Liver-specific knockout of B cell lymphoma 6 suppresses progression of non-alcoholic steatohepatitis in mice

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. Globally, hepatocellular carcinoma is associated with high morbidity and mortality rates. The major etiological factor for hepatocellular carcinomas is chronic hepatitis, which is induced by infections from hepatitis B virus (HBV) and hepatitis C virus (HCV). The non-viral etiological factors for hepatocellular carcinoma are excessive alcohol and lipid intake. The symptoms of hepatitis and hepatocellular carcinomas induced by HBV and HCV can be controlled by antiviral drugs, such as nucleic acid analogue preparations for HBV and direct-acting antivirals for HCV 1. In addition to the incidences of visceral fat-type obesity, the incidences of metabolic disorders, such as high blood pressure, hyperglycaemia, and dyslipidaemia are rapidly increasing due to unhealthy lifestyle habits, such as the consumption of high-fat diet and lack of exercise. Non-alcoholic fatty liver disease (NAFLD), a metabolic syndrome, shows abnormal lipid accumulation in the liver. Many patients with NAFLD do not exhibit major pathological symptoms, except simple fatty livers. However, NAFLD may progress to hepatitis and liver cirrhosis in some cases and liver tumours in severe cases, which could be lethal. The progression of non-alcoholic steatohepatitis (NASH) has classically been explained by two-hit hypothesis 2. Steatohepatitis is induced by abnormal accumulation of lipids in the liver, an upstream pathological change, followed by increased oxidative stress and enhanced secretion of inflammatory cytokines. The prolonged inflammatory condition promotes the progression from liver fibrosis to cirrhosis and hepatocellular carcinomas. There are multiple risk factors reported for various NASH pathologies, which has led to the proposal of parallel hits hypothesis for the progression of NASH 3. Recently, there has been increased incidence of serious liver d...

ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis

“…These data are in line with recently published findings demonstrating liver-specific ablation of Bcl6 suppresses the progression of non-alcoholic steatohepatitis (NASH) in mice. 47 ROCK2 inhibition also disrupted GC B-cell development as well as pathogenic antibody production and sequestration in the liver. The interaction of IgG with Fc gamma receptor on macrophages activates their pro-inflammatory phenotype and potentially contributes to fibrogenesis.…”

B-cell lymphoma 6 alleviates nonalcoholic fatty liver disease in mice through suppression of fatty acid transporter CD36

“…Furthermore, we observed that HFD induces a reduction of BCL6 in the fatty liver of NAFLD mice, which has not been previously characterized. Hiromi Chikada and colleagues reported that BCL6 liver knockout mice exhibited suppressed NASH progression, which was caused by feeding mice 7 weeks of the high-fat diet, which was defined as choline-deficient L-amino acids (CDAHFD) [ 17 ]. Sommars et al previously reported that BCL6 is an effective PPARα antagonist that turns off genes involved in fat burning when mice eat [ 10 ].…”

The DNA binding protein BCL6 regulates NFκB-controlled endothelial inflammatory gene expression

“…DNA motif prediction analysis resulted in PPARs colocalizations in BCL6 genes specially under fasting challenge. In the liver, BCL6 broadly regulates metabolic and oncogenic processes [[35, 96, 97]], and suppresses growth hormone signaling, insulin resistance and steatosis in an adipocyte-intrinsic manner [74, 98]. Furthermore, BCL6 depletion reduced the effect of metabolic impairment associated to PPARα deficiency reflected in a dysregulated fatty acid oxidation, hypo-ketonemia and steatosis sensitivity.…”

“…Other BCL6 liver knockout studies reported lower hepatic levels of triglyceride contrary to serum cholesterol, and HDL cholesterol. Moreover, BCL6 are associated with metabolic regulation thought upregulated β-oxidation-related genes and Socs2 as well as downregulated proinflammatory cytokines like TNFα and IL-6 [[35, 96, 97].…”