The Enzymes of Neutral Lipid Synthesis

Abstract

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 gen