Nobiletin Protects Against Alcoholic Liver Disease in Mice via the BMAL1‐AKT‐Lipogenesis Pathway

Scope Alcoholic liver disease (ALD) is a global public health concern. Nobiletin, a polymethoxyflavone abundant in citrus fruits, enhances circadian rhythms and ameliorates diet‐induced hepatic steatosis, but its influences on ALD are unknown. This study investigates the role of brain and muscle Arnt‐like protein‐1 (Bmal1), a key regulator of the circadian clock, in nobiletin‐alleviated ALD. Methods and results This study uses chronic ethanol feeding plus an ethanol binge to establish ALD models in Bmal1flox/flox and Bmal1 liver‐specific knockout (Bmal1LKO) mice. Nobiletin mitigates ethanol‐induced liver injury (alanine aminotransferase [ALT]), glucose intolerance, hepatic apoptosis, and lipid deposition (triglyceride [TG], total cholesterol [TC]) in Bmal1flox/flox mice. Nobiletin fails to modulated liver injury (ALT, aspartate aminotransferase [AST]), apoptosis, and TG accumulation in Bmal1LKO mice. The expression of lipogenic genes (acetyl‐CoA carboxylase alpha [Acaca], fatty acid synthase [Fasn]) and fatty acid oxidative genes (carnitine pamitoyltransferase [Cpt1a], cytochrome P450, family 4, subfamily a, polypeptide 10 [Cyp4a10], and cytochrome P450, family4, subfamily a, polypeptide 14 [Cyp4a14]) is inhibited, and the expression of proapoptotic genes (Bcl2 inteacting mediator of cell death [Bim]) is enhanced by ethanol in Bmal1flox/flox mice. Nobiletin antagonizes the expression of these genes in Bmal1flox/flox mice and not in Bmal1LKO mice. Nobiletin activates protein kinase B (PKB, also known as AKT) phosphorylation, increases the levels of the carbohydrate response element binding protein (ChREBP), ACC1, and FASN, and reduces the level of sterol‐regulatory element binding protein 1 (SREBP1) and phosphorylation of ACC1 in a Bmal1‐dependent manner. Conclusion Nobiletin alleviates ALD by increasing the expression of genes involved in fatty acid oxidation by increasing AKT phosphorylation and lipogenesis in a Bmal1‐dependent manner. Nobiletin mitigates ethanol‐induced liver injury, apoptosis, and lipid accumulation in mice; however, these beneficial effects disappear when liver Bmal1 is depleted. Nobiletin reactivates ethanol‐suppressed fatty acid β‐oxidation through activating AKT, which improves the transcription of lipogenic genes. Activation of this pathway depends on Bmal1.