Establishment and analysis of a mouse model that regulates sex-related differences in liver drug metabolism

Chikada, Hiromi; Ida, Kinuyo; Ando, Emi; Inagaki, Yutaka; Sakamoto, Akemi; Kamiya, Akihide

doi:10.1038/s41374-018-0088-6

Cited by 25 publications

(32 citation statements)

References 54 publications

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“…In contrast, the serum levels of β-oestradiol, the most active oestrogen, in male WT and male Bcl6-LKO mice were comparable 11 . Liver-specific Bcl6-deficient mice have lost the gender differences in expression of several liver function genes such as drug-metabolizing enzymes, and livers of male Bcl6-LKO mice show expression patterns similar to female WT mice due to hepatocytic Bcl6-deficiency 11 . The fertility and blood sex hormone levels were not affected in Bcl6-LKO mice, indicating that Bcl6 specifically changed liver gender-dependent functions.…”

Section: Discussionmentioning

confidence: 80%

“…Serum profiles of Bcl6-LKO mice. The Bcl6-LKO mice were generated by crossing Bcl6-floxed mice with albumin-Cre mice as described previously 11 . The body weight and liver weight, as well as the serum lipid components, of Bcl6-LKO mice were analysed.…”

Section: Resultsmentioning

confidence: 99%

“…It was suggested that Bcl6 expression in non-liver tissues, such as adipose tissues, can promote lipid metabolic changes in whole-body Bcl6 knockout mice. Previously, we performed microarray expression analysis using Bcl6-LKO mouse livers (shown in GSE89091 and GSE107435) 11 , which revealed changes in the expression of several fatty acid-modifying enzymes. These lipid modification genes may affect fatty acid metabolism in the Bcl6-deficient liver.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, NASH-induced liver tumours, which were observed in male mice, were dependent on Bcl6. Recently, we had reported about the Bcl6-mediated regulation of liver functional genes, especially gender-specific drug metabolic genes 11 . These results suggest a correlation between gender and progression of liver diseases and tumours.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, liver-specific Bcl6 knockout mice (Bcl6-LKO mice) are an appropriate model to analyse the function of Bcl6 in the adult liver. We reported that Bcl6 regulates the expression of cytochrome P450 metabolic enzymes in the liver using Bcl6-LKO mice 11 . Moreover, Sommars et al recently reported that Bcl6 expression in the liver was important for the regulation of β-oxidation 12 .…”

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confidence: 99%

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

Chikada

Ida

Nishikawa

et al. 2020

Sci Rep

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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...

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Section: Discussionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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