Liver-Specific β-Catenin Knockout Mice Exhibit Defective Bile Acid and Cholesterol Homeostasis and Increased Susceptibility to Diet-Induced Steatohepatitis

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.

Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia–reperfusion injury

“…Choline is an essential nutrient required for efficient phosphatidylcholine synthesis necessary for the packaging and export of VLDL particles to extrahepatic organs. Feeding mice a CD diet results in hepatic steatosis with predominant TG content and unchanged cholesterol levels compared to chow-fed mice (Fig 1A), consistent with previous reports [10,20,21]. In contrast, increased hepatic cholesterol levels but unchanged TG content are observed in mice fed the HC diet ( Fig 1B).…”

Specific Contribution of Methionine and Choline in Nutritional Nonalcoholic Steatohepatitis

“…However, none of the diets changed the total cholesterol content at any of the time points examined (Fig. 2C), in agreement with previous findings (6,28,29). These biochemical characteristics were consistent with the staining of liver samples with oil red and filipin, which monitor the level of neutral lipids and free cholesterol, respectively (Fig.…”

Increased serum leukocyte cell-derived chemotaxin 2 (LECT2) levels in obesity and fatty liver

“…In a mouse model of high-fat diet-induced obesity, the Wnt/β-catenin signaling pathway was demonstrated to regulate hepatic metabolism (3). In contrast, in another study, liver-specific β-catenin knockout mice revealed increased susceptibility to methionine-and cholinedeficient diet-induced steatohepatitis (4). These reports suggest that this pathway plays an important role in hepatic metabolism.…”