title: Gly482Ser mutation impairs the effects of peroxisome proliferator-activated receptor γ coactivator-1α on decreasing fat deposition and stimulating phosphoenolpyruvate carboxykinase expression in hepatocytes.
abstract: Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a transcriptional coactivator of nuclear receptor peroxisome proliferator-activated receptor γ that critically regulates glucose and fat metabolism. Although clinical evidence suggests that Gly482Ser polymorphism of PGC-1α is associated with an increased incidence of nonalcoholic fatty liver disease, a direct role for Gly482Ser mutation in altering PGC-1α actions on hepatocyte fat deposition remains to be explored. We hypothesized that Gly482Ser mutation impairs the abilities of PGC-1α in ameliorating overnutrition-induced hepatocyte fat deposition and in stimulating hepatocyte expression of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; encoded by a key PGC-1α target gene). In the present study, treatment of cultured hepatocytes with palmitate induced fat deposition, serving as a cell model of hepatic steatosis. Upon overexpression of wild-type PGC-1α, H4IIE cells exhibited a significant decrease in palmitate-induced hepatocyte fat deposition compared with control cells and/or cells upon overexpression of mutant PGC-1α (Gly482Ser). Overexpression of wild-type PGC-1α, but not mutant PGC-1α, also caused a significant increase in hepatocyte expression of carnitine palmitoyl transferase 1a, a rate-determining enzyme that transfers long-chain fatty acids into mitochondria for oxidation. In addition, overexpression of mutant PGC-1α did not stimulate PEPCK-C expression as overexpression of wild-type PGC-1α did, likely due to a decrease in the ability of mutant PGC-1α in increasing PEPCK promoter transcription activity. Together, these results suggest that Gly482Ser mutation impairs the abilities of PGC-1α in decreasing fat deposition and in stimulating PEPCK-C expression in cultured hepatocytes.
authors.affiliation: Department of Endocrinology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. yanmingch@qq.com
authors.forename: Yanming
authors.initials: Y
authors.lastname: Chen
authors.forename: Panwei
authors.initials: P
authors.lastname: Mu
authors.forename: Shengqing
authors.initials: S
authors.lastname: He
authors.forename: Xixiang
authors.initials: X
authors.lastname: Tang
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.forename: Honggui
authors.initials: H
authors.lastname: Li
authors.forename: Hang
authors.initials: H
authors.lastname: Xu
authors.forename: Shih-Lung
authors.initials: SL
authors.lastname: Woo
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Qian
authors.forename: Longyi
authors.initials: L
authors.lastname: Zeng
authors.forename: Chaodong
authors.initials: C
authors.lastname: Wu
mesh_terms: D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000235:genetics; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism; D009154:Mutation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D018076:DNA, Complementary; D007328:Insulin; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase; C583748:carnitine palmitoyltransferase-1a, rat; D019764:Phosphoenolpyruvate Carboxykinase (ATP)