Monoacylglycerol O-acyltransferase 1 (MGAT1) localizes to the ER and lipid droplets promoting triacylglycerol synthesis
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Monoacylglycerol acyltransferase 1 (MGAT) is a microsomal enzyme that catalyzes the synthesis of diacylglycerol (DAG) and triacylglycerol (TAG). However, the subcellular localization and catalytic function domain of this enzyme is poorly understood. In this report, we identified that murine MGAT1 localizes to the endoplasmic reticulum (ER) under normal conditions, whereas MGAT1 co-localize to the lipid droplets (LD) under conditions of enriching fatty acids, contributing to TAG synthesis and LD expansion. For the enzyme activity, both the N-terminal transmembrane domain and catalytic HPHG motif are required. We also show that the transmembrane domain of MGAT1 consists of two hydrophobic regions in the N-terminus, and the consensus sequence FLXLXXXn, a putative neutral lipid-binding domain, exists in the first transmembrane domain. Finally, MGAT1 interacts with DGAT2, which serves to synergistically increase the TAG biosynthesis and LD expansion, leading to enhancement of lipid accumulation in the liver and fat.
Abstract
Monoacylglycerol acyltransferase 1 (MGAT) is a microsomal enzyme that catalyzes the synthesis of diacylglycerol (DAG) and triacylglycerol (TAG). However, the subcellular localization and catalytic function domain of this enzyme is poorly understood. In this report, we identified that murine MGAT1 localizes to the endoplasmic reticulum (ER) under normal conditions, whereas MGAT1 co-localize to the lipid droplets (LD) under conditions of enriching fatty acids, contributing to TAG synthesis and LD expansion. For the enzyme activity, both the N-terminal transmembrane domain and catalytic HPHG motif are required. We also show that the transmembrane domain of MGAT1 consists of two hydrophobic regions in the N-terminus, and the consensus sequence FLXLXXXn, a putative neutral lipid-binding domain, exists in the first transmembrane domain. Finally, MGAT1 interacts with DGAT2, which serves to synergistically increase the TAG biosynthesis and LD expansion, leading to enhancement of lipid accumulation in the liver and fat.
참고문헌 (33)
- Marchesini G, "Nonalcoholic fatty liver disease: a feature of the metabolic syndrome", Diabetes, 50, pp.1844~1850 (2001)
- Angulo P, "Nonalcoholic fatty liver disease", N Engl J Med, 346, pp.1221~1231 (2002)
- Hamaguchi M, "The metabolic syndrome as a predictor of nonalcoholic fatty liver disease", Ann Intern Med, 143, pp.722~728 (2005)
- Brunt EM, "Pathology of nonalcoholic fatty liver disease", Nat Rev Gastroenterol Hepatol, 7, pp.195~203 (2010)
- Phan CT, "Intestinal lipid absorption and transport", Front Biosci, 6, pp.D299~D319 (2001)
- 이유정, "New mechanisms contributing to hepatic steatosis: glucose, insulin, and lipid signaling", Animal Cells and Systems, 18(2), pp.77~82 (2014), 한국통합생물학회[DOI]
- Shi Y, "Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism", Am J Physiol Endocrinol Metab, 297, pp.E10~E18 (2009)
- Yen CL, "Identification of a gene encoding MGAT1, a monoacylglycerol acyltransferase", Proc Natl Acad Sci U S A, 99, pp.8512~8517 (2002)
- Cheng D, "Identification of acyl coenzyme A:monoacylglycerol acyltransferase 3, an intestinal specific enzyme implicated in dietary fat absorption", J Biol Chem, 278, pp.13611~13614 (2003)
- Yen CL, "MGAT2, a monoacylglycerol acyltransferase expressed in the small intestine", J Biol Chem, 278, pp.18532~18537 (2003)
- Cao J, "A predominant role of acyl-CoA:monoacylglycerol acyltransferase-2 in dietary fat absorption implicated by tissue distribution, subcellular localization, and up-regulation by high fat diet", J Biol Chem, 279, pp.18878~18886 (2004)
- Yue YG, "The acyl coenzymeA:monoacylglycerol acyltransferase 3 (MGAT3) gene is a pseudogene in mice but encodes a functional enzyme in rats", Lipids, 46, pp.513~520 (2011)
- Cao J, "Catalytic properties of MGAT3, a putative triacylgycerol synthase", J Lipid Res, 48, pp.583~591 (2007)
- Holmes RS, "Comparative genomics and proteomics of vertebrate diacylglycerol acyltransferase (DGAT), acyl CoA wax alcohol acyltransferase (AWAT) and monoacylglycerol acyltransferase (MGAT)", Comp Biochem Physiol Part D Genomics Proteomics, 5, pp.45~54 (2010)
- Lockwood JF, "Human intestinal monoacylglycerol acyltransferase: differential features in tissue expression and activity", Am J Physiol Endocrinol Metab, 285, pp.E927~E937 (2003)
- Hayashi Y, "Hepatic Monoacylglycerol O- acyltransferase 1 as a Promising Therapeutic Target for Steatosis, Obesity, and Type 2 Diabetes", Mol Ther Nucleic Acids, 3, pp.e154~ (2014)
- Lee YJ, "Nuclear receptor PPARgamma-regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis", Proc Natl Acad Sci U S A, 109, pp.13656~13661 (2012)
- Hall AM, "Evidence for regulated monoacylglycerol acyltransferase expression and activity in human liver", J Lipid Res, 53, pp.990~999 (2012)
- Yu JH, "Monoacylglycerol O-acyltransferase 1 is regulated by peroxisome proliferator-activated receptor gamma in human hepatocytes and increases lipid accumulation", Biochem Biophys Res Commun, 460, pp.715~720 (2015)
- Reddy RK, "Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation", J Biol Chem, 278, pp.20915~20924 (2003)
- Stone SJ, "Membrane topology and identification of key functional amino acid residues of murine acyl-CoA:diacylglycerol acyltransferase- 2", J Biol Chem, 281, pp.40273~40282 (2006)
- Thiam AR, "The biophysics and cell biology of lipid droplets", Nat Rev Mol Cell Biol, 14, pp.775~786 (2013)
- Wilfling F, "Lipid droplet biogenesis", Curr Opin Cell Biol, 29, pp.39~45 (2014)
- Wilfling F, "The endoplasmic reticulum enzyme DGAT2 is found in mitochondria-associated membranes and has a mitochondrial targeting signal that promotes its association with mitochondria", J Biol Chem, 284, pp.5352~5361 (2009)
- Wilfling F, "Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets", Dev Cell, 24, pp.384~399 (2013)
- Cheng D, "Human acyl-CoA:diacylglycerol acyltransferase is a tetrameric protein", Biochem J, 359, pp.707~714 (2001)
- McFie PJ, "Topological orientation of acyl-CoA:diacylglycerol acyltransferase- 1 (DGAT1) and identification of a putative active site histidine and the role of the n terminus in dimer", tetramer formation, 2010, pp.285, 37377~37387
- Zhang J, "Monoacylglycerol acyltransferase-2 is a tetrameric enzyme that selectively heterodimerizes with diacylglycerol acyltransferase-1", J Biol Chem, 289, pp.10909~10918 (2014)
- Jin Y, "Diacylglycerol acyltransferase-2 (DGAT2) and monoacylglycerol acyltransferase-2 (MGAT2) interact to promote triacylglycerol synthesis", J Biol Chem, 289, pp.28237~28248 (2014)
- Hall AM, "Abrogating monoacylglycerol acyltransferase activity in liver improves glucose tolerance and hepatic insulin signaling in obese mice", Diabetes, 63, pp.2284~2296 (2014)
- Soufi N, "Inhibiting monoacylglycerol acyltransferase 1 ameliorates hepatic metabolic abnormalities but not inflammation and injury in mice", J Biol Chem, 289, pp.30177~30188 (2014)
- Alam M, "Mutation of F417 but not of L418 or L420 in the lipid binding domain decreases the activity of triacylglycerol hydrolase", J Lipid Res, 47, pp.375~383 (2006)
- Cao J, "Targeting Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases", J Biol Chem, 286, pp.41838~41851 (2011)