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. β-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 β-catenin demonstrate
mitochondrial dysfunction, defective oxidative phosphorylation, and increased oxidative stress. β-
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 β-catenin affects fatty acid oxidation and fasting ketogenesis
and thereby profoundly affects systemic energy homeostasis. Given the combined roles of
Wnt/β-catenin signaling in hepatocellular bioenergetics and regeneration, the Wnt pathway also contributes
to alcohol-induced hepatic fibrogenesis and hepatocarcinogenesis. Targeting the Wnt/β-catenin
pathway represents an attractive strategy for the treatment of alcohol-induced liver disease.
Keywords: Alcoholic liver disease, alcohol metabolism, alcoholic steatohepatitis, mitochondrial dysfunction, oxidative stress.
Rights & PermissionsPrintExport