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

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 proinflam-matory cytokines expression leading to inflammation,oxidative stress,and mitochondrial dysfunction de-noted as“two-hit hypothesis”,advancing with a“third hit”of insufficient hepatocyte proliferation,lead-ing 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 regula-tors 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 dur-ing the NAFLD progression and NASH to hepatic fibrosis and HCC.Therefore,in this review,we have em-phasized the role of Wnt/β-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.

Reply to“Wnt/beta-catenin signaling inhibitors and nonalcoholic fatty liver disease:Potential therapeutic implications”

The Author Reply:We sincerely appreciated the interest of Polyzos et al.,in our review article and sharing their improvised thoughts regarding the Wnt signaling modulators for the treatment of postmenopausal women with osteoporosis and nonalcoholic fatty liver disease(NAFLD).Several experimental studies have showed that the aberrant Wnt/β-catenin signaling promotes the development and/or progression of a variety of chronic liver diseases including NAFLD[1,2].Therefore,our review emphasized on the modulation of Wnt/β-catenin signaling and the role of its mediators in NAFLD progression.Given that NAFLD prevalence is constantly increas-ing,and that osteoporosis is associated with women over 50 years of age with NAFLD[3],there is an unmet need for an effective treatment.Sclerostin blocks the canonical Wnt signaling pathway of bone formation.Therefore,romosozumab,a humanized anti-sclerostin monoclonal antibody,was approved for the treatment of osteoporosis.Romosozumab binds to sclerostin,permitting the en-gagement of Wnt ligands with their co-receptors,resulting in an increase in bone formation and bone mineral density.