title: A new transgenic rat model of hepatic steatosis and the metabolic syndrome.
abstract: Fatty liver is extremely common in insulin-resistant patients with either obesity or lipodystrophy and it has been proposed that hepatic steatosis be considered an additional feature of the metabolic syndrome. Although insulin resistance can promote fatty liver, excessive hepatic accumulation of fat can also promote insulin resistance and could contribute to the pathogenesis of the metabolic syndrome. We sought to create a new nonobese rat model with hypertension, hepatic steatosis, and the metabolic syndrome by transgenic overexpression of a sterol-regulatory element-binding protein (SREBP-1a) in the spontaneously hypertensive rat (SHR). SREBPs are transcription factors that activate the expression of multiple genes involved in the hepatic synthesis of cholesterol, triglycerides, and fatty acids. The new transgenic strain of SHR overexpressing a dominant-positive form of human SREBP-1a under control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter exhibited marked hepatic steatosis with major biochemical features of the metabolic syndrome, including hyperglycemia, hyperinsulinemia, and hypertriglyceridemia. Both oxidative and nonoxidative skeletal muscle glucose metabolism were significantly impaired in the SHR transgenic strain and glucose tolerance deteriorated as the animals aged. The SHR transgenic strain also exhibited reduced body weight and reduced adipose tissue stores; however, the level of hypertension in the transgenic SHR was similar to that in the nontransgenic SHR control. The transgenic SHR overexpressing SREBP-1a represents a nonobese rat model of fatty liver, disordered glucose and lipid metabolism, and hypertension that may provide new opportunities for studying the pathogenesis and treatment of the metabolic syndrome associated with hepatic steatosis.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, USA.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Qi
authors.forename: Jiaming
authors.initials: J
authors.lastname: Wang
authors.forename: Vaclav
authors.initials: V
authors.lastname: Zidek
authors.forename: Vladimir
authors.initials: V
authors.lastname: Landa
authors.forename: Petr
authors.initials: P
authors.lastname: Mlejnek
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kazdová
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.forename: Theodore W
authors.initials: TW
authors.lastname: Kurtz
mesh_terms: D052242:Adiponectin; D000273:Adipose Tissue / Q000473:pathology; D000375:Aging / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics* / Q000503:physiopathology; D015870:Gene Expression; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D020738:Leptin / Q000097:blood; D008099:Liver / Q000473:pathology; D024821:Metabolic Syndrome / Q000235:genetics* / Q000503:physiopathology; D051381:Rats; D011918:Rats, Inbred SHR; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics*; D019076:Transgenes
chemical_list: D052242:Adiponectin; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; C497387:SREBF1 protein, human; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors