Wnt/beta-catenin signaling and its modulators in nonalcoholic fatty liver diseases

Hepatobiliary Pancreat Dis Int. 2023 Aug;22(4):333-345. doi: 10.1016/j.hbpd.2022.10.003. Epub 2022 Oct 20.


Nonalcoholic fatty liver disease (NAFLD) is a global health concern associated with significant morbidity and mortality. NAFLD is a spectrum of diseases originating from simple steatosis, progressing through nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis that may lead to hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is mediated by the triglyceride accumulation followed by proinflammatory cytokines expression leading to inflammation, oxidative stress, and mitochondrial dysfunction denoted as "two-hit hypothesis", advancing with a "third hit" of insufficient hepatocyte proliferation, leading to the increase in hepatic progenitor cells contributing to fibrosis and HCC. Wnt/β-catenin signaling is responsible for normal liver development, regeneration, hepatic metabolic zonation, ammonia and drug detoxification, hepatobiliary development, etc., maintaining the overall liver homeostasis. The key regulators of canonical Wnt signaling such as LRP6, Wnt1, Wnt3a, β-catenin, GSK-3β, and APC are abnormally regulated in NAFLD. Many experimental studies have shown the aberrated Wnt/β-catenin signaling during the NAFLD progression and NASH to hepatic fibrosis and HCC. Therefore, in this review, we have emphasized the role of Wnt/β-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.

Keywords: Chronic liver diseases; Fatty liver; Fibrosis; Oxidative stress; Steatosis; Wnt/β-catenin.

Publication types

  • Review

MeSH terms

  • Carcinoma, Hepatocellular* / pathology
  • Disease Progression
  • Fibrosis
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Liver / pathology
  • Liver Cirrhosis / pathology
  • Liver Neoplasms* / pathology
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Wnt Signaling Pathway / physiology
  • beta Catenin


  • beta Catenin
  • Glycogen Synthase Kinase 3 beta