Glucose-dependent Regulation of Cholesterol Ester Metabolism in Macrophages by Insulin and Leptin

Insulin resistance, obesity, and diabetes are characterized by hyperglycemia, hyperinsulinemia, and hyperleptinemia and are associated with increased risk of atherosclerosis. In an effort to understand how this occurs, we have investigated whether these factors cause disregulation of cholesterol ester metabolism in J774.2 macrophages. Raising glucose levels alone was sufficient to increase uptake of acetylated low density lipoprotein but did not stimulate synthesis of cholesterol esters. In the presence of high glucose, both insulin and leptin increased the rate of cholesterol ester synthesis, although they did not further increase uptake of acetylated low density lipoprotein. However, in the presence of high glucose both insulin and leptin caused a significant increase in the activity of acyl-CoA: cholesterol O-acyltransferase (ACAT) combined with a significant reduction in the level of hormone-sensitive lipase (HSL). Because ACAT is the main enzyme responsible for cholesterol ester synthesis and HSL contributes significantly to neutral cholesterol ester hydrolase activity, this suggests that glucose primes the J774.2 cells so that in the presence of high insulin or leptin they will store cholesterol esters. This contrasts with 3T3-L1 adipocytes, where HSL activity and expression are increased by insulin in high glucose conditions. These findings may provide an explanation for the observation that in conditions characterized by hyperglycemia, hyperleptinemia, and hyperinsulinemia, triglyceride lipolysis in adipocytes is increased while hydrolysis of cholesterol esters in macrophages is decreased, contributing to foam cell formation. Insulin resistance, obesity, and diabetes are characterized by hyperglycemia, hyperinsulinemia, and hyperleptinemia and are associated with increased risk of atherosclerosis. In an effort to understand how this occurs, we have investigated whether these factors cause disregulation of cholesterol ester metabolism in J774.2 macrophages. Raising glucose levels alone was sufficient to increase uptake of acetylated low density lipoprotein but did not stimulate synthesis of cholesterol esters. In the presence of high glucose, both insulin and leptin increased the rate of cholesterol ester synthesis, although they did not further increase uptake of acetylated low density lipoprotein. However, in the presence of high glucose both insulin and leptin caused a significant increase in the activity of acyl-CoA: cholesterol O-acyltransferase (ACAT) combined with a significant reduction in the level of hormone-sensitive lipase (HSL). Because ACAT is the main enzyme responsible for cholesterol ester synthesis and HSL contributes significantly to neutral cholesterol ester hydrolase activity, this suggests that glucose primes the J774.2 cells so that in the presence of high insulin or leptin they will store cholesterol esters. This contrasts with 3T3-L1 adipocytes, where HSL activity and expression are increased by insulin in high glucose conditions. These findings may provide an explanation for the observation that in conditions characterized by hyperglycemia, hyperleptinemia, and hyperinsulinemia, triglyceride lipolysis in adipocytes is increased while hydrolysis of cholesterol esters in macrophages is decreased, contributing to foam cell formation. cholesteryl esters acyl-CoA:cholesterol O-acyltransferase low density lipoprotein acetylated LDL neutral cholesteryl ester hydrolase hormone-sensitive lipase phosphate-buffered saline Atherosclerosis-related disorders are the principle cause of death in the Western world, and insulin resistance, type-2 diabetes, and obesity are well recognized risk factors for coronary heart disease. Individuals in these categories have a 2–3-fold increased risk of developing macrovascular heart disease (1DeFronzo R.A. Ferrannini E. Diabetes Care. 1991; 14: 173-194Crossref PubMed Scopus (4122) Google Scholar, 2Yip J. Facchini F.S. Reaven G.M. J. Clin. Endocrinol. Metab. 1998; 83: 2773-2776Crossref PubMed Scopus (282) Google Scholar, 3Bressler P. Bailey S.R. Matsuda M. DeFronzo R.A. Diabetologia. 1996; 39: 1345-1350Crossref PubMed Scopus (183) Google Scholar, 4Laakso M. Diabetes. 1999; 48: 937-942Crossref PubMed Scopus (633) Google Scholar, 5Heine R.J. Dekker J.M. Diabetologia. 2002; 45: 461-475Crossref PubMed Scopus (137) Google Scholar). Insulin resistance, type-2 diabetes, and obesity are characterized by hyperleptinemia, hyperinsulinemia, and hyperglycemia, suggesting these may be acting as proatherogenic factors (6Considine R.V. Sinha M.K. Heiman M.L. Kriauciunas A. Stephens T.W. Nyce M.R. Ohannesian J.P. Marko C.C. McKee L.J. Bauer T.L. Caro J.F. N. Engl. J. Med. 1996; 334: 292-295Crossref PubMed Scopus (5462) Google Scholar, 7Shepherd P.R. Kahn B.B. N. Engl. J. Med. 1999; 341: 248-257Crossref PubMed Scopus (1043) Google Scholar, 8DeFronzo R.A. Diabetes. 1988; 37: 667-687Crossref PubMed Google Scholar). Indeed, there is good evidence that a range of growth factors and cytokines can act to promote atherogenesis (9Raines E.W. Ross R. Bioessays. 1996; 18: 271-282Crossref PubMed Scopus (46) Google Scholar), and the importance of glucose levels is shown by the fact that there is a very strong positive correlation between glycated hemoglobin levels and mortality from cardiovascular disease, even in non-diabetic subjects (10Khaw K. Wareham N. Luben R. Bingham S. Oakes S. Welch A. Day N. Br. Med. J. 2001; 322: 1-6Crossref PubMed Scopus (18) Google Scholar). However, the molecular mechanisms underlying the increased rate of atherogenesis in these groups is poorly understood, and little is known about the specific roles of leptin, insulin, and glucose in this process. The first lesion of atherosclerosis (fatty streak or type-1 lesion) is characterized by an accumulation in the intima of the vascular epithelia of lipid-laden macrophage foam cells (11Stary H.C. Chandler A.B. Glagov S. Guyton J.R. Insull W. Rosenfeld M.E. Schaffer S.A. Schwartz C.J. Wagner W.D. Wissler R.W. Circulation. 1994; 89: 2462-2478Crossref PubMed Scopus (978) Google Scholar, 12Ross R. N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (18955) Google Scholar). Cholesterol cannot efflux from the cell when esterified, but the bulk (∼75%) of the lipid in foam cells is in the form of cholesteryl esters (CEs)1 (11Stary H.C. Chandler A.B. Glagov S. Guyton J.R. Insull W. Rosenfeld M.E. Schaffer S.A. Schwartz C.J. Wagner W.D. Wissler R.W. Circulation. 1994; 89: 2462-2478Crossref PubMed Scopus (978) Google Scholar, 12Ross R. N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (18955) Google Scholar). Regulation of cellular CE levels is complex, but a cycle exists between free cholesterol and esterified cholesterol in the cell; the balance of this cycle is a major determinant of the level of the intracellular pool of CE in foam cells. In this cycle, CE synthesis is controlled by acyl-CoA:cholesterol O-acyltransferases (ACATs), a family of intracellular enzymes responsible for catalyzing the intracellular formation of cholesteryl esters from cholesterol and long-chain fatty acyl coenzyme A (13Chang T.Y. Chang C.C.Y. Cheng D. Annu. Rev. Biochem. 1997; 66: 613-638Crossref PubMed Scopus (435) Google Scholar, 14Tabas I. Curr. Opin. Lipidol. 1995; 6: 260-268Crossref PubMed Scopus (58) Google Scholar). To maintain low levels of free cholesterol within the cell, ACAT activity is up-regulated by LDL and exogenous free cholesterol (15Brown M.S. Goldstein J.L. Science. 1986; 232: 34-47Crossref PubMed Scopus (4288) Google Scholar). The expression and activity of ACAT is increased in human monocytes during differentiation and foam cell formation (16Wang H.X. Germain S.J. Benfield P.P. Gillies P.J. Arterioscler. Thromb. Vasc. Biol. 1996; 16: 809-814Crossref PubMed Scopus (52) Google Scholar), and ACAT has been shown to play a crucial role in the accumulation of CE in foam cells (14Tabas I. Curr. Opin. Lipidol. 1995; 6: 260-268Crossref PubMed Scopus (58) Google Scholar). However, there have been no studies of the regulation of ACAT in macrophages by insulin, leptin, and glucose. The breakdown of CE to produce free cholesterol in macrophages is controlled by the neutral cholesteryl ester hydrolase (nCEH) (17Yeaman S.J. Smith G.M. Jepson C.A. Wood S.L. Emmison N. Adv. Enzyme Regul. 1994; 34: 355-370Crossref PubMed Scopus (65) Google Scholar, 18Brown M.S., Ho, Y.K. Goldstein J.L. J. Biol. Chem. 1980; 255: 9344-9352Abstract Full Text PDF PubMed Google Scholar). There is now strong evidence that hormone-sensitive lipase (HSL), the rate-limiting enzyme of triglyceride lipolysis in adipocytes, is the enzyme contributing the major part of nCEH activity in macrophage cell culture models such as the J774.2 cells (17Yeaman S.J. Smith G.M. Jepson C.A. Wood S.L. Emmison N. Adv. Enzyme Regul. 1994; 34: 355-370Crossref PubMed Scopus (65) Google Scholar, 19Escary J. Choy H.A. Reue K. Schotz M.C. Arterioscler. Thromb. Vasc. Biol. 1998; 18: 991-998Crossref PubMed Scopus (55) Google Scholar). The exact contribution of HSL to nCEH activity in macrophages in vivois less clear, because although HSL is clearly detected in murine macrophages, deletion of the HSL gene caused little difference in nCEH activity in peritoneal macrophages (20Osuga 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 (494) Google Scholar). The most likely explanation for this is that there is a compensatory increase in other cholesterol esterases in macrophages in these animals. However, the importance of HSL as a nCEH is shown by the observation that nCEH activity is ablated in a wide range of tissues in the HSL knockout mice (20Osuga 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 (494) Google Scholar). Further, the same group has recently demonstrated cholesterol esters can be eliminated from macrophage foam cells by overexpressing HSL (21Okazaki H. Osuga J.I. Tsukamoto K. Isoo N. Kitamine T. Tamura Y. Tomita S. Sekiya M. Yahagi N. Iizuka Y. Okhashi K. Harada K. Gotoda T. Shimano H. Kimura S. Nagai R. Yamada N. Ishibashi S. J. Biol. Chem. 2002; 277: 31893-31899Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Together, the evidence indicates that regulation of HSL is likely to play an important role in determining CE levels in cells, and it is therefore important to understand the mechanisms affecting the activity of this enzyme. The effects of glucose, insulin, and leptin on the mechanisms regulating CE metabolism in macrophages have not been well studied. Indeed there are no reports of effects of these factors on LDL uptake or ACAT activity in macrophages, although the recent finding that increasing glucose concentrations cause an increase in the expression of the CD36 scavenger receptor indicates that hyperglycemia might have a direct role in stimulating LDL uptake (22Griffin E., Re, A. Hamel N., Fu., C. Bush H. McAffrey T. Asch A.S. Nature Medicine. 2001; 7: 840-846Crossref PubMed Scopus (207) Google Scholar). However, we have recently reported that insulin and leptin acutely stimulate HSL activity in J774.2 macrophages (23O'Rourke L. Yeaman S.J. Shepherd P.R. Diabetes. 2001; 50: 955-961Crossref PubMed Scopus (83) Google Scholar), suggesting they may have a regulatory role in CE metabolism in these cells. Recent data also suggest chronic exposure of cells to glucose and insulin is also likely to have effects on HSL gene expression because insulin and glucose regulate lipolysis and HSL expression in adipocytes (24Botion L.M. Green A. Diabetes. 1999; 48: 1691-1697Crossref PubMed Scopus (71) Google Scholar, 25Smih F. Rouet P. Lucas S. Mairal A. Sengenes C. Lafontan M. Vaulont S. Casado M. Langin D. Diabetes. 2002; 51: 293-300Crossref PubMed Scopus (63) Google Scholar) and glucose increases HSL expression in pancreatic β-cells (26Winzell M.S. Svensson H. Arner P. Ahren B. Holm C. Diabetes. 2001; 50: 2225-2230Crossref PubMed Scopus (36) Google Scholar). Therefore we have investigated whether glucose levels, in combination with high levels of insulin or leptin, might effect CE synthesis in macrophages and whether there are detectable effects on cholesterol uptake, ACAT activity, or HSL activity in these cells. 125I-Protein A, cholesterol 1-14Coleate, 1-14Coleic acid and 1-14Coleoyl-CoA were obtained from AmershamBiosciences. DiI-acetylated LDL was purchased from Intracel. RPMI 1640 and newborn calf serum were obtained from Invitrogen. Fetal calf serum and Dulbecco's modified Eagle's medium were from Sigma. was by was obtained from other were from Sigma. The murine macrophage cell J774.2 was in RPMI medium with calf serum for and 3T3-L1 adipocytes were and as R.J. K. Shepherd P.R. Biochem. J. 1996; PubMed Scopus Google Scholar). serum was J774.2 macrophages were in RPMI serum (fatty and levels of glucose. were on J774.2 cells. with leptin or insulin in or glucose, the cells were with and and in and of were with HSL for with for a further Western were to and with and with A a were the acetylated LDL uptake cells were in RPMI or with or the of insulin or leptin, for the of the was were in was a To nCEH activity in J774.2 cell were with of of were with of by was as D. P.R. J. Biol. Chem. Full Text PDF PubMed Google Scholar). To nCEH activity in of was to the and activity was acid from was by of enzyme activity the of of that activity in HSL very well with activity in cell conditions investigated not The ACAT was to the of C. L. J. J. Biochem. 14: PubMed Scopus Google Scholar, C. M. 1996; PubMed Scopus Google Scholar) with serum and with insulin or leptin for in low or high glucose J774.2 cells were in and by a The ACAT of of with and in a of were for The was on cholesteryl esters were by on in acid and a were the was as were by density in a as J.P. 1986; PubMed Scopus Google Scholar). LDL was acetylated by the of by Goldstein J.L. M.S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). to cells were serum were in the of RPMI or glucose and insulin or leptin, acetylated and serum and for were in and of of was by for for The was to a and the was with as the was to the was by were in and by on in acid were detected and a and were the were and were for cholesterol for and for investigated the effects of leptin, insulin, and glucose on CE metabolism in macrophages. J774.2 macrophages were with acetylated LDL and and the of was a with insulin or These were both and glucose to whether CE formation. that increasing glucose levels in the did not the formation of CE the Further, in glucose insulin not CE formation in the macrophages, although in glucose insulin cause a increase in CE formation are in the of leptin where of of the macrophages with leptin in glucose not increase CE formation. In formation of CE is significantly increased in cells glucose. The of CE in cells in glucose is the level of formation in cells in glucose This indicates the increase in glucose levels to the effects of leptin and insulin on CE formation. To whether this in the CE of macrophages is to increased uptake of modified was to uptake the same conditions of macrophages in high glucose in uptake with low glucose but there was no significant by insulin or leptin, suggesting the effect on the rate of CE synthesis of the enzymes that regulate cholesterol ester synthesis and investigated the effects of leptin, insulin, and glucose on ACAT activity to whether the increase in CE synthesis with an increase in ACAT ACAT activity was by To that this ACAT activity, were in the presence of a known ACAT and this was to activity not ACAT activity was in J774.2 cells for with both low and high glucose levels not To the effects of glucose, leptin, and insulin, J774.2 macrophages were for with insulin or leptin or glucose. insulin increased ACAT activity leptin did not ACAT activity glucose levels alone did not significantly ACAT activity, but both insulin and leptin significantly ACAT activity glucose with levels low also investigated effects on neutral cholesterol activity, on nCEH activity associated with HSL because there is strong evidence that HSL as an nCEH in macrophages J. Choy H.A. Reue K. Schotz M.C. Arterioscler. Thromb. Vasc. Biol. 1998; 18: 991-998Crossref PubMed Scopus (55) Google Scholar, C.A. Kraemer F.B. Yeaman S.J. Biochem. J. 1996; PubMed Scopus Google Scholar). In J774.2 macrophages, HSL also for a of the cellular neutral cholesterol activity, as demonstrated by the fact that of HSL nCEH activity in cell by while HSL levels by a This indicates that in HSL expression or activity to in the levels of CE in these cells. To whether this was the J774.2 macrophages were to insulin or leptin in the presence of or glucose for to and HSL activity and expression were in glucose alone no effect on HSL activity not Insulin caused a increase in HSL activity in cells in glucose but in macrophages in high glucose insulin caused a significant in HSL activity also investigated the effect of leptin on HSL activity in macrophages. with leptin for in a significant increase in HSL activity in macrophages in glucose. However, to with insulin, in J774.2 cells in high glucose leptin a significant reduction in HSL activity of with the activity in high effect of insulin, leptin, and glucose on nCEH activity associated with HSL in macrophages were in insulin or leptin calf and or glucose. HSL was and neutral cholesterol activity was the of in was and of and with in the same glucose Western to whether the in HSL activity with in the level of HSL in cells. in glucose levels alone did not HSL levels The effects of insulin on HSL expression in macrophages the effects on HSL activity, with insulin very little effect in low glucose but a significant in HSL expression in high glucose also HSL expression in the same it HSL activity, HSL expression in conditions and increasing levels in conditions HSL activity has been most in adipocytes, where it has been reported that insulin and high glucose increase triglyceride lipolysis (24Botion L.M. Green A. Diabetes. 1999; 48: 1691-1697Crossref PubMed Scopus (71) Google Scholar) and HSL expression F. Rouet P. Lucas S. Mairal A. Sengenes C. Lafontan M. Vaulont S. Casado M. Langin D. Diabetes. 2002; 51: 293-300Crossref PubMed Scopus (63) Google Scholar). This suggest macrophages, HSL activity expression is increased these conditions in Therefore we investigated the effect of insulin and high glucose on HSL expression and activity in 3T3-L1 insulin caused a increase in HSL activity and expression in high glucose, and no effect was in low glucose The of the that conditions insulin leptin promote cholesterol ester in macrophages. However, we a by increases in glucose levels for insulin and leptin to stimulate cholesterol ester a has important because heart disease is associated with obesity, insulin resistance, and diabetes in and atherosclerosis is diabetes is (1DeFronzo R.A. Ferrannini E. Diabetes Care. 1991; 14: 173-194Crossref PubMed Scopus (4122) Google Scholar, 2Yip J. Facchini F.S. Reaven G.M. J. Clin. Endocrinol. Metab. 1998; 83: 2773-2776Crossref PubMed Scopus (282) Google Scholar, 3Bressler P. Bailey S.R. Matsuda M. DeFronzo R.A. Diabetologia. 1996; 39: 1345-1350Crossref PubMed Scopus (183) Google Scholar, 4Laakso M. Diabetes. 1999; 48: 937-942Crossref PubMed Scopus (633) Google Scholar, 5Heine R.J. Dekker J.M. Diabetologia. 2002; 45: 461-475Crossref PubMed Scopus (137) Google Scholar, K. Wareham N. Luben R. Bingham S. Oakes S. Welch A. Day N. Br. Med. J. 2001; 322: 1-6Crossref PubMed Scopus (18) Google Scholar, R.W. Curr. Opin. Lipidol. 2001; PubMed Scopus Google Scholar). have effects on of the major regulating cholesterol metabolism that are likely to to the increased rate of cholesterol ester The first of these is increased uptake of modified LDL by high glucose. mechanisms have been by glucose increase In the first it has recently been shown (22Griffin E., Re, A. Hamel N., Fu., C. Bush H. McAffrey T. Asch A.S. Nature Medicine. 2001; 7: 840-846Crossref PubMed Scopus (207) Google Scholar) that glucose increases expression of the CD36 scavenger A explanation may in the observation that CD36 can act as a receptor for N. Nagai R. M. H. A. S. H. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). glucose be to glucose, and therefore increased uptake the cell by both CD36 and the scavenger receptor A and is However, the increase in uptake by glucose alone not with an increase in cholesterol ester so the increased uptake of alone is not sufficient to increase the rate of cholesterol ester The investigated in ACAT we that insulin and leptin both stimulate ACAT Insulin ACAT activity in low glucose and a level of high glucose, the leptin effect is in low glucose but is to that of insulin in high glucose. that the increased ACAT activity is likely because of increased ACAT the fact that this effect is such are likely to be in the form because this is most in macrophages (16Wang H.X. Germain S.J. Benfield P.P. Gillies P.J. Arterioscler. Thromb. Vasc. Biol. 1996; 16: 809-814Crossref PubMed Scopus (52) Google Scholar, P.J. Oka K. M. Chang C.C.Y. Chang T.Y. L. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), and in this form is by cholesterol levels P.J. Oka K. M. Chang C.C.Y. Chang T.Y. L. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). To the of has from determining whether this is the in However, evidence indicates that the increase in ACAT activity, although likely to increased CE synthesis, is not sufficient to stimulate CE This is shown by the finding that glucose alone increases uptake, also ACAT activity and is not associated with an increase in CE synthesis these conditions. The that be contributing to cholesterol ester is the rate of cholesterol ester breakdown we HSL is a major nCEH in the J774.2 cells. have shown (23O'Rourke L. Yeaman S.J. Shepherd P.R. Diabetes. 2001; 50: 955-961Crossref PubMed Scopus (83) Google Scholar) that exposure leptin an insulin a in HSL activity in J774.2 macrophages in glucose. However, the did not the chronic regulation of HSL in macrophages by insulin, leptin, and glucose, the factors that the and There is evidence that the combination of insulin and glucose are important in regulating HSL in other cell HSL activity is up-regulated in 3T3-L1 adipocytes and pancreatic β-cells to high glucose levels F. Rouet P. Lucas S. Mairal A. Sengenes C. Lafontan M. Vaulont S. Casado M. Langin D. Diabetes. 2002; 51: 293-300Crossref PubMed Scopus (63) Google Scholar, M.S. Svensson H. Arner P. Ahren B. Holm C. Diabetes. 2001; 50: 2225-2230Crossref PubMed Scopus (36) Google Scholar), chronic exposure to insulin has been reported to increase HSL expression levels in adipocytes D. Diabetes. PubMed Scopus Google Scholar) and to increase lipolysis in a in adipocytes (24Botion L.M. Green A. Diabetes. 1999; 48: 1691-1697Crossref PubMed Scopus (71) Google Scholar). the studies in adipocytes by the combined effects of insulin and glucose on lipolysis are most likely to effects on HSL because in high glucose insulin caused a increase in HSL activity and expression in 3T3-L1 adipocytes, no effect was in low glucose. However, the regulation of HSL expression and activity in macrophages is clearly from that in adipocytes and exposure of cells to insulin, and in leptin, in low glucose increased HSL expression and activity, with findings (23O'Rourke L. Yeaman S.J. Shepherd P.R. Diabetes. 2001; 50: 955-961Crossref PubMed Scopus (83) Google Scholar). This to macrophages from increases in lipid In the of leptin, this with the that of the roles of leptin is to lipid accumulation in cells Y. L. Proc. Natl. Acad. Sci. 1999; PubMed Scopus Google Scholar). increases in glucose concentrations no direct effect on HSL they did act to the cells such that of leptin or insulin caused a reduction in HSL expression and glucose with leptin or insulin to HSL activity in macrophages. This effect is most likely an effect on expression in in activity because the in activity with the in level of The act to promote CE accumulation in J774.2 macrophages where HSL for so of the nCEH This is by the recent finding (21Okazaki H. Osuga J.I. Tsukamoto K. Isoo N. Kitamine T. Tamura Y. Tomita S. Sekiya M. Yahagi N. Iizuka Y. Okhashi K. Harada K. Gotoda T. Shimano H. Kimura S. Nagai R. Yamada N. Ishibashi S. J. Biol. Chem. 2002; 277: 31893-31899Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar) that of HSL cholesterol ester in human macrophages. have recently that HSL is detectable levels in human macrophages not that these findings are also likely to have in cholesterol ester metabolism in In findings that a combination of hyperglycemia and or hyperleptinemia stimulate CE synthesis in J774.2 macrophages. have also mechanisms by high glucose levels play a role in this increased uptake of modified increased ACAT activity, and nCEH activity associated with This contrasts with adipocytes where HSL is up-regulated in the presence of high glucose and These findings lipolysis is increased in adipocytes in the and free fatty acid levels while cholesterol ester hydrolysis in macrophages is The finding that these effects of insulin and leptin were in the presence of glucose concentrations to hyperglycemia in is because this foam cell formation is in and death from heart disease with glucose levels (10Khaw K. Wareham N. Luben R. Bingham S. Oakes S. Welch A. Day N. Br. Med. J. 2001; 322: 1-6Crossref PubMed Scopus (18) Google Scholar). this a that in human macrophages to the increased of atherosclerosis in insulin and for HSL and and for on human