No abstract

Although the role of Wnt/beta-catenin signaling in liver growth and development is well established, its contribution in non-neoplastic hepatic pathologies has not been investigated. Here, we examine the role of beta-catenin in a murine model of diet-induced liver injury. Mice with hepatocyte-specific beta-catenin deletion (KO) and littermate controls were fed the steatogenic methionine and choline-deficient (MCD) diet or the corresponding control diet for 2 weeks and characterized for histological, biochemical, and molecular changes. KO mice developed significantly higher steatohepatitis and fibrosis on the MCD diet compared with wild-type mice. Both wild-type and KO livers accumulated triglyceride on the MCD diet but, unexpectedly, higher hepatic cholesterol levels were observed in KO livers on both control and MCD diets. Gene expression analysis showed that hepatic cholesterol accumulation in KO livers was not attributable to increased synthesis or uptake. KO mice had lower expression of bile acid synthetic enzymes but exhibited higher hepatic bile acid and serum bilirubin levels, suggesting defects in bile export. Therefore, loss of beta-catenin in the liver leads to defective cholesterol and bile acid metabolism in the liver and increased susceptibility to developing steatohepatitis in the face of metabolic stress.

Background-Inhibition of hepatoma cells by cyclooxygenase (COX)-2 dependent and independent mechanisms has been shown previously. Here, we examine the effect of Celecoxib, a COX-2-inhibitor and R-Etodolac, an enantiomer of the nonsteroidal anti-inflammatory drug Etodolac, which lacks COX-inhibitory activity, on the Wnt/β-catenin pathway and human hepatoma cells.

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.

No abstract