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Abstract
Objective: Non-Alcoholic Steato Hepatitis (NASH) is now recognized as a global liver disease. Medication combined with diet and exercise regimen is used to treat NASH, because NASH is associated with metabolic syndrome, such as insulin resistance or dyslipidemia. However, it currently remains unclear whether NASH affects the metabolic power and activity in the liver especially for hypo-cholesterolemic drugs. To address this issue, we measured major Cytochrome P450 (CYP) subtype activities in mice with diet-induced NASH. Methods: C57BL/6J mice (male, 8 weeks of age) were fed a High-Fat and High-Cholesterol (HFHC) diet or normal chow diet (control) ad libitum for 12 weeks. Plasma lipid levels and hepatic lipid contents were then measured. The mRNA expression levels of the CYP subtypes and inflammatory cytokines in the liver were assessed using quantitative RT-PCR methods. Liver microsomal CYP activities were evaluated by luminogenic CYP assays. Results: Body weight was significantly lower and the liver weight was higher in HFHC-fed mice than in control mice. Plasma levels of AST, ALT, and ALP were higher in HFHC-fed mice. Oil red O staining and the evaluation of hepatic lipid contents revealed the accumulation of lipids in the liver of HFHC-fed mice. Furthermore, increased inflammatory cytokine (ex. IL-1β, IL-6, and TNF-α) mRNA expression in the liver and a pathological analysis confirmed the characteristics of NASH in HFHC-fed mice. CYP1A1, 1A2, and 3A activities were higher in HFHC-fed mice than in control, which were coincident with mRNA expression levels in the liver. However, CYP2C activity was significantly lower, even though CYP2C29 mRNA expression was higher in HFHC-fed mice than in control mice. Conclusion: These results indicated that major CYP subtypes activities in the liver were influenced in NASH mice model. It could be occurred in human, and physicians need to consider the administration of appropriate medication to patients with NASH.
Highlights
Non-Alcoholic Steatohepatitis (NASH) is recognized as a global liver disease
CYP1A1, 1A2, and 3A activities were higher in High-Fat and High-Cholesterol (HFHC)-fed mice than in control, which were coincident with mRNA expression levels in the liver
NASH is characterized by the liver biopsy findings of alcoholic hepatitis, in addition to elevated plasma indicators of hepatic damage and accumulation of lipids in the liver reported in Non-Alcoholic Fatty Liver Disease (NAFLD)
Summary
NASH is characterized by the liver biopsy findings of alcoholic hepatitis, in addition to elevated plasma indicators of hepatic damage and accumulation of lipids in the liver reported in Non-Alcoholic Fatty Liver Disease (NAFLD). NASH progresses to mild fatty degeneration, inflammation, cell degeneration, fibrosis, cirrhosis, and cancer [1,2]. It is important to treat NASH before it progresses to a more severe state. Statins or probucol reduce hyperlipidemia, metformin and thiazolidine derivatives improve insulin resistance, and angiotensin II-converting enzyme antagonists reduce blood pressure. It has not yet been established whether the hepatic condition of NASH, such as the accumulation of lipids or inflammation, could influence drug metabolism
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