Energy Supply Shifted from Glucose to Ketone Bodies Trigger the Nonalcoholic Steatohepatitis in Early Stage by Minipigs Model

 Nonalcoholic fatty liver disease (NAFLD) is a burgeoning global health problem and includes a disease spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma. The development and progression of NASH can require decades. Because of ethical constraints on obtaining human liver tissue, the quality and interpretation of longitudinal data from humans are necessarily limited. The pig is an exceptional model of obesity and metabolic syndrome research because the metabolic features, cardiovascular systems, and omnivorous habits are similar to those of humans. Further, the advancement in porcine genomics, proteomics, and genetic modification techniques will facilitate the use of pig models in extensive applications in the biomedical field.

This study examined the development of metabolic syndromes in Bama minipigs fed a high-fat high-sucrose diet (HFHSD) for 23 months using histological, serum and profiling the gene expression patterns of the livers from HFHSD pigs as compared to the controls. Pathology findings revealed microvesicular steatosis, iron overload, arachidonic acid synthesis, lipid peroxidation, reduced antioxidation capacity, increased cellular damage, inflammatory in the liver. RNA-seq analysis revealed that 164 genes were differentially expressed between the livers of the HFHSD and control groups. The pathogenesis characteristic of NASH in early stage exhibited as, hyperinsulinemia promoted the de novo synthesis of fatty acids and nascent triglyceride, which were deposited as lipid droplets in the hepatocytes. Hyperinsulinemia shifted the energy supply from glucose to ketone bodies, and the high ketone body concentration induced overexpression of cytochrome P450 2E1 (CYP2E1). The iron overload and CYP2E1 and alcohol dehydrogenase 4 overexpression mediated reactive oxygen species (ROS) production, which resulted in arachidonic and linoleic acid peroxidation, leading to malondialdehyde production, and a cellular response to ROS-mediated DNA damage.

This study was supported by grants from the National Natural Science Foundation of China (31372276), the State Key Development Program for Basic Research of China (2012CB517501), the National Basic Research Program (2011CBA01005), the National Key Technology Support Program (2012BAI39B04), the Agricultural Science and Technology Innovation Program (ASTIP-IAS05, ASTIP-IAS-TS-4), the Development Program of China (2012AA020603) and The Science and Technology Project of Shenzhen(CXZZ20140504105105077).

This work has been published on Scientific Reports on 11 Setember 2015. More details are available on the links bellow: http://www.nature.com/articles/srep13980