title: Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice.
abstract: Peroxisome proliferator-activated receptor γ (PPARγ) is the target for thiazolidinones (TZDs), drugs that improve insulin sensitivity and fatty liver in humans and rodent models, related to a reduction in hepatic de novo lipogenesis (DNL). The systemic effects of TZDs are in contrast to reports suggesting hepatocyte-specific activation of PPARγ promotes DNL, triacylglycerol (TAG) uptake and fatty acid (FA) esterification. As these hepatocyte-specific effects of PPARγ could counterbalance the positive therapeutic actions of systemic delivery of TZDs, the current study used a mouse model of adult-onset, liver (hepatocyte)-specific PPARγ knockdown (aLivPPARγkd). This model has advantages over existing congenital knockout models, by avoiding compensatory changes related to embryonic knockdown, thus better modeling the impact of altering PPARγ on adult physiology, where metabolic diseases most frequently develop. The impact of aLivPPARγkd on hepatic gene expression and endpoints in lipid metabolism was examined after 1 or 18 weeks (Chow-fed) or after 14 weeks of low- or high-fat (HF) diet. aLivPPARγkd reduced hepatic TAG content but did not impact endpoints in DNL or TAG uptake. However, aLivPPARγkd reduced the expression of the FA translocase (Cd36), in 18-week Chow- and HF-fed mice, associated with increased NEFA after HF feeding. Also, aLivPPARγkd dramatically reduced Mogat1 expression, that was reflected by an increase in hepatic monoacylglycerol (MAG) levels, indicative of reduced MOGAT activity. These results, coupled with previous reports, suggest that Cd36-mediated FA uptake and MAG pathway-mediated FA esterification are major targets of hepatocyte PPARγ, where loss of this control explains in part the protection against steatosis observed after aLivPPARγkd.
authors: Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.|Biologic Resources LaboratoryUniversity of Illinois at Chicago, Chicago, Illinois, USA.
authors: Abigail
authors: A
authors: Wolf Greenstein
authors: Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors: Neena
authors: N
authors: Majumdar
authors: Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors: Peng
authors: P
authors: Yang
authors: Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors: Papasani V
authors: PV
authors: Subbaiah
authors: Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors: Rhonda D
authors: RD
authors: Kineman
authors: Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA jcordoba@uic.edu.|Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors: Jose
authors: J
authors: Cordoba-Chacon
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*
chemical_list: D047495:PPAR gamma
keywords: Cd36; LC/MS; Mogat1; adult-onset hepatocyte-specific knockdown; diet-induced steatosis