title: Hyperinsulinemia shifted energy supply from glucose to ketone bodies in early nonalcoholic steatohepatitis from high-fat high-sucrose diet induced Bama minipigs.
abstract: The minipig can serve as a good pharmacological model for human subjects. However, the long-term pathogenesis of high-calorie diet-induced metabolic syndromes, including NASH, has not been well described in minipigs. We examined the development of metabolic syndromes in Bama minipigs that were fed a high-fat, high-sucrose diet (HFHSD) for 23 months, by using histology and serum biochemistry and by profiling the gene expression patterns in the livers of HFHSD pigs compared to controls. The pathology findings revealed microvesicular steatosis, iron overload, arachidonic acid synthesis, lipid peroxidation, reduced antioxidant capacity, increased cellular damage, and inflammation in the liver. RNA-seq analysis revealed that 164 genes were differentially expressed between the livers of the HFHSD and control groups. The pathogenesis of early-stage NASH was characterized by hyperinsulinemia and by de novo synthesis of fatty acids and nascent triglycerides, which were deposited as lipid droplets in hepatocytes. Hyperinsulinemia shifted the energy supply from glucose to ketone bodies, and the high ketone body concentration induced the overexpression of cytochrome P450 2E1 (CYP2E1). The iron overload, CYP2E1 and alcohol dehydrogenase 4 overexpression promoted reactive oxygen species (ROS) production, which resulted in arachidonic and linoleic acid peroxidation and, in turn, led to malondialdehyde production and a cellular response to ROS-mediated DNA damage.
authors.affiliation: State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, No.2 Yuanmingyuan West Road, Beijing, 100193, P.R. China.
authors.forename: Shu-lin
authors.initials: SL
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, No.2 Yuanmingyuan West Road, Beijing, 100193, P.R. China.
authors.forename: Ji-han
authors.initials: JH
authors.lastname: Xia
authors.affiliation: College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing, 100193, P.R. China.
authors.forename: Yuan-yuan
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Shanghai Key Laboratory of Children's Digestion and Nutrition, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, P.R. China.
authors.forename: Jian-gao
authors.initials: JG
authors.lastname: Fan
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, No.2 Yuanmingyuan West Road, Beijing, 100193, P.R. China.|College of Animal Science, Yangtze University, Jinzhou, 434023, Hubei, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing, 100193, P.R. China.
authors.forename: Zhan-zhao
authors.initials: ZZ
authors.lastname: Zhao
authors.affiliation: Department of Gastroenterology, Shanghai Key Laboratory of Children's Digestion and Nutrition, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, P.R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, No.2 Yuanmingyuan West Road, Beijing, 100193, P.R. China.
authors.forename: Yu-lian
authors.initials: YL
authors.lastname: Mu
authors.affiliation: State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, No.2 Yuanmingyuan West Road, Beijing, 100193, P.R. China.
authors.forename: Lei-lei
authors.initials: LL
authors.lastname: Xin
authors.affiliation: College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing, 100193, P.R. China.
authors.forename: Yao-xing
authors.initials: YX
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, No.2 Yuanmingyuan West Road, Beijing, 100193, P.R. China.
authors.forename: Kui
authors.initials: K
authors.lastname: Li
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001835:Body Weight; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004249:DNA Damage; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005355:Fibrosis; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006946:Hyperinsulinism / Q000150:complications* / Q000378:metabolism*; D006965:Hyperplasia; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D007657:Ketone Bodies / Q000378:metabolism*; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D013552:Swine; D059467:Transcriptome; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: D000975:Antioxidants; D005227:Fatty Acids; D007657:Ketone Bodies; D014280:Triglycerides; D002784:Cholesterol; D005947:Glucose