title: Regulation of synthesis and oxidation of fatty acids by adiponectin receptors (AdipoR1/R2) and insulin receptor substrate isoforms (IRS-1/-2) of the liver in a nonalcoholic steatohepatitis animal model.
abstract: Nonalcoholic steatohepatitis (NASH) is one of the most frequent causes of abnormal liver dysfunction associated with synthesis and oxidation of fatty acids. Adiponectin receptors (AdipoR1/R2) and insulin receptor substrates (IRS-1/-2) are known as modulators of these fatty acid metabolisms in the liver; however, the regulatory roles of these receptors in the synthesis and oxidation of fatty acids are unclear in the liver of NASH. In this study, we examined the roles of hepatic AdipoR1/R2 and IRS-1/-2 in NASH using an animal model. After feeding a high-fat and high-cholesterol diet to obese fa/fa Zucker rats for 8 weeks, rats showed fatty liver spontaneously with inflammation and fibrosis that are characteristic of NASH. The expression levels of AdipoR1/R2 and IRS-2 were significantly decreased, whereas IRS-1 was significantly increased, in NASH. As a result of the decrease of AdipoR1/R2 expression, the messenger RNA expression levels of genes located downstream of AdipoR1/R2, adenosine monophosphate-activated protein kinase α1/α2, which inhibits fatty acid synthesis, and peroxisome proliferator-activated receptor α, which activates fatty acid oxidation, also decreased. Expression level of sterol regulatory element binding protein-1c was found to be elevated, suggesting the up-regulation of IRS-1, and resulted in increased fatty acid synthesis. Furthermore, increase of forkhead box protein A2 expression was observed, which might be associated with the down-regulation of IRS-2, facilitating fatty acid oxidation. Taken together, increased synthesis and oxidation of fatty acids by up- or down-regulation of AdipoR or IRS may contribute to the progression of NASH. Thus, AdipoR and IRS might be crucially important regulators for the synthesis and oxidation of fatty acids in the liver of NASH.
authors.affiliation: Laboratory of Biomedical Science, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa 252-0880, Japan.
authors.forename: Tokio
authors.initials: T
authors.lastname: Matsunami
authors.forename: Yukita
authors.initials: Y
authors.lastname: Sato
authors.forename: Satomi
authors.initials: S
authors.lastname: Ariga
authors.forename: Takuya
authors.initials: T
authors.lastname: Sato
authors.forename: Toshiko
authors.initials: T
authors.lastname: Shimomura
authors.forename: Haruka
authors.initials: H
authors.lastname: Kashimura
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yukawa
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000494:pharmacology; D004041:Dietary Fats / Q000494:pharmacology; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000502:physiology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020675:Peroxisomes / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D054419:Receptors, Adiponectin / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D005227:Fatty Acids; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D054419:Receptors, Adiponectin; D014280:Triglycerides; C504339:adiponectin receptor 1, rat; C506573:adiponectin receptor 2, rat