Berberine alleviates alcoholic liver diseaseactivating intestinal nuclear receptor subfamily 1 group D member 1.

OBJECTIVES: To elucidate the hepatoprotective mechanism of berberine (BBR) against alcohol-induced liver injury. METHODS: Chronic and acute alcohol-induced liver injury models in mice were established to mimic human alcoholic liver disease (ALD). The therapeutic effect of BBR was evaluated in both models. The severity of liver injury, lipid metabolism and circadian clock related factors were assessed using histopathology, biochemical assays, and Western blotting. Intestinal-specific nuclear receptor subfamily 1 group D member 1 (Rev-erbα) knockout mice were used to validate intestinal Rev-erbα as the key mediator. RESULTS: BBR alleviated hepatic steatosis and inflammation in both chronic and acute ALD models. Mechanistically, BBR activated intestinal REV-ERBα, upregulating intestinal fatty acid desaturase 2 (FADS2) expression, suppressing hepatic sterol regulatory element binding protein-1 (SREBP-1c) and its downstream lipogenic genes. These effects were abolished in intestinal specific Rev-erba knockout mice. BBR was most effective against ALD when administered during the peak expression phase of REV-ERBα (Zeitgeber Time 6). CONCLUSIONS: Intestinal REV-ERBα represents a promising therapeutic target for ALD, and chrono-modulated BBR administration may enhance treatment efficacy. This study underscores the role of gut-liver axis in ALD pathogenesis and provides a rationale for developing time-tailored therapies.