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.
Highlights
Was proposed as an initial model for the pathogenesis of NASH3
A modified “two-hit” hypothesis proposed that free fatty acids (FFAs) derived from diet, lipolysis, or de novo lipogenesis play a direct role in promoting oxidative stress and inflammation-mediated liver injury, whereas the esterification of FFAs to triglycerides for storage and export can function as a protective mechanism against FAA accumulation[4,5]
No significant changes in TG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), or low-density lipoprotein cholesterol (LDL-C) were observed throughout the entire rearing period
Summary
Was proposed as an initial model for the pathogenesis of NASH3. The “first hit” is hepatic steatosis due to triglyceride accumulation. Bama minipigs were fed a HFHSD for 23 months and monitored for the development of metabolic syndrome and NASH using serum biochemistry, hepatic profiles, histopathological approaches, and gene expression profiling of the liver from HFHSD pigs. Comprehensive analyses of these data revealed that the pathogenic characteristics of early stage NASH include the following: de novo synthesis of fatty acids and nascent TG deposition, energy supply shift, reactive oxygen species (ROS) production, lipid peroxidation, cellular damage and inflammation
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