Adipose-Specific Lipin-1 Overexpression Renders Hepatic Ferroptosis and Exacerbates Alcoholic Steatohepatitis in Mice

Lipin-1 is a Mg-dependent phosphatidic acid phosphohydrolase involved in the generation of diacylglycerol during synthesis of phospholipids and triglycerides. Ethanol-mediated inhibitory effects on adipose-specific lipin-1 expression were associated with experimental steatohepatitis in rodents. In the present study, using an adipose-specific lipin-1 overexpression transgenic (-Tg) mouse model, we tested a hypothesis that adipose-specific lipin-1 overexpression in mice might dampen ethanol-induced liver damage. Experimental alcoholic steatohepatitis was induced by pair-feeding ethanol to -Tg and wild-type (WT) mice using the chronic-plus-binge ethanol feeding protocol. Unexpectedly, following the chronic-plus-binge ethanol challenge, -Tg mice exhibited much more pronounced steatosis, exacerbated inflammation, augmented elevation of serum liver enzymes, hepatobiliary damage, and fibrogenic responses compared with the WT mice. Mechanistically, overexpression of adipose lipin-1 in mice facilitated the onset of hepatic ferroptosis, which is an iron-dependent form of cell death, and subsequently induced ferroptotic liver damage in mice under ethanol exposure. Concurrently, adipose lipin-1 overexpression induced defective adiponectin signaling pathways in ethanol-fed mice. : We identified ferroptosis as a mechanism in mediating the detrimental effects of adipose-specific lipin-1 overexpression in mice under chronic-plus-binge ethanol exposure. Our present study sheds light on potential therapeutic approaches for the prevention and treatment of human alcoholic steatohepatitis.