Abstract
The prevalence of non-alcoholic steatohepatitis (NASH) rapidly increases with metabolic disorders such as dyslipidaemia, high blood pressure, and hyperglycaemia. B cell lymphoma 6 (Bcl6), a transcriptional repressor, is essential for the formation of germinal centre B cells. In this study, we analysed the role of Bcl6 in NASH progression-associated pathological changes, such as hepatic lipid accumulation, liver fibrosis, and hepatocarcinogenesis. The roles of Bcl6 in NASH were analysed using liver-specific Bcl6 knockout (Bcl6-LKO) and control wild-type (WT) mice. The murine NASH model was established by feeding the mice with choline-deficient, L-amino-acid-defined, high-fat diet (CDAHFD). Feeding the WT mice with CDAHFD for 7 weeks induced the formation of histopathological features resembling human NASH, such as hepatic lipid accumulation, hepatocellular injury, and fibrosis. These histopathological changes were significantly attenuated in Bcl6-LKO mice. Additionally, feeding the male WT mice with CDAHFD for 38 weeks induced the formation of liver tumours, which was suppressed in Bcl6-LKO mice. These findings indicate that Bcl6 is involved in the progression of NASH and NASH-derived tumours.
Highlights
Hepatocellular carcinoma is associated with high morbidity and mortality rates
The short-term CDAHFD feeding resulted in the induction of non-alcoholic steatohepatitis (NASH)-like pathologies, such as liver injury, hepatic lipid accumulation, and liver fibrosis in WT mice, which were suppressed in B cell lymphoma 6 (Bcl6)-LKO mice
Long-term CDAHFD feeding-induced liver tumours in WT mice, which was specific to male gender, was suppressed in Bcl6-LKO mice
Summary
Hepatocellular carcinoma is associated with high morbidity and mortality rates. We analysed the potential roles of Bcl[6] in NASH progression and NASH-induced hepatocarcinogenesis in mice fed with choline-deficient, L-amino-acid-defined, high-fat diet (CDAHFD). This diet markedly increased the rates of hepatic injury, hepatic lipid accumulation, and hepatic fibrosis in wild-type (WT) mice. Hepatocarcinogenesis induced by the consumption of CDAHFD for 38 weeks in male WT mice was significantly reduced in Bcl6-LKO mice These results indicated that Bcl[6] was involved in the progression of NASH and NASH-derived tumours
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