Isocaloric high protein dietary pattern ameliorates chronic alcohol-induced liver dysfunction <em>via</em> a BDH2 involved mechanism

Emerging evidence shows that the proportion of dietary macronutrients determines the pathological progression of multiple metabolic diseases, however, whether and how this affect alcohol-associated liver diseases (ALD) are largely unclear. The present study was conducted to explore the role of dietary protein proportions on ALD and to unveil its potential mechanisms. C57BL/6N mice were administrated with isocaloric Lieber-DeCarli alcohol liquid diets with different proportions of protein, including normal protein (NP, <strong>15% energy</strong>), high protein (HP, 30% energy), and low protein (LP, 10% energy), respectively. Our results showed that HP diet significantly ameliorated alcohol-induced hepatic steatosis, liver injury, oxidative stress, and inflammation, which were aggravated in LP diet-fed mice. Alcohol consumption-stimulated lipid metabolism-associated genes dysregulation was improved by HP diet. Liver transcriptome sequencing analysis and further validation identified that alcohol dramatically down-regulated 3-hydroxybutyrate dehydrogenase 2 (<em>Bdh2</em>) along with the reduction of<em> </em>β-hydroxybutyric acid, which were rescued by HP diet intervention. <em>Bdh2 </em>was also decreased in the liver of patients with ALD and alcohol-exposed hepatocytes. Spearman correlation analysis revealed that <em>Bdh2</em> was negatively associated with the indices of hepatic steatosis, liver injury, and oxidative stress. Genetically knocking-down <em>Bdh2 </em>significantly enhanced alcohol-induced hepatotoxicity, lipid accumulation, and pro-inflammatory factors expression in cultured hepatocytes. In summary, HP diet intervention alleviates chronic alcohol consumption induced liver dysfunction in mice. BDH2 is a potential novel target for ALD prevention <em>via</em> restoring the ketogenic pathway that contributes to HP diet-improved ALD. HP dietary pattern might be a promising choice for ALD management.