Liver‐specific beta‐catenin knockout mice show increased liver injury in the methionine‐choline‐deficient diet model of steatohepatitis

Abstract

Background: Beta‐catenin regulates expression of multiple regulators of oxidative stress in the liver and thus, may be involved in the pathogenesis of nonalcoholic steatohepatitis. Here, we examined the role of beta‐catenin in steatohepatitis using the murine methionine‐choline‐deficient (MCD) diet model. Methods: Two‐month‐old liver‐specific beta‐catenin knockout mice and genetically matched control littermates were fed either the MCD diet or control diet for 2 weeks and then sacrificed for analysis. Results: On the control diet, beta‐catenin knockout mice showed mild microvesicular steatohepatitis and two‐fold higher transaminases, compared with normal histology and liver enzymes in the control animals. On the MCD diet, beta‐catenin knockout animals exhibited severe macrovesicular steatosis (80–100%), grade 3–4 inflammation, and stage 1–2 fibrosis, compared with mild to moderate steatohepatitis and no fibrosis in the control animals. Both MCD‐fed strains had five‐ to ten‐fold higher transaminase levels, but only knockout mice had ten‐fold higher total bilirubin level. Conclusions: Liver‐specific loss of beta‐catenin causes a striking increase in liver injury and fibrosis in mice fed the MCD diet, suggesting an important protective role of beta‐catenin in the pathogenesis of liver injury in this model of steatohepatitis.