Attenuation of Adipocyte Triacylglycerol Hydrolase Activity Decreases Basal Fatty Acid Efflux

Fatty acids released from adipose triacylglycerol stores by lipolysis provide vertebrates with an important source of energy. We investigated the role of microsomal triacylglycerol hydrolase (TGH) in the mobilization of adipocyte triacylglycerols through inactivation of the TGH activity by RNA interference or chemical inhibition. Attenuation of TGH activity resulted in decreased basal but not isoproterenol-stimulated efflux of fatty acids from 3T3-L1 adipocytes. Lack of TGH activity was accompanied by accumulation of cellular triacylglycerols and cholesteryl esters without any changes in the expression of enzymes catalyzing triacylglycerol synthesis (diacylglycerol acyltransferases 1 and 2) or degradation (adipose triglyceride lipase and hormone-sensitive lipase). Inhibition of TGH-mediated lipolysis also did not affect insulin-stimulated Glut4 translocation from intracellular compartments to the plasma membrane or glucose uptake into adipocytes. These data suggest that TGH plays a role in adipose tissue triacylglycerol metabolism and may be a suitable pharmacological target for lowering fatty acid efflux from adipose tissue without altering glucose import. Fatty acids released from adipose triacylglycerol stores by lipolysis provide vertebrates with an important source of energy. We investigated the role of microsomal triacylglycerol hydrolase (TGH) in the mobilization of adipocyte triacylglycerols through inactivation of the TGH activity by RNA interference or chemical inhibition. Attenuation of TGH activity resulted in decreased basal but not isoproterenol-stimulated efflux of fatty acids from 3T3-L1 adipocytes. Lack of TGH activity was accompanied by accumulation of cellular triacylglycerols and cholesteryl esters without any changes in the expression of enzymes catalyzing triacylglycerol synthesis (diacylglycerol acyltransferases 1 and 2) or degradation (adipose triglyceride lipase and hormone-sensitive lipase). Inhibition of TGH-mediated lipolysis also did not affect insulin-stimulated Glut4 translocation from intracellular compartments to the plasma membrane or glucose uptake into adipocytes. These data suggest that TGH plays a role in adipose tissue triacylglycerol metabolism and may be a suitable pharmacological target for lowering fatty acid efflux from adipose tissue without altering glucose import. Obesity is a chronic disease with increasing prevalence in most of the world but particularly in Western countries (1Organization World Health O) WH Obesity: Preventing and Managing the Global Epidemic, Report of a WHO Consultation on Obesity, Geneva, June 3–5, 1997, World Health Organization, Geneva. 1998; Google Scholar). It is estimated that obesity-related illnesses cause about 300,000 deaths per year in the United States alone (2Allison D.B. Fontaine K.R. Manson J.E. Stevens J. VanItallie T.B. J. Am. Med. Assoc. 1999; 282: 1530-1538Crossref PubMed Scopus (1532) Google Scholar). Obese individuals are at risk for a number of medical conditions including cardiovascular disease, hypertension, dyslipidemias, and type 2 diabetes. Obese insulin-resistant subjects have higher levels of circulating fatty acids due to increased flux of free fatty acids (FA) 3The abbreviations used are: FA, fatty acid; ATGL, adipose triglyceride lipase; DG, diacylglycerol; DMEM, Dulbecco's modified Eagle's medium; E600, diethyl-p-nitrophenylphosphate; ER, endoplasmic reticulum; Glut4, glucose transporter 4; HSL, hormone-sensitive lipase; PDI, protein disulfide isomerase; TG, triacylglycerol; TGH, TG hydrolase; BSA, bovine serum albumin; TGHi, 4,4,4-trifluoro-2-[2-(3-methylphenyl)hydrazono]-1-(2-thienyl) butane-1,3-dione; shRNA, short-hairpin RNA; PBS, phosphate-buffered saline. released from adipose tissue triacylglycerol (TG) stores. As a consequence, accumulation of excess lipid and lipid precursors in non-adipose tissues ensues and culminates in cell dysfunction and/or cell death, a condition known as lipotoxicity (3Lewis G.F. Carpentier A. Adeli K. Giacca A. Endocr. Rev. 2002; 23: 201-229Crossref PubMed Scopus (829) Google Scholar). One of the strategies that may lead to decreased circulating fatty acid levels and increased insulin sensitivity is through pharmacological inhibition of lipolysis of adipose tissue TG. The enzymes that have been postulated to mediate hydrolysis of adipose tissue TG and, thus, provide an energy source (FA) to other tissues are hormone-sensitive lipase (HSL) (4Holm C. Biochem. Soc. Trans. 2003; 31: 1120-1124Crossref PubMed Scopus (0) Google Scholar) and the recently discovered adipose triglyceride lipase (ATGL) (5Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Science. 2004; 306: 1383-1386Crossref PubMed Scopus (1533) Google Scholar), also termed desnutrin (6Villena J.A. Roy S. Sarkadi-Nagy E. Kim K.H. Sul H.S. J. Biol. Chem. 2004; 279: 47066-47075Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar) or calcium-independent phospholipase A2 (7Jenkins C.M. Mancuso D.J. Yan W. Sims H.F. Gibson B. Gross R.W. J. Biol. Chem. 2004; 279: 48968-48975Abstract Full Text Full Text PDF PubMed Scopus (685) Google Scholar). About 40% of TG lipolytic activity is retained in the white adipose tissue of HSL null mice (8Osuga J-I. 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 (504) Google Scholar, 9Haemmerle 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 (488) Google Scholar), and inhibition of ATGL in cytosols prepared from HSL null adipocytes decreases total lipase activity by 80% (5Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Science. 2004; 306: 1383-1386Crossref PubMed Scopus (1533) Google Scholar). Therefore, it can be concluded that ATGL together with HSL accounts for the majority of isoproterenol-stimulated cytosolic activity in the adipose tissue. We have characterized another neutral intracellular TG hydrolase (TGH) in hepatic microsomes (10Lehner R. Verger R. Biochemistry. 1997; 36: 1861-1868Crossref PubMed Scopus (100) Google Scholar). TGH (also termed Ces3) associates with hepatic lipid droplets (11Lehner R. Cui Z. Biochem. J. 1999; PubMed Scopus Google Scholar) and hepatic TG R. Biochem. J. 1999; PubMed Scopus Google Scholar, S. M. R. J. 2003; PubMed Scopus Google Scholar, R. Biochem. J. 2004; PubMed Scopus Google Scholar, M. W. R. Biol. PubMed Scopus Google Scholar). TGH is also in 3T3-L1 adipocytes R. 2003; PubMed Scopus Google Scholar, E. R. Biochem. J. PubMed Scopus Google Scholar) and adipose tissue S. R. PubMed Scopus Google Scholar, R. M. W. K. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, R. H. M. G. H. G. M. Strauss J.G. Lass A. Zimmermann R. Haemmerle G. Zechner R. Hermetter A. Full Text Full Text PDF PubMed Scopus Google Scholar) it been also to with adipocyte lipid droplets R. M. W. K. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). Therefore, that the hydrolase may a role in the mobilization of adipocyte TG as it in the It been that TGH in that with glucose transporter from adipocytes W. J. J. T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of into adipocytes the Glut4 to plasma Therefore, it was concluded that TGH plays a role in Glut4 the role of the in data suggest that of HSL expression to decreased uptake R. Haemmerle G. Wagner Strauss J.G. Zechner R. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). HSL not adipose TG lipolysis but in the accumulation of 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 (488) Google Scholar). the protein in and inactivation of the insulin activity 2000; PubMed Scopus Google Scholar). the of glucose uptake in HSL null adipocyte to be the of in insulin that inhibition of basal lipolysis by TGH efflux but not lead to accumulation of in 3T3-L1 adipocytes. that TGH not with Glut4 in 3T3-L1 adipocytes in basal or insulin-stimulated conditions and that inhibition of TG lipolysis in 3T3-L1 adipocytes not insulin-stimulated Glut4 translocation from intracellular to plasma membrane or insulin-stimulated glucose uptake in bovine cholesteryl fatty bovine serum and from was and from and disulfide from The and acid from from and from was from modified and bovine serum from other of or higher of 3T3-L1 from in bovine in or for the on the in to by the of and insulin for and in The 2 or with adipocytes at of a RNA for was used to TGH short-hairpin RNA expression the and of TGH from of the The and The into was with and of 3T3-L1 and of at in with of or the for and into B. the cell the to and microsomes at to TGH protein levels by and activity as a RNA and RNA was from 3T3-L1 cell to the synthesis from 2 of total RNA was by The and and ATGL, and and and and and The at for at for and at for The by on 3T3-L1 adipocytes in 1 of and 1 and by a by and the at for to cytosolic lipid and membrane with and in 1 of by droplets from 3T3-L1 adipocytes that with fatty in the or of for 1 in and 1 and the with of and at for to cytosolic lipid and membrane of protein in cell or in The to a membrane and with or by with as by 3T3-L1 adipocytes in the or of lipase for The of the used in the was to be in inhibition of TGH activity in and in S. M. R. J. 2003; PubMed Scopus Google Scholar). with and in an and cytosolic and membrane prepared as in cytosols or by of in 1 and of or and of the in and at with R. 36: PubMed Scopus Google Scholar). The of the was a at and as and in phosphate-buffered on and at for in a to cell was and used in at for in a to cell from cell and with in the of lipid and cholesteryl as R. Biochem. J. 1999; PubMed Scopus Google Scholar, S. M. R. J. 2003; PubMed Scopus Google Scholar). The was in a of and to The in acid to neutral TG, and cholesteryl R. Biochem. J. 1999; PubMed Scopus Google Scholar, S. M. R. J. 2003; PubMed Scopus Google Scholar). by to and the was by in the of lipid lipid cell prepared from or or 3T3-L1 at of in the of known of DG, FA, cholesteryl and from by the and neutral with the and by as T. S. G. R. R. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). from 3T3-L1 adipocytes with and in of acid or of acid per for The adipocytes with and for with 1 of in in the or of lipase or as in and by and in was by of and from 3T3-L1 in fatty in the or of for to at and the of fatty acids was with and was with triglyceride of released and in 3T3-L1 the 3T3-L1 adipocytes in fatty for and with The and in and by TG and from the and to esters by with of in for 2 at fatty acid esters by are as the of fatty acid adipocytes in in the or of lipase for The with without glucose and in without glucose with or without lipase for 2 in the or of insulin for an 1 by with for with PBS, in 1 of PBS, and The glucose uptake was by the in cell Glut4 3T3-L1 adipocytes as for glucose in the or of the with in for with in for 2 with and in the of Glut4 was by with and TGH was by with was with or as in the at and at The with a are as the was by the of TGH in 3T3-L1 is with the M. W. R. Biol. PubMed Scopus Google Scholar, M. R. Biochemistry. 2002; PubMed Scopus Google Scholar) and is also to with lipid droplets in the (10Lehner R. Verger R. Biochemistry. 1997; 36: 1861-1868Crossref PubMed Scopus (100) Google Scholar, R. Cui Z. Biochem. J. 1999; PubMed Scopus Google Scholar, M. W. R. Biol. PubMed Scopus Google Scholar) and and adipocytes R. M. W. K. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). of TGH and HSL of adipocytes with with a lipase or with insulin and the as in conditions The the majority of of HSL also with the The of HSL with the been also by F.B. S. J-I. Ishibashi S. S. 2002; PubMed Scopus Google Scholar). As TGH was with membrane a of TGH was in the TGH with the lipid droplets R. M. W. K. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar), may be in with the as by the of an membrane protein with a lipase or insulin did not the levels of TGH or HSL in the membrane or cytosolic Inhibition of in lipolytic activity of 3T3-L1 adipocyte was of as of the total lipase activity was in the with the of the activity with TGH accounts for the majority of microsomal lipase activity HSL and ATGL are in the or on cytosolic lipid 1 and lipid and membrane lipase in 3T3-L1 adipocytes with insulin in the or of the lipase was to the and TGH activity through of the (10Lehner R. Verger R. Biochemistry. 1997; 36: 1861-1868Crossref PubMed Scopus (100) Google Scholar, R. Cui Z. Biochem. J. 1999; PubMed Scopus Google Scholar, S. M. R. J. 2003; PubMed Scopus Google Scholar). decreased the lipase activity by that adipose TGH activity is to with to a as in S. M. R. J. 2003; PubMed Scopus Google Scholar). of the with insulin on the lipase that insulin is not in the of TGH in the adipose a to that in K.R. R. PubMed Scopus Google Scholar). also decreased lipolytic activity by with insulin resulted in a in the lipase activity but not TGH levels The inhibition of the lipase activity may be due to insulin-stimulated of HSL HSL was to be the of the lipase T. B. E. J.A. G. C. Biochem. J. PubMed Scopus Google Scholar), insulin may also affect the activity of ATGL accumulation of was the not TGH activity and TGH-mediated TG can be by S. M. R. J. 2003; PubMed Scopus Google Scholar). is and be cell and the in 1 not be to any inhibition. the is in the lipase lipase activity is decreased by and membrane lipase activity is by that TGH the majority of the lipase activity in 3T3-L1 of lipase activity in and from 3T3-L1 adipocytes 3T3-L1 adipocytes for as and and and lipase to in a Inhibition of TGH from 3T3-L1 the of TGH inhibition on from the with basal and and isoproterenol-stimulated and conditions and resulted in a of from 3T3-L1 adipocytes in and These suggest that the basal lipolysis is not on the of HSL, with HSL A. G. J. A. M. E. A. C.M. N. Gross R.W. C. PubMed Scopus Google Scholar). efflux was most due to the of HSL activity by translocation of the lipase to the droplets C. G. H. J.A. C. J. Biol. 2003; PubMed Scopus Google Scholar, C. J.A. C. C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) with of ATGL (5Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. 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TGH and for TGH protein levels and TGH activity of resulted in a of TGH expression and to an 80% of TGH activity in microsomal in lipolytic activity in cell was decreased by of TGH expression was not accompanied with changes in the expression of HSL or ATGL, that the of lipase activity is due to TGH levels The expression of a protein with in lipase activity Kim J.E. T. W. J.E. J. Full Text Full Text PDF PubMed Scopus Google Scholar), was also not of TGH also did not lead to decreased expression of in TG synthesis (diacylglycerol 1 and 2) and of a protein that with HSL and inhibition of the lipase by fatty acids released by lipolysis K. Kraemer F.B. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar, R. S. K. A. Kraemer F.B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The expression of TGH is accompanied with a in triacylglycerol that HSL ATGL can for the of TGH activity TGH as an in cellular levels and TGH adipocytes. the of TGH activity also to a in cellular cholesteryl the role of TGH in hydrolysis R. M. W. K. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, S. R.W. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, T.B. PubMed Scopus Google Scholar, E. T.B. PubMed Scopus Google Scholar). The in levels most the for the neutral lipid with a basal conditions of fatty of and of of cell released from adipocytes. expression and activity of TGH resulted in of from adipocytes or conditions and increased efflux from and TGH adipocytes by a that ATGL and HSL for the of TGH hydrolysis of TG expression of TGH also decreased of the of released by adipocytes of TGH expression by RNA interference decreases fatty acid and by 3T3-L1 adipocytes. Fatty acid from insulin and 3T3-L1 adipocytes by as is as a of fatty acid released from cellular was by of TGH by RNA the of TG and from 3T3-L1 of the adipocyte TG was by TG was of acid and acid together for of total TGH increased levels of and decreased levels of and acid with a in acid and acid in TG. with that of cellular TG. The majority of fatty acids in the cellular TG. was increased in TGH cell TG with cell TG and decreased in the of TGH may suggest of TGH for TG acid in the TGH with of adipocytes and W. J. J. T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) the of TGH in of to adipocytes insulin-stimulated translocation of Glut4 W. J. J. T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Therefore, it was concluded that TGH plays a role in Glut4 TGH is to the in (10Lehner R. Verger R. Biochemistry. 1997; 36: 1861-1868Crossref PubMed Scopus (100) Google Scholar, R. Cui Z. Biochem. J. 1999; PubMed Scopus Google Scholar, M. W. R. Biol. PubMed Scopus Google Scholar, M. R. Biochemistry. 2002; PubMed Scopus Google Scholar). Glut4 been to be and R. Rev. Biol. 2002; PubMed Scopus Google Scholar, S. T.B. W. Biol. 2003; PubMed Scopus Google Scholar), have the of TGH in 3T3-L1 adipocytes by TGH with the protein in basal and insulin-stimulated conditions in the or of lipase Glut4 did not any 3T3-L1 adipocytes Glut4 was in an intracellular in with R. Rev. Biol. 2002; PubMed Scopus Google Scholar). As with translocation of Glut4 to the plasma membrane was TGH did not any with Glut4 in basal or insulin-stimulated inhibition of TGH by did not to with translocation of Glut4 from intracellular compartments to the plasma Inhibition of TGH-mediated into 3T3-L1 of the HSL in adipose tissue glucose uptake and metabolism R. Haemmerle G. Wagner Strauss J.G. Zechner R. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). been to be due to levels of intracellular of the lipase activity of HSL and through of 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 (488) Google Scholar). We inhibition of TGH-mediated insulin-stimulated glucose uptake in 3T3-L1 adipocytes. TGH-mediated lipolysis and fatty acid from adipocytes with insulin 1 and the did not to insulin-stimulated Glut4 translocation and or insulin-stimulated glucose uptake the role of TGH in glucose the in TGH adipocytes. to adipocytes with decreased TGH expression did not insulin-stimulated glucose uptake together the data that TGH not a role in glucose uptake but mediate basal triacylglycerol tissue the of TG in the insulin TG acid and glucose uptake as as TG and energy is free fatty acids are from TG stores by lipolysis and by serum in the plasma for to tissues for 2002; PubMed Scopus Google Scholar, 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The to be for lipolysis in adipose tissue TG is of the about of the basal TG lipase activity of the adipose that another TG lipase activity in adipocytes (8Osuga J-I. 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 (504) Google Scholar, 9Haemmerle 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 (488) Google Scholar, N. J. E. PubMed Scopus Google Scholar). other intracellular neutral TG in adipocytes in to HSL are TGH S. R. PubMed Scopus Google Scholar, R. M. W. K. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar) and ATGL (5Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Science. 2004; 306: 1383-1386Crossref PubMed Scopus (1533) Google Scholar). HSL and ATGL are cytosolic TGH is to (10Lehner R. Verger R. Biochemistry. 1997; 36: 1861-1868Crossref PubMed Scopus (100) Google Scholar). TGH was to a role in hepatic TG metabolism R. Biochem. J. 1999; PubMed Scopus Google Scholar, S. M. R. J. 2003; PubMed Scopus Google Scholar, R. Biochem. J. 2004; PubMed Scopus Google Scholar, M. W. R. Biol. PubMed Scopus Google Scholar, R. 2003; PubMed Scopus Google Scholar). of TGH in resulted in increased hydrolysis of TG and increased of the lipolytic for into TG R. Biochem. J. 1999; PubMed Scopus Google Scholar, M. W. R. Biol. PubMed Scopus Google Scholar). chemical inhibition of TGH resulted in decreased mobilization of TG for S. M. R. J. 2003; PubMed Scopus Google Scholar). TGH is also in the adipose tissue E. R. Biochem. J. PubMed Scopus Google Scholar, S. R. PubMed Scopus Google Scholar, R. M. W. K. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar), that TGH may also be in the mobilization of and may to plasma free fatty acid increased of circulating fatty acids have been in the of and hepatic insulin and in of insulin Therefore, inhibition of adipose tissue lipolysis and, decreased of fatty acids from the an pharmacological suggest that of lipolysis may lead to the accumulation of intracellular levels 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 (488) Google Scholar) that affect insulin-stimulated glucose uptake into the adipose a condition that in of We to inhibition of the basal lipase (TGH) activity in decreased efflux of fatty acids from adipocytes and inhibition of TGH glucose uptake into the HSL is characterized as a cytosolic and translocation to the lipid is by a that on of and protein by as and (4Holm C. Biochem. Soc. Trans. 2003; 31: 1120-1124Crossref PubMed Scopus (0) Google Scholar, C. G. H. J.A. C. J. Biol. 2003; PubMed Scopus Google Scholar, C. J.A. C. C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the other the activity of TGH to be to the and may the basal lipase activity in the adipose tissue. data that the majority of the basal lipase activity in HSL null adipocytes be to TGH R. M. W. K. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar), and lipolysis may to the plasma free fatty acid ATGL was also to fatty acid in basal conditions (5Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Science. 2004; 306: 1383-1386Crossref PubMed Scopus (1533) Google Scholar, O. M. PubMed Scopus Google Scholar). of HSL and ATGL expression in 3T3-L1 adipocytes resulted in an of fatty acid efflux from isoproterenol-stimulated but the of HSL and ATGL expression decreased basal fatty acid by O. M. PubMed Scopus Google Scholar). in ATGL null suggest that ATGL not a role in basal as fatty acid and from white adipose tissue in the and type mice basal conditions G. Lass A. Zimmermann R. G. C. J. G. R. Theussl C. S. Wagner E.F. M. G. Zechner R. Science. PubMed Scopus Google Scholar). Inhibition of hepatic TGH resulted in lipolysis of TG S. M. R. J. 2003; PubMed Scopus Google Scholar). data that inhibition of TGH in adipocytes in a of basal fatty acid and the of expression of ATGL and of HSL activity of the to an of intracellular levels 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 (488) Google Scholar), inhibition of TGH-mediated triacylglycerol lipolysis in adipocytes not to and acids are the fatty acids in 3T3-L1 adipocyte TG. Attenuation of TGH expression to an of acid in cellular TG and acid in the for the or in TG are by to data W. J. J. T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) that of TGH in compartments and an role of TGH in Glut4 translocation to plasma Glut4 is to with compartments in 3T3-L1 adipocytes M. Biol. 2000; PubMed Scopus Google Scholar) and in adipose tissue R. Rev. Biol. 2002; PubMed Scopus Google Scholar). of Glut4 and in adipocytes been also S. T.B. W. Biol. 2003; PubMed Scopus Google Scholar). Glut4 with the is most the of the protein and data of TGH with a known protein PDI, a that is with in hepatic TGH (11Lehner R. Cui Z. Biochem. J. 1999; PubMed Scopus Google Scholar, M. W. R. Biol. PubMed Scopus Google Scholar). We have not been to any TGH with the by M. W. R. Biol. PubMed Scopus Google Scholar). of TGH with an in 3T3-L1 Glut4 was in a from the TGH and Glut4 also to be in in basal and insulin-stimulated Inhibition of TGH activity not did not affect the of Glut4 to from an intracellular to plasma membrane insulin but also did not affect glucose uptake into the adipocytes. These are important inhibition of the HSL, to with glucose metabolism in the cell R. Haemmerle G. Wagner Strauss J.G. Zechner R. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). data suggest that TGH may a suitable pharmacological target for the lipotoxicity with the of insulin Inhibition of TGH in adipose the flux of fatty acids to the and inhibition of TGH in the be to the of without accompanied by We for in and of for the We also Kraemer for the

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