Acyl-coenzyme A: cholesterol acyltransferase family

Abstract

The enzymes of the acyl-coenzyme A: cholesterol acyltransferase (ACAT) family are responsible for the in vivo synthesis of neutral lipids. They are potential drug targets for the intervention of atherosclerosis, hyperlipidemia, obesity, type II diabetes and even Alzheimer’s disease. ACAT family enzymes are integral endoplasmic reticulum (ER) membrane proteins and can be divided into ACAT branch and acyl-coenzyme A: diacylglycerol acyltransferase 1 (DGAT1) branch according to their substrate specificity. The ACAT branch catalyzes synthesis of cholesteryl esters using long-chain fatty acyl-coenzyme A and cholesterol as substrates, while the DGAT1 branch catalyzes synthesis of triacylglycerols using fatty acyl-coenzyme A and diacylglycerol as substrates. In this review, we mainly focus on the recent progress in the structural research of ACAT family enzymes, including their disulfide linkage, membrane topology, subunit interaction and catalysis mechanism.

Keywords

lipid / acyl-coenzyme A: cholesterol acyltransferase (ACAT) / acyl-coenzyme A: diacylglycerol acyltransferase 1 (DGAT1) / acyltransferase / catalysis

References

[1] Anderson R A, Joyce C, Davis M, Reagan J W, Clark M, Shelness G S, Rudel L L (1998). Identification of a form of acyl-CoA:cholesterol acyltransferase specific to liver and intestine in nonhuman primates. J Biol Chem, 273: 26747-26754

[2] Beck B, Drevon C A (1978). Properties and subcellular distribution of acyl-CoA: cholesterol acyltransferase (ACAT) in guinea-pig liver. Scand J Gastroenterol, 13: 97-105

[3] Buhman K F, Accad M, Farese R V (2000). Mammalian acyl-CoA: cholesterol acyltransferases. Biochim Biophys Acta, 1529: 142-154

[4] Cadigan K M, Chang C C, Chang T Y (1989). Isolation of Chinese hamster ovary cell lines expressing human acyl-coenzyme A/cholesterol acyltransferase activity. J Cell Biol, 108: 2201-2210

[5] Cadigan K M, Heider J G, Chang T Y (1988). Isolation and characterization of Chinese hamster ovary cell mutants deficient in acyl-coenzyme A: cholesterol acyltransferase activity. J Biol Chem, 263: 274-282

[6] Cases 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 R V Jr (1998a). ACAT-2, a second mammalian acyl-CoA: cholesterol acyltransferase. Its cloning, expression, and characterization. J Biol Chem, 273: 26755-26764

[7] Cases 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 R V Jr (1998b). Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci USA, 95: 13018-13023

[8] Cases S, Stone S J, Zhou P, Yen E, Tow B, Lardizabal K D, Voelker T, Farese R V Jr (2001). Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem, 276: 38870-38876

[9] Chang C, Dong R, Miyazaki A, Sakashita N, Zhang Y, Liu J, Guo M, Li B L, Chang T Y (2006). Human acyl-CoA: cholesterol acyltransferase (ACAT) and its potential as a target for pharmaceutical intervention against atherosclerosis. Acta Biochim Biophys Sin (Shanghai), 38: 151-156

[10] Chang C C, Chen J, Thomas MA, Cheng D, Del Priore V A, Newton R S, Pape M E, Chang T Y (1995). Regulation and immunolocalization of acyl-coenzyme A: cholesterol acyltransferase in mammalian cells as studied with specific antibodies. J Biol Chem, 270: 29532-29540

[11] Chang C C, Huh H Y, Cadigan K M, Chang T Y (1993). Molecular cloning and functional expression of human acyl-coenzyme A: cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells. J Biol Chem, 268: 20747-20755

[12] Chang C C, Lee C Y, Chang E T, Cruz J C, Levesque M C, Chang T Y (1998). Recombinant acyl-CoA: cholesterol acyltransferase-1 (ACAT-1) purified to essential homogeneity utilizes cholesterol in mixed micelles or in vesicles in a highly cooperative manner. J Biol Chem, 273: 35132-35141

[13] Chang C C, Sakashita N, Ornvold K, Lee O, Chang E T, Dong R, Lin S, Lee C Y, Strom S C, Kashyap R, Fung J J, Farese R V Jr, Patoiseau J F, Delhon A, Chang T Y (2000). Immunological quantitation and localization of ACAT-1 and ACAT-2 in human liver and small intestine. J Biol Chem, 275: 28083-28092

[14] Chang T Y, Chang C C, Cheng D (1997). Acyl-coenzyme A: cholesterol acyltransferase. Annu Rev Biochem, 66: 613-638

[15] Chang T Y, Chang C C, Lin S, Yu C, Li B L, Miyazaki A (2001a). Roles of acyl-coenzyme A:cholesterol acyltransferase-1 and-2. Curr Opin Lipidol, 12: 289-296

[16] Chang T Y, Chang C C, Lu X, Lin S (2001b). Catalysis of ACAT may be completed within the plane of the membrane: a working hypothesis. J Lipid Res, 42: 1933-1938

[17] Chen H C, Farese R V Jr (2000). DGAT and triglyceride synthesis: a new target for obesity treatment? Trends Cardiovasc Med, 10: 188-192

[18] Chen H C, Farese R V Jr (2005). Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. Arterioscler Thromb Vasc Biol, 25: 482-486

[19] Chen H C, Jensen D R, Myers H M, Eckel R H, Farese R V Jr (2003a). Obesity resistance and enhanced glucose metabolism in mice transplanted with white adipose tissue lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Invest, 111: 1715-1722

[20] Chen H C, Ladha Z, Smith S J, Farese R V Jr (2003b). Analysis of energy expenditure at different ambient temperatures in mice lacking DGAT1. Am J Physiol Endocrinol Metab, 284: E213-218

[21] Chen H C, Smith S J, Ladha Z, Jensen D R, Ferreira L D, Pulawa L K, McGuire J G, Pitas R E, Eckel R H, Farese R V Jr (2002a). Increased insulin and leptin sensitivity in mice lacking acyl CoA: diacylglycerol acyltransferase 1. J Clin Invest, 109: 1049-1055

[22] Chen H C, Stone S J, Zhou P, Buhman K K, Farese R V Jr (2002b). Dissociation of obesity and impaired glucose disposal in mice overexpressing acyl coenzyme a: diacylglycerol acyltransferase 1 in white adipose tissue. Diabetes, 51: 3189-3195

[23] Chen N, Liu L, Zhang Y, Ginsberg H N, Yu Y H (2005). Whole-body insulin resistance in the absence of obesity in FVB mice with overexpression of Dgat1 in adipose tissue. Diabetes, 54: 3379-3386

[24] Cheng D, Chang C C, Qu X, Chang T Y (1995). Activation of acyl-coenzyme A: cholesterol acyltransferase by cholesterol or by oxysterol in a cell-free system. J Biol Chem, 270: 685-695

[25] Cheng D, Meegalla R L, He B, Cromley D A, Billheimer J T, Young P R (2001). Human acyl-CoA: diacylglycerol acyltransferase is a tetrameric protein. Biochem J, 359: 707-714

[26] Drevon C A, Norum K R (1975). Cholesterol esterification and lipids in plasma and liver from newborn and young guinea pigs raised on milk and non-milk diet. Nutr Metab, 18: 137-151

[27] Farese R V Jr (1998). Acyl CoA: cholesterol acyltransferase genes and knockout mice. Curr Opin Lipidol, 9: 119-123

[28] Fazio S, Linton M (2006). Failure of ACAT inhibition to retard atherosclerosis. N Engl J Med, 354: 1307-1309

[29] Guo Z Y, Chang C C, Chang T Y (2007). Functionality of the seventh and eighth transmembrane domains of acyl-coenzyme A: cholesterol acyltransferase 1. Biochemistry, 46: 10063-10071

[30] Guo Z Y, Chang C C, Lu X, Chen J, Li B L, Chang T Y (2005a). The disulfide linkage and the free sulfhydryl accessibility of acyl-coenzyme A: cholesterol acyltransferase 1 as studied by using mPEG5000-maleimide. Biochemistry, 44: 6537-6546

[31] Guo Z Y, Lin S, Heinen J A, Chang C C, Chang T Y (2005b). The active site His-460 of human acyl-coenzyme A: cholesterol acyltransferase 1 resides in a hitherto undisclosed transmembrane domain. J Biol Chem, 280: 37814-37826

[32] Haugen R, Norum K R (1976). Coenzyme-A-dependent esterification of cholesterol in rat intestinal mucosa. Scand J Gastroenterol, 11: 615-621

[33] Hofmann K (2000). A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. Trends Biochem Sci, 25: 111-112

[34] Hutter-Paier B, Huttunen H J, Puglielli L, Eckman C B, Kim D Y, Hofmeister A, Moir R D, Domnitz S B, Frosch M P, Windisch M, Kovacs D M (2004). The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease. Neuron, 44: 227-238

[35] Huttunen HJ, Greco C, Kovacs DM (2007). Knockdown of ACAT-1 reduces amyloidogenic processing of APP. FEBS Lett, 581: 1688-1692

[36] Joyce C W, Shelness G S, Davis M A, Lee R G, Skinner K, Anderson R A, Rudel L L (2000). ACAT1 and ACAT2 membrane topology segregates a serine residue essential for activity to opposite sides of the endoplasmic reticulum membrane. Mol Biol Cell, 11: 3675-3687

[37] Katzen F, Beckwith J (2003). Role and location of the unusual redox-active cysteines in the hydrophobic domain of the transmembrane electron transporter DsbD. Proc Natl Acad Sci USA, 100: 10471-10476

[38] Khelef N, Buton X, Beatini N, Wang H, Meiner V, Chang T Y, Farese R V Jr, Maxfield F R, Tabas I (1998). Immunolocalization of acyl-coenzyme A: cholesterol O-acyltransferase in macrophages. J Biol Chem, 273: 11218-11224

[39] Kosolapov A., Deutsch C (2003). Folding of the voltage-gated K⁺ channel T1 recognition domain. J Biol Chem, 287: 4305-4313

[40] Lee O, Chang C C, Lee W, Chang T Y (1998). Immunodepletion experiments suggest that acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) protein plays a major catalytic role in adult human liver, adrenal gland, macrophages, and kidney, but not in intestines. J Lipid Res, 39: 1722-1727

[41] Lee R G, Willingham M C, Davis M A, Skinner K A, Rudel L L (2000). Differential expression of ACAT1 and ACAT2 among cells within liver, intestine, kidney, and adrenal of nonhuman primates. J Lipid Res, 41: 1991-2001

[42] Lin S, Cheng D, Liu M S, Chen J, Chang T Y (1999). Human acyl-CoA: cholesterol acyltransferase-1 in the endoplasmic reticulum contains seven transmembrane domains. J Biol Chem, 274: 23276-23285

[43] Lin S, Lu X, Chang C C, Chang T Y (2003). Human acyl-coenzyme A: cholesterol acyltransferase expressed in Chinese hamster ovary cells: membrane topology and active site location. Mol Biol Cell, 14: 2447-2460

[44] Liu J, Chang C C, Westover E J, Covey D F, Chang T Y (2005). Investigating the allosterism of acyl-CoA: cholesterol acyltransferase (ACAT) by using various sterols: in vitro and intact cell studies. Biochem J, 391: 389-397

[45] Lu X, Lin S, Chang C C, Chang T Y (2002). Mutant acyl-coenzyme A: cholesterol acyltransferase 1 devoid of cysteine residues remains catalytically active. J Biol Chem, 277: 711-718

[46] Lu J, Deutsch C (2001). Pegylation: a method for assessing the topology accessibility in Kv1.3. Biochemistry, 40: 13288-13301

[47] Matynia A, Anagnostaras S G, Wiltgen B J, Lacuesta M, Fanselow M S, Silva A J (2008). A high through-put reverse genetic screen identifies two genes involved in remote memory in mice. PLoS ONE, 3: e2121

[48] Meiner V L, Cases S, Myers H M, Sande E R, Bellosta S, Schambelan M, Pitas R E, McGuire J, Herz J, Farese R V Jr (1996). Disruption of the acyl-CoA: cholesterol acyltransferase gene in mice: evidence suggesting multiple cholesterol esterification enzymes in mammals. Proc Natl Acad Sci USA, 93: 14041-14046

[49] Miyazaki A, Kanome T, Watanabe T (2005). Inhibitors of acyl-coenzyme a: cholesterol acyltransferase. Curr Drug Targets Cardiovasc Haematol Disord, 5: 463-469

[50] Miyazaki A, Sakashita N, Lee O, Takahashi K, Horiuchi S, Hakamata H, Morganelli P M, Chang C C, Chang T Y (1998). Expression of ACAT-1 protein in human atherosclerotic lesions and cultured human monocytes-macrophages. Arterioscler Thromb Vasc Biol, 18: 1568-1574

[51] Nissen S E, Tuzcu E M, Brewer H B, Sipahi I, Nicholls S J, Ganz P, Schoenhagen P, Waters D D, Pepine C J, Crowe T D, Davidson M H, Deanfield J E, Wisniewski L M, Hanyok J J, Kassalow L M; ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Investigators (2006). Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med, 354: 1253-1263 (Erratum in: N Engl J Med, 355: 638)

[52] Norum K R, Lilljeqvist A C, Drevon C A (1977). Coenzyme-A-dependent esterification of cholesterol in intestinal mucosa from guinea-pig. Influence of diet on the enzyme activity. Scand J Gastroenterol, 12: 281-288

[53] Oelkers P, Behari A, Cromley D, Billheimer J T, Sturley S L (1998). Characterization of two human genes encoding acyl coenzyme A: cholesterol acyltransferase-related enzymes. J Biol Chem, 273: 26765-26771

[54] Orland M D, Anwar K, Cromley D, Chu C H, Chen L, Billheimer J T, Hussain M M, Cheng D (2005). Acyl coenzyme A dependent retinol esterification by acyl coenzyme A: diacylglycerol acyltransferase 1. Biochim Biophys Acta, 1737: 76-82

[55] Puglielli L, Konopka G, Pack-Chung E, Ingano L A, Berezovska O, Hyman B T, Chang T Y, Tanzi R E, Kovacs D M (2001). Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol, 3: 905-912

[56] Rudel L L, Lee R G, Cockman T L (2001). Acyl coenzyme A: cholesterol acyltransferase types 1 and 2: structure and function in atherosclerosis. Curr Opin Lipidol, 12: 121-127

[57] Sakashita N, Miyazaki A, Takeya M, Horiuchi S, Chang C C, Chang T Y, Takahashi K (2000). Localization of human acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) in macrophages and in various tissues. Am J Pathol, 156: 227-236

[58] Smith S J, Cases S, Jensen D R, Chen H C, Sande E, Tow B, Sanan D A, Raber J, Eckel R H, Farese R V Jr (2000). Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet, 25: 87-90

[59] Tardif J C, Grégoire J, L'Allier P L, Anderson T J, Bertrand O, Reeves F, Title L M, Alfonso F, Schampaert E, Hassan A, McLain R, Pressler M L, Ibrahim R, Lespérance J, Blue J, Heinonen T, Rodés-Cabau J; Avasimibe and Progression of Lesions on UltraSound (A-PLUS) Investigators (2004). Effects of the acyl coenzyme A: cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation, 110: 3372-3377

[60] Turkish A R, Henneberry A L, Cromley D, Padamsee M, Oelkers P, Bazzi H, Christiano A M, Billheimer J T, Sturley S L (2005). Identification of two novel human acyl-CoA wax alcohol acyltransferases: members of the diacylglycerol acyltransferase 2 (DGAT2) gene superfamily. J Biol Chem, 280: 14755-14764

[61] Uelmen PJ, Oka K, Sullivan M, Chang C C, Chang T Y, Chan L (1995). Tissue-specific expression and cholesterol regulation of acylcoenzyme A: cholesterol acyltransferase (ACAT) in mice. Molecular cloning of mouse ACAT cDNA, chromosomal localization, and regulation of ACAT in vivo and in vitro. J Biol Chem, 270: 26192-26201

[62] Wongsiriroj N, Piantedosi R, Palczewski K, Goldberg I J, Johnston T P, Li E, Blaner W S (2008). The molecular basis of retinoid absorption: a genetic dissection. J Biol Chem, 283: 13510-13519

[63] Yang H, Bard M, Bruner DA, Gleeson A, Deckelbaum R J, Aljinovic G, Pohl T M, Rothstein R, Sturley S L (1996). Sterol esterification in yeast: a two-gene process. Science, 272: 1353-1356

[64] Yen C L, Monetti M, Burri B J, Farese R V Jr (2005). The triacylglycerol synthesis enzyme DGAT1 also catalyzes the synthesis of diacylglycerols, waxes, and retinyl esters. J Lipid Res, 46: 1502-1511

[65] Yu C, Chen J, Lin S, Liu J, Chang C C, Chang T Y (1999). Human acyl-CoA: cholesterol acyltransferase-1 is a homotetrameric enzyme in intact cells and in vitro. J Biol Chem, 274: 36139-36145

[66] Yu C, Kennedy N J, Chang C C, Rothblatt J A (1996). Molecular cloning and characterization of two isoforms of Saccharomyces cerevisiae acyl-CoA: sterol acyltransferase. J Biol Chem, 271: 24157-24163

[67] Yu C, Zhang Y, Lu X, Chen J, Chang C C, Chang T Y (2002). Role of the N-terminal hydrophilic domain of acyl-coenzyme A: cholesterol acyltransferase 1 on the enzyme's quaternary structure and catalytic efficiency. Biochemistry, 41: 3762-3769

[68] Zhang Y, Yu C, Liu J, Spencer T A, Chang C C, Chang T Y (2003). Cholesterol is superior to 7-ketocholesterol or 7 alpha-hydroxycholesterol as an allosteric activator for acyl-coenzyme A: cholesterol acyltransferase 1. J Biol Chem, 278: 11642-11647

[69] Zhao G, Souers A J, Voorbach M, Falls H D, Droz B, Brodjian S, Lau Y Y, Iyengar R R, Gao J, Judd A S, Wagaw S H, Ravn M M, Engstrom K M, Lynch J K, Mulhern M M, Freeman J, Dayton B D, Wang X, Grihalde N, Fry D, Beno D W, Marsh K C, Su Z, Diaz G J, Collins C A, Sham H, Reilly R M, Brune M E, Kym P R (2008). Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor. J Med Chem, 51: 380-383

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg