Adipose‐Specific Lipin‐1 Overexpression Renders Hepatic Ferroptosis and Exacerbates Alcoholic Steatohepatitis in Mice.
Creator
Zhou Zhou; Ye Ting Jie; Bonavita Gregory; Daniels Michael; Kainrad Noah; Jogasuria Alvin; You Min
Publisher
Hepatology Communications
Date
2019
2019-05
Description
Lipin‐1 is a Mg2+‐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 (Lpin1‐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 Lpin1‐Tg and wild‐type (WT) mice using the chronic‐plus‐binge ethanol feeding protocol. Unexpectedly, following the chronic‐plus‐binge ethanol challenge, Lpin1‐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. Conclusion: 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. [ABSTRACT FROM AUTHOR]
Intestinal SIRT1 Deficiency Protects Mice from Ethanol-Induced Liver Injury by Mitigating Ferroptosis
Creator
Zhou Zhou; Ye Ting Jie; DeCaro Elizabeth; Buehler Brian; Stahl Zachary; Bonavita Gregory; Daniels Michael; You Min
Publisher
The American Journal Of Pathology
Date
2019
2019-10-11
Description
Aberrant liver sirtuin 1 (SIRT1), a mammalian NAD+-dependent protein deacetylase, is implicated in the pathogenesis of alcoholic liver disease. However, the role of intestinal SIRT1 in alcoholic liver disease is presently unknown. This study investigated the involvement of intestine-specific SIRT1 in ethanol-induced liver dysfunction in mice. Ethanol feeding studies were performed on knockout mice with intestinal-specific SIRT1 deletion [SIRT1i knockout (KO)] and flox control [wild-type (WT)] mice with a chronic-plus-binge ethanol feeding protocol. After ethanol administration, hepatic inflammation and liver injury were substantially attenuated in the SIRT1iKO mice compared with the WT mice, suggesting that intestinal SIRT1 played a detrimental role in the ethanol-induced liver injury. Mechanistically, the hepatic protective effect of intestinal SIRT1 deficiency was attributable to ameliorated dysfunctional iron metabolism, increased hepatic glutathione contents, and attenuated lipid peroxidation, along with normalization of a panel of genes implicated in the ferroptosis process in the livers of ethanol-fed mice. This study demonstrates that ablation of intestinal SIRT1 protected mice from the ethanol-induced inflammation and liver damage. The protective effects of intestinal SIRT1 deficiency are mediated, at least partially, by mitigating hepatic ferroptosis. Targeting intestinal SIRT1 or dampening hepatic ferroptosis signaling may have therapeutic potential for alcoholic liver disease in humans.