B-Cell Receptor-Associated Protein 31 Deficiency Aggravates Ethanol-Induced Liver Steatosis and Liver Injury via Attenuating Fatty Acid Oxidation and Glycogen Synthesis.

Alcoholic liver disease (ALD) is a spectrum of alcohol-induced disorders and represents a major global health challenge. B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum-resident chaperone involved in protein transport, apoptosis, cancer biology, and lipid metabolism. To explore its role in ALD, we used hepatocyte-specific BAP31 knockout mice (BAP31-LKO) and wild-type (WT) littermates exposed to ethanol to assess BAP31's biochemical and metabolic impact. Following ethanol exposure, BAP31-LKO mice exhibited elevated serum alanine transaminase (23.2%, p < 0.05) and aspartate transaminase (31.4%, p < 0.05) levels compared to WT mice. Increased malondialdehyde (8.5%, p < 0.05) and reduced superoxide dismutase (22.8%, p < 0.05) in BAP31-LKO mice indicate exacerbated liver injury. Furthermore, BAP31 deficiency increased triglyceride (35.7%, p < 0.05) and free fatty acid (16.2%, p < 0.05) accumulation following ethanol treatment, while the expression of fatty acid oxidation-related genes, including Pparα, Cd36, Fatp2, Cpt2, and Acox1, was reduced in BAP31-LKO mice. The mRNA levels of Xbp1, Xbp1s, and Chop, as well as protein levels of p-eIF2α, IRE1α, GRP78, and CHOP, were increased in BAP31-LKO mice compared to WT controls, indicating aggravated ethanol-induced ER stress. Hepatic glycogen content was also reduced in BAP31-LKO mice, along with reduced Ppp1r3c expression, demonstrating impaired glycogen synthesis. Consistently, BAP31 knockdown amplified ethanol-induced lipid accumulation, inflammation, impaired glycogen storage, ER stress, and suppression of Pparα signaling in HepG2 cells. Together, these findings demonstrate that BAP31 deficiency exacerbates ethanol-induced liver steatosis, inflammation, and liver injury by impairing fatty acid oxidation and glycogen synthesis, and by amplifying ER stress responses.