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

Zhou, Zhou; Ye, Ting Jie; Bonavita, G; Daniels, Michael J.; Kainrad, Noah; Jogasuria, Alvin; You, Min

doi:10.1002/hep4.1333

Cited by 44 publications

(38 citation statements)

References 41 publications

(179 reference statements)

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“…Of interest, augmented iron concentrations were found in the livers of ethanol-fed female mice compared with ethanol-fed male mice. 15,37 It is possible that the sex-specific responses in hepatic iron contents may lead to the sex differences in ferroptosis and liver damage in mice after ethanol challenge. The detailed mechanisms underlying sex differences in ferroptosis and their relationship with ethanol-induced liver damage are currently under investigation in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Hematoxylin and eosin staining and Prussian Blue staining were performed with a commercial staining kit (Sigma, St. Louis, MO). 15 Immunohistochemistry staining of myeloperoxidase (MPO) was performed with a primary MPO antibody (Biocare Medical, Pacheco, CA) and a horseradish peroxidaseebased secondary detection kit (Vector Laboratories, Burlingame, CA).…”

Section: Histologic Analysismentioning

confidence: 99%

“…5,6,12 Iron Assay Iron concentrations were measured with an Iron Assay Kit (ab83366; Abcam) according to the manufacturer's instructions. 5,15 GSH and NADP þ and NADPH Assays Hepatic glutathione (GSH) level was assessed with a GSH luminesce assay kit (Promega, Madison, WI) according to the manufacturer's instructions. 15 Hepatic nicotinamide adenine dinucleotide phosphate (NADP) þ and NADPH concentrations were assessed with a NADPH colorimetric assay kit (Abcam).…”

Section: Mpo Activity Assaymentioning

confidence: 99%

“…Liver glutathione peroxidase (GPX) enzyme activity was analyzed with a commercialized colorimetric assay kit (Biovision). 15…”

Section: Gpx Activity Assaymentioning

confidence: 99%

“…Primary antibodies and secondary antibodies linked with horseradish peroxidase were used for detection as previously described. 5,6,15…”

Section: Western Blot Analysismentioning

confidence: 99%

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Intestinal SIRT1 Deficiency Protects Mice from Ethanol-Induced Liver Injury by Mitigating Ferroptosis

Zhou

DeCaro

et al. 2020

The American Journal of Pathology

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Aberrant liver sirtuin 1 (SIRT1), a mammalian NAD þ-dependent protein deacetylase, is implicated in the pathogenesis of alcoholic liver disease (ALD). However, the role of intestinal SIRT1 in ALD 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 chroniceplusbinge 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 inhibition 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 ALD in humans.

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Section: Discussionmentioning

confidence: 99%