.B. Tsutsumi O. Yamada N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 787-792Crossref PubMed Scopus (497) Google Scholar).Depending on the nutritional condition, plasma NEFA strongly affect lipid synthesis and utilization in hepatic and peripheral tissues (25.Raclot T. Dauzats M. Langin D. Biochem. Biophys. Res. Commun. 1998; 245: 510-513Crossref PubMed Scopus (32) Google Scholar). Accordingly, decreased NEFA release in HSL-ko mice is expected to result in decreased hepatic VLDL synthesis and other metabolic changes. To test this hypothesis, we studied the role of HSL deficiency on the metabolism of plasma lipids and lipoproteins in HSL-ko mice. We demonstrate that decreased plasma NEFA levels in HSL-deficient mice are associated with decreased hepatic VLDL synthesis, decreased ketogenesis, and the depletion of TG stores in the liver. Additionally, the catabolism of plasma VLDL is increased because of the coordinate up-regulation of the tissue-specific LPL activity in muscle and WAT, which results in drastically reduced plasma TG levels and increased HDL cholesterol concentrations in fed and fasted HSL-ko mice.DISCUSSIONThe physiological importance of HSL for the metabolism of AT-associated fat stores is evident from recent studies in HSL-deficient mice (23.Osuga J. Ishibashi S. Oka T. Yagyu H. Tozawa R. Fujimoto A. Shionoiri F. Yahagi N. Kraemer F.B. Tsutsumi O. Yamada N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 787-792Crossref PubMed Scopus (497) Google Scholar, 24.Haemmerle G. Zimmermann R. Hayn M. Theussl C. Waeg G. Wagner E. Sattler W. Magin T.M. Wagner E.F. Zechner R. J. Biol. Chem. 2002; 277: 4806-4815Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar, 35.Wang S.P. Laurin N. Himms-Hagen J. Rudnicki M.A. Levy E. Robert M.F. Pan L. Oligny L. Mitchell G.A. Obes. Res. 2001; 9: 119-128Crossref PubMed Scopus (189) Google Scholar, 36.Roduit R. Masiello P. Wang S.P. Li H. Mitchell G.A. Prentki M. Diabetes. 2001; 50: 1970-1975Crossref PubMed Scopus (100) Google Scholar). In the absence of HSL, the hydrolysis of TG and diglycerides is impaired, leading to a pronounced decrease of plasma NEFA concentrations especially in fasted animals (23.Osuga J. Ishibashi S. Oka T. Yagyu H. Tozawa R. Fujimoto A. Shionoiri F. Yahagi N. Kraemer F.B. Tsutsumi O. Yamada N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 787-792Crossref PubMed Scopus (497) Google Scholar). In the present study we show that decreased plasma NEFA concentrations cause marked alterations in the plasma lipoprotein pattern with decreased plasma TG levels and increased total and HDL cholesterol concentrations. In the liver, HSL-ko mice exhibited decreased VLDL synthesis, decreased TG storage droplets, and decreased ketogenesis.Generally, NEFA that enter hepatocytes are subsequently processed by one of two possible pathways. First, re-esterification of NEFA at the endoplasmic reticulum leads to the formation of cytoplasmic lipid storage droplets. Second, mitochondrial import feeds into β-oxidation or ketogenesis. According to current models, lipid storage droplets represent the major pool of fatty acids for subsequent VLDL production (37.Lewis G.F. Curr. Opin. Lipidol. 1997; 8: 146-153Crossref PubMed Scopus (244) Google Scholar). Following TG hydrolysis by a currently unidentified TG hydrolase and re-esterification at the endoplasmic reticulum (38.Speake B.K. Murray A.M. Noble R.C. Prog. Lipid. Res. 1998; 37: 1-32Crossref PubMed Scopus (281) Google Scholar), TG are incorporated into VLDL by a process that involves microsomal lipid transfer protein (MTP) (39.Gordon D.A. Curr. Opin. Lipidol. 1997; 8: 131-137Crossref PubMed Scopus (81) Google Scholar). Our data are consistent with this model and show that in a condition of decreased plasma NEFA level, as observed in fasted HSL-ko mice, both cytoplasmic fat stores and VLDL synthesis are decreased. It is interesting to note that additional potential sources of fatty acids to fuel lipid droplet and VLDL production, such as hepatic de novo fatty acid synthesis and/or remnant particle uptake from the vascular system, cannot entirely compensate for the deficiency of fatty acid transport from AT to the liver.Considering the second possible fate of NEFA that enter hepatocytes, namely mitochondrial import for β-oxidation or ketogenesis, it was interesting to observe a pronounced decrease in the ketone body concentration in plasma suggesting that this second pathway of fatty acid processing is also less efficient when HSL-mediated production of NEFA from fat stores is absent. Alternatively, increased ketone body utilization by peripheral tissues might also contribute to the drastic decrease in ketone body concentration in plasma of fasted animals. In view of the importance of ketone bodies as an energy substrate, particularly in the brain, low rates of hepatic ketone body production in HSL-ko mice might cause a serious problem during prolonged fasting in HSL-deficient animals.Decreased hepatic VLDL production as a result of the defective TG lipolysis in AT of HSL-ko mice was also associated with alterations in the catabolic pathways of VLDL. VLDL turnover experiments revealed significantly increased FCR values in HSL-ko mice compared with controls. The increased FCR is explained mainly by the much smaller TG pool size in HSL-deficient animals. In fact, when the ACR was calculated as a product of the FCR × pool size, a decreased ACR was found in HSL-deficient mice. Because in steady state conditions the ACR is a measure of the production rate, this result confirms our observations of decreased VLDL synthesis in Triton WR-1339 experiments.The decreased TG pool in fasted HSL-ko animals was not only a result of decreased VLDL production but was also caused by the induction of LPL activities in cardiac and skeletal muscle. The statistically highly significant increase of LPL activities in muscle might reflect an effort to increase the uptake of energy substrate in a situation of extremely low plasma concentrations of NEFA and TG-rich lipoproteins. The regulation of LPL in AT was found to be less uniform. Independent of the feeding/fasting state LPL was markedly reduced in BAT of HSL-ko mice. In WAT, LPL was induced in fasted mice but reduced in fed HSL-deficient mice compared with control mice. Increased LPL activity in the muscle and WAT of fasted mice is expected to effectively lower plasma TG in addition to the decreased VLDL synthesis in HSL-ko mice, because the tissue-specific LPL activity in cardiac muscle has been shown to be particularly powerful in the catabolism of TG-rich lipoproteins (40.Levak-Frank S. Hofmann W. Weinstock P.H. Radner H. Sattler W. Breslow J.L. Zechner R. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3165-3170Crossref PubMed Scopus (81) Google Scholar). Although LPL activity in BAT is decreased, the total tissue LPL activity is essentially unchanged because the tissue mass is increased in HSL-deficient mice (23.Osuga J. Ishibashi S. Oka T. Yagyu H. Tozawa R. Fujimoto A. Shionoiri F. Yahagi N. Kraemer F.B. Tsutsumi O. Yamada N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 787-792Crossref PubMed Scopus (497) Google Scholar, 35.Wang S.P. Laurin N. Himms-Hagen J. Rudnicki M.A. Levy E. Robert M.F. Pan L. Oligny L. Mitchell G.A. Obes. Res. 2001; 9: 119-128Crossref PubMed Scopus (189) Google Scholar). Taken together, it is reasonable to assume that the total LPL-mediated lipolytic activity of the body is determined by the tissue-specific activities in cardiac muscle, skeletal muscle, and WAT, which are all increased in fasted HSL-ko mice.The molecular mechanisms responsible for the coordinate regulation of LPL in the presence or absence of HSL remain to be elucidated. In human AT, such a coordinated regulation of LPL and HSL was observed, suggesting a control mechanism of fat storage and mobilization (41.Frayn K.N. Coppack S.W. Fielding B.A. Humphreys S.M. Adv. Enzyme Regul. 1995; 35: 163-178Crossref PubMed Scopus (150) Google Scholar). A coordinate regulation of the enzymes across tissue boundaries, however, has not been reported. Induction of LPL activity in muscle and WAT and reduction of LPL in BAT is a post-transcriptional process, because LPL mRNA levels were identical in these tissues in HSL-ko and control mice. Apparently, variations in LPL activities are a result of changes in enzyme processing or enzyme translocation to its final destination, the heparan sulfate anchors in the capillary endothelium. Post-transcriptional regulation of LPL has been observed in previous studies in response to hormones and cytokines such as insulin and interleukin-1 (42.Ewart H.S. Severson D.L. Biochem. J. 1999; 340: 485-490Crossref PubMed Scopus (20) Google Scholar, 43.Enerback S. Gimble J.M. Biochim. Biophys. Acta. 1993; 1169: 107-125Crossref PubMed Scopus (176) Google Scholar). The signals that trigger the post-transcriptional induction of LPL in HSL-deficient mice are presently unknown. However, several scenarios are conceivable. First, the lack of induction of LPL in WAT of HSL-ko mice in response to feeding indicates a defect in insulin action, because it is well documented that the postprandial up-regulation of WAT LPL is mediated by insulin. Second, the intracellular lipid stores in peripheral tissues, particularly the heart, might act as a “lipostat” signaling the increased requirement for fatty acids upon depletion. A similar function has been proposed for lipid stores in pancreatic β-cells (36.Roduit R. Masiello P. Wang S.P. Li H. Mitchell G.A. Prentki M. Diabetes. 2001; 50: 1970-1975Crossref PubMed Scopus (100) Google Scholar, 44.Winzell M.S. Svensson H. Arner P. Ahren B. Holm C. Diabetes. 2001; 50: 2225-2230Crossref PubMed Scopus (36) Google Scholar). Third, the decreased availability of fatty acids or a subclass thereof (e.g. essential fatty acids) from plasma or changes in the hormonal status because of HSL deficiency might induce the post-transcriptional processing of LPL. The lipostat hypothesis is also consistent with our observation that, in contrast to all other peripheral tissues, LPL is drastically down-regulated in BAT of HSL-deficient mice. We assume that increased BAT mass and BAT lipid content as observed in HSL-ko mice (23.Osuga J. Ishibashi S. Oka T. Yagyu H. Tozawa R. Fujimoto A. Shionoiri F. Yahagi N. Kraemer F.B. Tsutsumi O. Yamada N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 787-792Crossref PubMed Scopus (497) Google Scholar) inhibit LPL expression at the post-transcriptional level.The induction of LPL was highest in cardiac muscle, in accordance with the current concept that the heart is particularly dependent on NEFA uptake as oxidative fuel. However, despite this induction, the steady state concentration of cardiac muscle TG stores were decreased in HSL-ko mice. The normal heart also exhibits the capacity to store limited amounts of fatty acids as TG droplets (45.Saddik M. Lopaschuk G.D. J. Biol. Chem. 1991; 266: 8162-8170Abstract Full Text PDF PubMed Google Scholar). This myocardial TG content is kept relatively constant under physiological conditions, suggesting a strictly regulated equilibrium between oxidative fatty acid consumption and fatty acid uptake. In fasted HSL-ko mice, the cardiac TG pool was markedly reduced, indicating an imbalance of fatty acid uptake versus consumption, which was not compensated by the up-regulation of the tissue specific LPL activity.Decreased plasma TG levels as a result of decreased hepatic VLDL synthesis and increased peripheral VLDL catabolism are associated with increased plasma cholesterol and HDL cholesterol concentrations. These data are in agreement with the well established concept that increased catabolism of TG-rich lipoproteins due to the induction of LPL is an important determinant of HDL cholesterol levels. It is generally accepted that the LPL-mediated lipolysis of chylomicrons and VLDL provides “surface remnants” as precursor particles that together with hepatic preβ1-LpA-I particles are converted to mature α-LpA-I particles by the action of ABC-A1, lipid transfer proteins, and lecithin:cholesterol acyl transferase (46.Barrans A. Jaspard B. Barbaras R. Chap H. Perret B. Collet X. Biochim. Biophys. Acta. 1996; 1300: 73-85Crossref PubMed Scopus (88) Google Scholar, 47.Clay M.A. Pyle D.H. Rye K.A. Barter P.J. J. Biol. Chem. 2000; 275: 9019-9025Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 48.Rye K.A. Clay M.A. Barter P.J. Atherosclerosis. 1999; 145: 227-238Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 49.Oram J.F. Vaughan A.M. Curr. Opin. Lipidol. 2000; 11: 253-260Crossref PubMed Scopus (238) Google Scholar, 50.Brooks-Wilson A. Marcil M. Clee S.M. Zhang L.H. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O. Loubser O. 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It is reasonable to assume that the increased LPL activities found in muscle and WAT at least partially account for the observed increase in HDL cholesterol levels.In summary, we conclude that the phenotypic changes observed in HSL-deficient mice indicate an important function for the enzyme in the regulation of lipid homeostasis and lipoprotein metabolism. In mammals, white adipose tissue (WAT)1 is the most important storage organ of TG. The mobilization of TG during fasting or periods of increased energy demand, and the release of non-esterified fatty acids (NEFA) is an essential process that supplies non-adipose organs with substrates for energy conversion (1.Sztalryd C. Kraemer F.B. Am. J. Physiol. 1994; 266: 179-185Crossref PubMed Google Scholar, 2.Langfort J. Ploug T. Ihlemann J. Enevoldsen L.H. Stallknecht B. Saldo M. Kjaer M. Holm C. Galbo H. Adv. Exp. Med. Biol. 1998; 441: 219-228Crossref PubMed Scopus (46) Google Scholar). NEFA absorbed by skeletal and cardiac muscle are predominantly used for oxidation and energy production. In the liver, NEFA are also used for oxidation but, in addition, are utilized for several other metabolic processes. NEFA can be stored as hepatic TG droplets, used for the synthesis of ketone bodies, or incorporated into VLDL (3.Bulow J. Simonsen L. Wiggins D. Humphreys S.M. Frayn K.N. Powell D. Gibbons G.F. J. Lipid Res. 1999; 40: 2034-2043Abstract Full Text Full Text PDF PubMed Google Scholar, 4.Gibbons G.F. Islam K. Pease R.J. Biochim. Biophys. Acta. 2000; 1483: 37-57Crossref PubMed Scopus (247) Google Scholar). Once formed, VLDL particles are secreted from the liver into the vascular system where they are lipolyzed by endothelial cell associated lipoprotein lipase (LPL) (5.Goldberg I. Curr. Opin. Lipidol. 1996; 7: 184-192Crossref Scopus (1) Google Scholar, 6.Olivecrona T. Bengtsson-Olivecrona G. Borensztajn J. Lipoprotein Lipase. Evener, Chicago1987: 15-25Google Scholar). This process supplies peripheral tissues such as AT with NEFA, thereby closing an inter-tissue cycle of fatty acid transport. An important enzyme for the mobilization of TG and NEFA production in AT is hormone-sensitive lipase (HSL). This multifunctional neutral lipase hydrolyzes TG, diglycerides, cholesteryl esters, retinyl esters (7.Belfrage P. Jergil B. Stralfors P. Tornqvist H. FEBS Lett. 1977; 75: 259-264Crossref PubMed Scopus (61) Google Scholar, 8.Yeaman S.J. Biochim. Biophys. Acta. 1990; 1052: 128-132Crossref PubMed Scopus (181) Google Scholar, 9.Khoo J.C. Reue K. Steinberg D. Schotz M.C. J. Lipid Res. 1993; 34: 1969-1974Abstract Full Text PDF PubMed Google Scholar, 10.Wei S. Lai K. Patel S. Piantedosi R. Shen H. Colantuoni V. Kraemer F.B. Blaner W.S. J. Biol. Chem. 1997; 272: 14159-14165Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar), and possibly other, yet unidentified, substrates. Although the highest levels of expression are found in WAT and brown adipose tissue (BAT), the enzyme is also found in many other tissues including muscle (2.Langfort J. Ploug T. Ihlemann J. Enevoldsen L.H. Stallknecht B. Saldo M. Kjaer M. Holm C. Galbo H. Adv. Exp. Med. Biol. 1998; 441: 219-228Crossref PubMed Scopus (46) Google Scholar), macrophages (11.Contreras J.A. Holm C. Martin A. Gaspar M.L. Lasuncion M.A. Isr. J. Med. Sci. 1994; 30: 778-781PubMed Google Scholar), testis (12.Holm C. Belfrage P. Fredrikson G. Biochem. Biophys. Res. Commun. 1987; 148: 99-105Crossref PubMed Scopus (132) Google Scholar), and pancreas (13.Mulder H. Holst L.S. Svensson H. Degerman E. Sundler F. Ahren B. Rorsman P. Holm C. Diabetes. 1999; 48: 228-232Crossref PubMed Scopus (96) Google Scholar). In the postprandial state, HSL activity accounts for most of the detectable lipolysis in human WAT and thus determines whole-body lipid fuel availability (14.Frayn K.N. Shadid S. Hamlani R. Humphreys S.M. 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