High-trans fatty acid and high-sugar diets can cause mice with non-alcoholic steatohepatitis with liver fibrosis and potential pathogenesis

Abstract

Abstract Background and aims Even Non-alcoholic steatohepatitis (NASH) has been becoming the key role in process of liver fibrosis or cirrhosis, no any NASH involving liver fibrosis mice model which consistent with the mechanisms of fatty acid and glucose metabolism disorder was widely accepted. Here, we established a mouse model of nonalcoholic steatohepatitis (NASH) with liver fibrosis using a high-fat, high-carbohydrate diet (HFHC) and analyzed the potential pathogenesis using a transcriptome microarray. Methods Fifty mice were stratified by weight and randomly divided into the HFHC model and control (Con) groups. Ten mice were sacrificed at the beginning of the experiments, 10 mice of HFHC and Con group were euthanized at the end of 20 and 30 weeks. The following analyses were performed: biochemical analysis; histological assessment; evaluation of hepatic type I collagen (Col-I), α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) protein and mRNA expression levels; and transcriptomic gene chip analysis. Results Compared with the Con group at each time point, the body weight and liver wet weight of the HFHC model group of mice were significantly higher. At 30th weeks, alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood glucose (FBG) and fasting insulin (FINS) levels or activities and the triglyceride (TG) and hydroxyproline (HYP) content in the HFHC model group were significantly elevated. Severe steatosis was present in the liver tissues contributed from the HFHC group of mice. Typically, substantial perisinusoidal fibrosis with a cage-like structure and bridging formations were observed in the mice liver in HFHC group. Col-I, α-SMA and TGF-β1 protein and mRNA expression levels in liver tissues of HFHC mice dramatically increased over time. Compared with the Con group, the HFHC group had 151 differentially expressed genes that were involved in 41 signaling pathways. Conclusions After keeping 30 weeks HFHC diet treatment, the mice exhibited substantial liver fibrosis, hepatic steatosis, ballooning degeneration and inflammation. Basing on the transcriptome microarray assays, the experimental NASH involving liver fibrosis potentially related to dramatically changed ECM-receptor interaction, Toll-like receptor signaling and other signaling pathways.

Keywords

• NASH
• Fibrosis
• Animal model
• Pathogenesis