The Enzymes of Neutral Lipid Synthesis (2001)

acyl-CoA:cholesterol acyltransferase acyl-CoA:diacylglycerol acyltransferase kilobase(s) endoplasmic reticulum low density lipoprotein receptor-deficient apolipoprotein Fueled by fat-rich diets and sedentary lifestyles, atherosclerosis and obesity are major health issues in the Western world. Both diseases involve excessive accumulation of neutral lipids: cholesterol esters in arteries in atherosclerosis and triglycerides in adipocytes in obesity. The study of these diseases has sparked interest in the biochemistry and molecular biology of neutral lipid synthesis. The discovery of acyl-CoA:cholesterol acyltransferase (ACAT,1 EC 2.3.1.26), a cholesterol ester synthesis enzyme, dates back to the 1950s (1Goodman D.S. Deykin D. Shiratori T. J. Biol. Chem. 1964; 239: 1335-1345Abstract Full Text PDF PubMed Google Scholar). ACAT was identified as an intracellular enzyme in the endoplasmic reticulum (ER) that covalently joined cholesterol and fatty acyl-CoA molecules to form cholesterol esters (Fig. 1). ACAT activity was detected in macrophages and in tissues such as liver, small intestine, and adrenal glands (2Billheimer J.T. Gillies P.J. Esfahani M. Swaney J.B. Advances in Cholesterol Research. The Telford Press, Caldwell, NJ1990: 7-45Google Scholar, 3Chang T.Y. Chang C.C.Y. Cheng D. Annu. Rev. Biochem. 1997; 66: 613-638Crossref PubMed Scopus (442) Google Scholar, 4Brown M.S. Goldstein J.L. Krieger M. Ho Y.K. Anderson R.G.W. J. Cell Biol. 1979; 82: 597-613Crossref PubMed Scopus (384) Google Scholar). Another ER enzyme, acyl-CoA:diacylglycerol acyltransferase (DGAT, EC2.3.1.20), was identified in 1960 (5Weiss S.B. Kennedy E.P. Kiyasu J.Y. J. Biol. Chem. 1960; 235: 40-44Abstract Full Text PDF PubMed Google Scholar). The DGAT reaction is similar to that of ACAT except that diacylglycerol is the acyl group acceptor (Fig. 1). In the ensuing 30 years, much was learned about the biochemistry of ACAT and DGAT (2Billheimer J.T. Gillies P.J. Esfahani M. Swaney J.B. Advances in Cholesterol Research. The Telford Press, Caldwell, NJ1990: 7-45Google Scholar, 3Chang T.Y. Chang C.C.Y. Cheng D. Annu. Rev. Biochem. 1997; 66: 613-638Crossref PubMed Scopus (442) Google Scholar, 6Suckling K.E. Stange E.F. J. Lipid Res. 1985; 26: 647-671Abstract Full Text PDF PubMed Google Scholar, 7Buhman K.F. Accad M. Farese Jr., R.V. Biochim. Biophys. Acta. 2000; 1529: 142-154Crossref PubMed Scopus (174) Google Scholar, 8Bell R.M. Coleman R.A. Annu. Rev. Biochem. 1980; 49: 459-487Crossref PubMed Scopus (457) Google Scholar, 9Brindley D.N. Vance D.E. Vance J.E. Biochemistry of Lipids, Lipoproteins and Membranes. Elsevier Science Publishers B.V., Amsterdam1991: 171-203Google Scholar, 10Lehner R. Kuksis A. Prog. Lipid Res. 1996; 35: 169-201Crossref PubMed Scopus (256) Google Scholar, 11Farese Jr., R.V. Cases S. Smith S.J. Curr. Opin. Lipidol. 2000; 11: 229-234Crossref PubMed Scopus (122) Google Scholar). Both enzymes were found to play important roles in synthesizing neutral lipids for the assembly and secretion of lipoproteins, and ACAT was found to be responsible for synthesizing cholesterol esters in arterial macrophage foam cells. However, these hydrophobic proteins proved difficult to isolate, slowing progress in their understanding. Because of the pioneering work of Chang and colleagues (12Chang C.C.Y. Huh H.Y. Cadigan K.M. Chang T.Y. J. Biol. Chem. 1993; 268: 20747-20755Abstract Full Text PDF PubMed Google Scholar), the field of neutral lipid synthesis made great strides during the past decade. These investigators isolated ACAT by using a clever cloning strategy to isolate an ACAT cDNA. Thanks to the resultant molecular probes and to genetic studies in yeast and mice, we now know there are two mammalian ACAT enzymes and probably more than one DGAT enzyme. 2A second mammalian DGAT gene was recently reported (76Cases S. Stone S. Zhou P. Yen E. Tow B. Lardizabal K.D. Voelker T. Farese Jr., R.V. J. Biol. Chem. 2001; 276: 38870-38876Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar). A large number of ACAT- and DGAT-related genes are identifiable in species ranging from plants (13Hobbs D.H. Lu C. Hills M.J. FEBS Lett. 1999; 452: 145-149Crossref PubMed Scopus (171) Google Scholar, 14Zou J. Wei Y. Jako C. Kumar A. Selvaraj G. Taylor D.C. Plant J. 1999; 19: 645-653Crossref PubMed Google Scholar) to yeast (15Yang H. Bard M. Bruner D.A. Gleeson A. Deckelbaum R.J. Aljinovic G. Pohl T.M. Rothstein R. Sturley S.L. Science. 1996; 272: 1353-1356Crossref PubMed Scopus (226) Google Scholar, 16Yu C. Kennedy N.J. Chang C.C.Y. Rothblatt J.A. J. Biol. Chem. 1996; 271: 24157-24163Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 17Sturley S.L. Biochim. Biophys. Acta. 2000; 1529: 155-163Crossref PubMed Scopus (73) Google Scholar) to humans. Here we review recent advances in understanding the function of the mammalian members of this family, ACAT1, ACAT2, and DGAT. Characteristics of the human and mouse members of the ACAT/DGAT gene family are shown in TableI. The human ACAT1 gene encodes four mRNAs of 7.0, 4.3, 3.6, and 2.8 kilobases (kb) (12Chang C.C.Y. Huh H.Y. Cadigan K.M. Chang T.Y. J. Biol. Chem. 1993; 268: 20747-20755Abstract Full Text PDF PubMed Google Scholar, 18Pape M.E. Schultz P.A. Rea T.J. DeMattos R.B. Kieft K. Bisgaier C.L. Newton R.S. Krause B.R. J. Lipid Res. 1995; 36: 823-838Abstract Full Text PDF PubMed Google Scholar, 19Matsuda H. Hakamata H. Miyazaki A. Sakai M. Chang C.C.Y. Chang T.-Y. Kobori S. Shichiri M. Horiuchi S. Biochim. Biophys. Acta. 1996; 1301: 76-84Crossref PubMed Scopus (34) Google Scholar, 20Wang H. Germain S.J. Benfield P.P. Gillies P.J. Arterioscler. Thromb. Vasc. Biol. 1996; 16: 809-814Crossref PubMed Scopus (52) Google Scholar); all contain the same translational reading frame but differ in the length of the untranslated regions (21Li B.-L. Li X.-L. Duan Z.-J. Lee O. Lin S. Ma Z.-M. Chang C.C.Y. Yang X.-Y. Park J.P. Mohandas T.K. Noll W. Chan L. Chang T.-Y. J. Biol. Chem. 1999; 274: 11060-11071Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). The two shorter mRNAs are products of a proximal ACAT promoter. The 4.3-kb mRNA is derived from an unusual RNA recombination mechanism involvingtrans-splicing of two discontinuous precursor RNAs produced from chromosomes 1 and 7 (21Li B.-L. Li X.-L. Duan Z.-J. Lee O. Lin S. Ma Z.-M. Chang C.C.Y. Yang X.-Y. Park J.P. Mohandas T.K. Noll W. Chan L. Chang T.-Y. J. Biol. Chem. 1999; 274: 11060-11071Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). The origin of the 7.0-kb transcript is unknown. The human ACAT2 gene encodes a single mRNA of 2.2 kb, and the human DGAT gene encodes two mRNAs of 2.0 and 2.4 kb. Regions of shared sequence identity are present throughout the ACAT and DGAT proteins, but the greatest similarity is found in their C termini (Fig. 2). Human and mouse ACAT2 are ∼40% identical to human ACAT1, and DGAT is ∼20% identical to ACAT1.Table IProperties of ACAT/DGAT enzymesEnzymeGeneChromosomeNumber of exonsNumber of amino acidsSubstratesTissues with high levels of expressionAcyl acceptorFatty acyl-CoAsACAT1HumanSOAT11q2516550Cholesterol andWide range (includesAdrenal gland, steroidogenic tissues,MouseSoat11NR1-aNR, not reported.540various oxysterols16:0, 18:1, 18:2, and 20:4)macrophages, preputial gland (mouse),ACAT2sebaceous glands, liver (human)HumanSOAT21215522Cholesterol andWide range (includes 16:0,Liver, small intestineMouseSoat215NR525various oxysterols18:1, and 18:2)DGATHumanDGAT8qter171-bR. V. Farese, Jr., unpublished observations.488DiacylglycerolWide range (includes 16:0,Liver, small intestine, adipose tissue,MouseDgat15NR49818:1, 18:2, and 20:4)1-bR. V. Farese, Jr., unpublished observations.mammary gland, many others (lower mRNA levels)1-a NR, not reported.1-b R. V. Farese, Jr., unpublished observations. Open table in a new tab Little is known about the relationship between protein structure and function in ACAT/DGAT family members. One motif, FYXDWWN (amino acids 403–409 of human ACAT1), is highly conserved in all family members and may be involved in fatty acyl-CoA binding. Another motif, MKXXSF (amino acids 265–270 of human ACAT1), is conserved in ACAT family members. The serine of this motif is required for ACAT activity (22Joyce C.W. Shelness G.S. Davis M.A. Lee R.G. Skinner K. Anderson R.A. Rudel L.L. Mol. Biol. Cell. 2000; 11: 3675-3687Crossref PubMed Scopus (102) Google Scholar, 23Cao G. Goldstein J.L. Brown M.S. J. Biol. Chem. 1996; 271: 14642-14648Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). All three family members have a potential tyrosine phosphorylation motif and at least one N-linked glycosylation site, both of unknown significance. ACAT1 and ACAT2 contain an N-terminal leucine zipper motif. Although ACAT1 functions as a homotetramer (24Yu C. Chen J. Lin S. Liu J. Chang C.C.Y. Chang T.-Y. J. Biol. Chem. 1999; 274: 36139-36145Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar), it is unknown whether this leucine zipper motif participates in tetramer formation or whether ACAT2 and DGAT act as multimers. ACAT1 and ACAT2 do not form hetero-oligomeric complexes (25Chang C.C.Y. Sakashita N. Ornvold K. Lee O. Chang E.T. Dong R. Lin S. Lee C.-Y.G. Strom S.C. Kashyap R. Fung J.J. Farese Jr., R.V. Patoiseau J.-F. Delhon A. Chang T.Y. J. Biol. Chem. 2000; 275: 28083-28092Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). All ACAT/DGAT proteins possess multiple hydrophobic regions predicted to serve as transmembrane domains, although there is not yet a consensus structural model for the proteins. Investigations of human ACAT1 topology have yielded different results. One study, performed by inserting epitopes at different positions in the expressed protein (26Lin S. Cheng D. Liu M.-S. Chen J. Chang T.-Y. J. Biol. Chem. 1999; 274: 23276-23285Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar), found seven transmembrane domains. Another study, performed by expressing truncated forms of the protein (22Joyce C.W. Shelness G.S. Davis M.A. Lee R.G. Skinner K. Anderson R.A. Rudel L.L. Mol. Biol. Cell. 2000; 11: 3675-3687Crossref PubMed Scopus (102) Google Scholar), found five transmembrane domains. In both studies, the N terminus of the protein localized to the cytoplasm and the C terminus to the ER lumen (22Joyce C.W. Shelness G.S. Davis M.A. Lee R.G. Skinner K. Anderson R.A. Rudel L.L. Mol. Biol. Cell. 2000; 11: 3675-3687Crossref PubMed Scopus (102) Google Scholar, 26Lin S. Cheng D. Liu M.-S. Chen J. Chang T.-Y. J. Biol. Chem. 1999; 274: 23276-23285Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Topologic studies of human ACAT2 performed with the truncation mutant method also found five transmembrane domains with the N terminus in the cytoplasm and the C terminus in the ER lumen (22Joyce C.W. Shelness G.S. Davis M.A. Lee R.G. Skinner K. Anderson R.A. Rudel L.L. Mol. Biol. Cell. 2000; 11: 3675-3687Crossref PubMed Scopus (102) Google Scholar). The latter study found that a serine residue essential for ACAT activity was located in the cytoplasm for ACAT1 and in the ER lumen for ACAT2, suggesting that the active sites of these enzymes reside on opposite sides of the ER membrane. Several putative transmembrane sequences are conserved in ACAT1 and ACAT2 but not in DGAT (26Lin S. Cheng D. Liu M.-S. Chen J. Chang T.-Y. J. Biol. Chem. 1999; 274: 23276-23285Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar), suggesting that these regions are involved in cholesterol binding. The topology of DGAT has not been reported, but a putative diacylglycerol binding motif has been identified (27Oelkers P. Behari A. Cromley D. Billheimer J.T. Sturley S.L. J. Biol. Chem. 1998; 273: 26765-26771Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar). The tissue distributions of ACAT1 and ACAT2 are largely complementary. ACAT1 mRNA is present in many tissues, with the highest levels in macrophages and in adrenal and sebaceous glands (12Chang C.C.Y. Huh H.Y. Cadigan K.M. Chang T.Y. J. Biol. Chem. 1993; 268: 20747-20755Abstract Full Text PDF PubMed Google Scholar,28Uelmen P.J. Oka K. Sullivan M. Chang C.C.Y. Chang T.Y. Chan L. J. Biol. Chem. 1995; 270: 26192-26201Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 29Meiner V. Tam C. Gunn M.D. Dong L.-M. Weisgraber K.H. Novak S. Myers H.M. Erickson S.K. Farese Jr., R.V. J. Lipid Res. 1997; 38: 1928-1933Abstract Full Text PDF PubMed Google Scholar), all of which store cholesterol esters in cytoplasmic droplets. ACAT1 is also highly expressed in human atherosclerotic lesions, particularly in macrophage foam cells (30Miyazaki A. Sakashita N. Lee O. Takahashi K. Horiuchi S. Hakamata H. Morganelli P.M. Chang C.C.Y. Chang T.-Y. Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1568-1574Crossref PubMed Scopus (130) Google Scholar). ACAT2 is expressed predominantly in the liver and small intestine (27Oelkers P. Behari A. Cromley D. Billheimer J.T. Sturley S.L. J. Biol. Chem. 1998; 273: 26765-26771Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 31Cases S. Novak S. Zheng Y.-W. Myers H.M. Lear S.R. Sande E. Welch C.B. Lusis A.J. Spencer T.A. Krause B.R. Erickson S.K. Farese Jr., R.V. J. Biol. Chem. 1998; 273: 26755-26764Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar, 32Anderson R.A. Joyce C. Davis M. Reagan J.W. Clark M. Shelness G.S. Rudel L.L. J. Biol. Chem. 1998; 273: 26747-26754Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar). In humans, nonhuman primates, and mice, ACAT2 appears to be the major ACAT in the small intestine (25Chang C.C.Y. Sakashita N. Ornvold K. Lee O. Chang E.T. Dong R. Lin S. Lee C.-Y.G. Strom S.C. Kashyap R. Fung J.J. Farese Jr., R.V. Patoiseau J.-F. Delhon A. Chang T.Y. J. Biol. Chem. 2000; 275: 28083-28092Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 33Lee R.G. Willingham M.C. Davis M.A. Skinner K.A. Rudel L.L. J. Lipid Res. 2000; 41: 1991-2001Abstract Full Text Full Text PDF PubMed Google Scholar, 34Buhman K.K. Accad M. Novak S. Choi R.S. Wong J.S. Hamilton R.L. Turley S. Farese Jr., R.V. Nat. Med. 2000; 6: 1341-1347Crossref PubMed Scopus (297) Google Scholar) and the predominant isozyme in hepatocytes of nonhuman primates and mice (33Lee R.G. Willingham M.C. Davis M.A. Skinner K.A. Rudel L.L. J. Lipid Res. 2000; 41: 1991-2001Abstract Full Text Full Text PDF PubMed Google Scholar, 34Buhman K.K. Accad M. Novak S. Choi R.S. Wong J.S. Hamilton R.L. Turley S. Farese Jr., R.V. Nat. Med. 2000; 6: 1341-1347Crossref PubMed Scopus (297) Google Scholar). Whether ACAT1 or ACAT2 is the predominant enzyme in human hepatocytes is controversial. Both are expressed in human hepatocytes and HepG2 cells (25Chang C.C.Y. Sakashita N. Ornvold K. Lee O. Chang E.T. Dong R. Lin S. Lee C.-Y.G. Strom S.C. Kashyap R. Fung J.J. Farese Jr., R.V. Patoiseau J.-F. Delhon A. Chang T.Y. J. Biol. Chem. 2000; 275: 28083-28092Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). However, immunodepletion experiments found that ACAT1 accounts for ∼90% of ACAT activity in human liver (35Lee O. Chang C.C.Y. Lee W. Chang T.-Y. J. Lipid Res. 1998; 39: 1722-1727Abstract Full Text Full Text PDF PubMed Google Scholar), whereas ACAT2 accounts for most of the ACAT activity in adult small intestine and fetal liver but only 10–20% of activity in adult liver (25Chang C.C.Y. Sakashita N. Ornvold K. Lee O. Chang E.T. Dong R. Lin S. Lee C.-Y.G. Strom S.C. Kashyap R. Fung J.J. Farese Jr., R.V. Patoiseau J.-F. Delhon A. Chang T.Y. J. Biol. Chem. 2000; 275: 28083-28092Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). It is unclear whether the hepatic ACAT1 activity resides in hepatocytes or macrophage-derived Kupffer cells. ACAT1 expression was detected immunohistochemically in both cell types, with stronger staining in Kupffer cells (36Sakashita N. Miyazaki A. Takeya M. Horiuchi S. Chang C.C.Y. Chang T.-Y. Takahashi K. Am. J. Pathol. 2000; 156: 227-236Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). In nonhuman primates, ACAT1 was expressed only in Kupffer cells in the liver (33Lee R.G. Willingham M.C. Davis M.A. Skinner K.A. Rudel L.L. J. Lipid Res. 2000; 41: 1991-2001Abstract Full Text Full Text PDF PubMed Google Scholar). A significant proportion of the ACAT1 activity in human liver thus may be attributable to Kupffer cells. Another study found little evidence of ACAT2 expression in human hepatocytes (25Chang C.C.Y. Sakashita N. Ornvold K. Lee O. Chang E.T. Dong R. Lin S. Lee C.-Y.G. Strom S.C. Kashyap R. Fung J.J. Farese Jr., R.V. Patoiseau J.-F. Delhon A. Chang T.Y. J. Biol. Chem. 2000; 275: 28083-28092Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). DGAT mRNA and activity are ubiquitous in mouse and human tissues, with the highest levels in liver, small intestine, and adipose tissue (11Farese Jr., R.V. Cases S. Smith S.J. Curr. Opin. Lipidol. 2000; 11: 229-234Crossref PubMed Scopus (122) Google Scholar, 27Oelkers P. Behari A. Cromley D. Billheimer J.T. Sturley S.L. J. Biol. Chem. 1998; 273: 26765-26771Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 37Cases S. Smith S.J. Zheng Y.-W. Myers H.M. Lear S.R. Sande E. Novak S. Collins C. Welch C.B. Lusis A.J. Erickson S.K. Farese Jr., R.V. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13018-13023Crossref PubMed Scopus (886) Google Scholar, 38Smith S.J. Cases S. Jensen D.R. Chen H.C. Sande E. Tow B. Sanan D.A. Raber J. Eckel R.H. Farese Jr., R.V. Nat. Genet. 2000; 25: 87-90Crossref PubMed Scopus (743) Google Scholar) and somewhat lower levels in testis and adrenal gland (11Farese Jr., R.V. Cases S. Smith S.J. Curr. Opin. Lipidol. 2000; 11: 229-234Crossref PubMed Scopus (122) Google Scholar). This wide range of tissue expression is consistent with the involvement of DGAT in the glycerol phosphate pathway of triglyceride synthesis, which is common to most cells. DGAT protein expression in tissues has not been studied because of the lack of suitable antibodies. The intracellular localization of enzymes in this class has been examined only for ACAT1. In human melanoma cells and fibroblasts and in mouse macrophages, ACAT1 is located primarily in the ER (36Sakashita N. Miyazaki A. Takeya M. Horiuchi S. Chang C.C.Y. Chang T.-Y. Takahashi K. Am. J. Pathol. 2000; 156: 227-236Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 39Chang C.C.Y. Chen J. Thomas M.A. Cheng D. Del Priore V.A. Newton R.S. Pape M.E. Chang T.-Y. J. Biol. Chem. 1995; 270: 29532-29540Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 40Khelef N. Buton X. Beatini N. Wang H. Meiner V. Chang T.-Y. Farese Jr., R.V. Maxfield F.R. Tabas I. J. Biol. Chem. 1998; 273: 11218-11224Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). In mouse macrophages, a small portion of ACAT1 immunoreactivity localizes to a region near the trans-Golgi network (40Khelef N. Buton X. Beatini N. Wang H. Meiner V. Chang T.-Y. Farese Jr., R.V. Maxfield F.R. Tabas I. J. Biol. Chem. 1998; 273: 11218-11224Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 41Khelef N. Soe T.T. Quehenberger O. Beatini N. Tabas I. Maxfield F.R. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1769-1776Crossref PubMed Google Scholar). In macrophages, ACAT1 localization may change with different conditions (36Sakashita N. Miyazaki A. Takeya M. Horiuchi S. Chang C.C.Y. Chang T.-Y. Takahashi K. Am. J. Pathol. 2000; 156: 227-236Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 40Khelef N. Buton X. Beatini N. Wang H. Meiner V. Chang T.-Y. Farese Jr., R.V. Maxfield F.R. Tabas I. J. Biol. Chem. 1998; 273: 11218-11224Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). ACAT and DGAT substrates have been identified by expressing the proteins in insect cells or yeast devoid of sterol esterification activity. In insect cells, mouse and human ACAT1 and ACAT2 utilize a variety of oxysterols in addition to cholesterol as substrates (31Cases S. Novak S. Zheng Y.-W. Myers H.M. Lear S.R. Sande E. Welch C.B. Lusis A.J. Spencer T.A. Krause B.R. Erickson S.K. Farese Jr., R.V. J. Biol. Chem. 1998; 273: 26755-26764Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar,42Cheng D. Chang C.C.Y. Qu X.-M. Chang T.-Y. J. Biol. Chem. 1995; 270: 685-695Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). Ergosterol and plant sterols are poor substrates (31Cases S. Novak S. Zheng Y.-W. Myers H.M. Lear S.R. Sande E. Welch C.B. Lusis A.J. Spencer T.A. Krause B.R. Erickson S.K. Farese Jr., R.V. J. Biol. Chem. 1998; 273: 26755-26764Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar, 43Yang H. Cromley D. Wang H. Billheimer J.T. Sturley S.L. J. Biol. Chem. 1997; 272: 3980-3985Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). Both enzymes also utilize a wide variety of long chain fatty acyl-CoAs as substrates (31Cases S. Novak S. Zheng Y.-W. Myers H.M. Lear S.R. Sande E. Welch C.B. Lusis A.J. Spencer T.A. Krause B.R. Erickson S.K. Farese Jr., R.V. J. Biol. Chem. 1998; 273: 26755-26764Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar), although appears to be a for ACAT1 than ACAT2 (31Cases S. Novak S. Zheng Y.-W. Myers H.M. Lear S.R. Sande E. Welch C.B. Lusis A.J. Spencer T.A. Krause B.R. Erickson S.K. Farese Jr., R.V. J. Biol. Chem. 1998; 273: 26755-26764Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar, 43Yang H. Cromley D. Wang H. Billheimer J.T. Sturley S.L. J. Biol. Chem. 1997; 272: 3980-3985Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). In insect cells, DGAT only diacylglycerol as the acyl acceptor S. Smith S.J. Zheng Y.-W. Myers H.M. Lear S.R. Sande E. Novak S. Collins C. Welch C.B. Lusis A.J. Erickson S.K. Farese Jr., R.V. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13018-13023Crossref PubMed Scopus (886) Google Scholar). DGAT has a fatty acyl-CoA S. Smith S.J. Zheng Y.-W. Myers H.M. Lear S.R. Sande E. Novak S. Collins C. Welch C.B. Lusis A.J. Erickson S.K. Farese Jr., R.V. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13018-13023Crossref PubMed Scopus (886) Google Scholar). ACAT1 is primarily by T.Y. Chang C.C.Y. Cheng D. Annu. Rev. Biochem. 1997; 66: 613-638Crossref PubMed Scopus (442) Google Scholar). In cells, esterification in the expression of ACAT1 mRNA H. Hakamata H. Miyazaki A. Sakai M. Chang C.C.Y. Chang T.-Y. Kobori S. Shichiri M. Horiuchi S. Biochim. Biophys. Acta. 1996; 1301: 76-84Crossref PubMed Scopus (34) Google Scholar, 20Wang H. Germain S.J. Benfield P.P. Gillies P.J. Arterioscler. Thromb. Vasc. Biol. 1996; 16: 809-814Crossref PubMed Scopus (52) Google Scholar, T.J. DeMattos R.B. R. Newton R.S. Pape M.E. Biochim. Biophys. Acta. 1996; PubMed Scopus Google Scholar) or protein H. Germain S.J. Benfield P.P. Gillies P.J. Arterioscler. Thromb. Vasc. Biol. 1996; 16: 809-814Crossref PubMed Scopus (52) Google Scholar, C. Chen J. Lin S. Liu J. Chang C.C.Y. Chang T.-Y. J. Biol. Chem. 1999; 274: 36139-36145Abstract Full Text Full Text PDF PubMed Scopus (65) Google C.C.Y. Noll N. A. Chang W. Chang T.Y. Cell Mol. Genet. 20: PubMed Scopus Google Scholar). ACAT1 is by cholesterol or oxysterols C.C.Y. Lee C.-Y.G. Chang E.T. M.C. Chang T.-Y. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). ACAT1 activity may also be by intracellular a portion of ACAT1 immunoreactivity in macrophages is found near network and the N. Soe T.T. Quehenberger O. Beatini N. Tabas I. Maxfield F.R. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1769-1776Crossref PubMed Google Scholar). These are involved in with the and the of ACAT1 to these may be important for cholesterol ester synthesis during the formation of macrophage foam cells. The that of ACAT1 from the ER to small during foam cell formation is consistent with this (36Sakashita N. Miyazaki A. Takeya M. Horiuchi S. Chang C.C.Y. Chang T.-Y. Takahashi K. Am. J. Pathol. 2000; 156: 227-236Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). by phosphorylation has not been ACAT1 is also only the expression levels of the shorter ACAT1 mRNAs and In mice P.J. Oka K. Sullivan M. Chang C.C.Y. Chang T.Y. Chan L. J. Biol. Chem. 1995; 270: 26192-26201Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar) and M.E. Schultz P.A. Rea T.J. DeMattos R.B. Kieft K. Bisgaier C.L. Newton R.S. Krause B.R. J. Lipid Res. 1995; 36: 823-838Abstract Full Text PDF PubMed Google Scholar), a and ACAT1 mRNA levels in the In human HepG2 cells, fatty but not ACAT1 mRNA levels T. P.M. Sturley S.L. Deckelbaum R.J. 2001; PubMed Scopus Google Scholar). ACAT1 mRNA and protein expression levels also during the of macrophages H. Germain S.J. Benfield P.P. Gillies P.J. 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