CREBH knockout accelerates hepatic fibrosis in mouse models of diet-induced nonalcoholic fatty liver disease

Abstract

Aims: The primary focus of this study was to explore the effects of cyclic AMP response element-binding protein H (CREBH) on the development of nonalcoholic fatty liver disease (NAFLD).

Materials and methods: CREBH knockout (KO) and wildtype (WT) mice were averagely divided into a methionine and choline-deficient (MCD) or high fat (HF) diet group and respective chow diet (CD) groups. Mice were sacrificed after 4-week treatment for MCD model and 24-week treatment for HF model.

Key findings: Characteristics of nonalcoholic steatohepatitis-related liver fibrosis in KO-MCD/HF group were verified by hepatic histological analyses. Compared with WT-MCD/HF group, levels of plasma ALT and hepatic hydroxyproline increased in KO-MCD/HF group. Significantly higher levels of MCP-1, αSMA, Desmin, COL-1, TIMP-1, TGF-β1, TGF-β2 were found while MMP-9 and FGF21 mRNA levels decreased in KO-MCD/HF group. There was also a distinct difference of mRNA levels of TNFα, CTGF and CCND1 in KO-HF group compared with controls. Protein levels of MCP-1, BAX, αSMA, COL-1, TGF-β1 and SMAD2/3 significantly increased in KO-MCD/HF group and CCND1 was also upregulated in KO-HF group compared to their counterparts.

Significance: CREBH knockout may primarily regulate the TGF-β1 signaling pathway via TGF-β2 and FGF21 resulting in more severe inflammation and fibrosis in NAFLD.

Keywords: Cyclic AMP response element-binding protein H (CREBH); Hepatic fibrosis; Inflammation; Lipid metabolism; Nonalcoholic fatty liver disease (NAFLD).