LXRα deficiency promotes hepatic tumor development in nonalcoholic fatty liver disease and alters Akt/Gsk3β/β-catenin signaling.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide, with nonalcoholic fatty liver disease (NAFLD) emerging as an increasingly important risk factor. Liver X receptor alpha (LXRα) regulates hepatic lipid and cholesterol homeostasis, but its role in NAFLD-associated hepatic tumor development remains unclear. We examined hepatic LXRα expression in transcriptomic datasets and human liver tissue from cirrhosis and HCC to assess its association with chronic liver disease and hepatic malignancy. To model NAFLD-associated hepatic tumor development, wild-type (WT) and Lxrα knockout (KO) mice were fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) for 26 weeks. Hepatic LXRα expression was reduced in human cirrhosis and HCC. Relative to WT mice, CDAHFD-fed Lxrα KO mice developed more hepatic nodules, larger maximum nodules, hepatocellular adenomas, and increased GPC3 expression. LXRα deficiency also enhanced hepatocyte proliferation and altered Akt/Gsk3β/β-catenin signaling, with increased expression of proliferation markers and nuclear accumulation of β-catenin. In addition, LXRα deficiency exacerbated hepatic fibrosis, inflammation, oxidative damage, and neutrophil infiltration but did not significantly alter hepatic steatosis or hepatic and serum lipid levels. These findings implicate LXRα as a potential regulator of NAFLD-associated hepatic tumor development and clarify the mechanisms underlying this process.