PPARgamma2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is considered to be one of the master regulators of adipocyte differentiation. PPARgamma2 is abundantly expressed in mature adipocytes and is elevated in the livers of animals that develop fatty livers. The aim of this study was to determine the ability of PPARgamma2 to induce lipid accumulation in hepatocytes and to delineate molecular mechanisms driving this process. The hepatic cell line AML-12 was used to generate a cell line stably expressing PPARgamma2. Oil Red O staining revealed that PPARgamma2 induces lipid accumulation in hepatocytes. This phenotype is accompanied by a selective upregulation of several adipogenic and lipogenic genes including adipose differentiation-related protein (ADRP), adipocyte fatty acid-binding protein 4, sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase (FAS), and acetyl-CoA carboxylase, genes whose expression levels are known to increase in steatotic livers of ob/ob mice. Furthermore, the PPARgamma2-regulated induction of both SREBP-1 and FAS parallels an increase in de novo triacylglycerol synthesis in hepatocytes. Triacylglycerol synthesis and lipid accumulation are further enhanced by culturing hepatocytes with troglitazone in the absence of exogenous lipids. These results correspond with an increase in the lipid droplet protein, ADRP, and the data demonstrate that ADRP functions to coat lipid droplets in hepatocytes as observed by confocal microscopy. Taken together, these observations propose a role for PPARgamma2 as an inducer of steatosis in hepatocytes and suggest that this phenomenon occurs through an induction of pathways regulating de novo lipid synthesis.
Schadinger
Susan E
SE
Dept. of Biochemistry, Boston Univ. School of Medicine, 715 Albany St., Boston, MA 02118, USA.
Bucher
Nancy L R
NL
Schreiber
Barbara M
BM
Farmer
Stephen R
SR
D000103:Acetyl-CoA Carboxylase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001391:Azo Compounds / Q000737:chemistry; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002839:Chromans / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D064429:Fatty Acid Synthases / Q000096:biosynthesis / Q000235:genetics; D050556:Fatty Acid-Binding Proteins; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018613:Microscopy, Confocal; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D000070780:Perilipin-2; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014280:Triglycerides / Q000096:biosynthesis; D000077288:Troglitazone
D001391:Azo Compounds; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D002839:Chromans; D004268:DNA-Binding Proteins; D050556:Fatty Acid-Binding Proteins; D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D047495:PPAR gamma; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase; C011049:oil red O; D000077288:Troglitazone