Role of the Wnt/beta-Catenin Pathway in the Pathogenesis of Alcoholic Liver Disease

Abstract

The Wnt pathway is a highly conserved signal transduction pathway that plays an important role in diverse aspects of hepatic physiology. The Wnt pathway, consisting of canonical and noncanonical arms, is composed of secreted glycoproteins, cell surface receptors and co-receptors, and complex intracellular regulatory machinery that regulate a large number of cellular functions. ß-Catenin is the main effector of the canonical Wnt pathway and hepatocyte-specific loss of the protein leads to increased susceptibility to alcoholic steatohepatitis. Hepatocytes with disrupted ß-catenin demonstrate mitochondrial dysfunction, defective oxidative phosphorylation, and increased oxidative stress. ß- Catenin knockout mice have decreased expression of alcohol metabolizing enzymes and increased blood alcohol levels that along with hypoglycemia and hyperammonemia, lead to increased mortality upon alcohol exposure. Disruption of hepatic ß-catenin affects fatty acid oxidation and fasting ketogenesis and thereby profoundly affects systemic energy homeostasis. Given the combined roles of Wnt/ß-catenin signaling in hepatocellular bioenergetics and regeneration, the Wnt pathway also contributes to alcohol-induced hepatic fibrogenesis and hepatocarcinogenesis. Targeting the Wnt/ß-catenin pathway represents an attractive strategy for the treatment of alcohol-induced liver disease.

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