Abstract

BACKGROUND: &Aims: Src homology and collagen (Shc) proteins are major adapters to extra-cellular signals however the regulatory role of Shc isoforms in sterile inflammatory responses in alcoholic hepatitis (AH) has not been fully investigated. We hypothesized that in an isoform-specific manner Shc modulates pre-apoptotic signals, calreticulin (CRT) membrane exposure and recruitment of inflammatory cells.METHODS: Liver biopsy samples from patients with AH vs. healthy subjects were studied for Shc expression using DNA microarray data and immunohistochemistry. ShcKD (hypomorph) and age-matched wild type (WT) mice were pair-fed according to the chronic-plus-binge alcohol (NIAAA) diet. To analyze hepatocyte-specific effects, AAV8-TBG-Cre (ShcHepKO)-mediated deletion was performed in fl/fl Shc mice. Lipid peroxidation, proinflammatory signals, redox radicals, NADH/NAD+ ratio, as well as cleaved caspase 8, BAP31, Bax, and Bak, in vivo. CRT translocation was studied in ethanol-exposed p46Shc?SH2-transfected hepatocytes by membrane biotinylation in conjunction with p-Eif2alpha, BAP31, caspase 8, Bax/Bak. The effects of idebenone, a novel Shc inhibitor was studied in alcohol/pair-fed mice.RESULTS: Shc was significantly induced in patients with AH (p<0.01). ALT, NADH/NAD+ ratios, production of redox radicals, lipid peroxidation improved (p<0.05), and IL-1beta, MCP-1, and CXCL10 were reduced in ShcKD and ShcHepKO mice. In vivo, Shc-dependent induction, and in hepatocytes, p46Shc-dependent increase in pre-apoptotic proteins Bax/Bak, caspase 8, BAP31 cleavage and membrane translocation of CRT/Erp57 were seen. Idebenone protected against alcohol-mediated liver injury.CONCLUSION: Alcohol induces p46Shc-dependent activation of pre-apoptotic pathways and translocation of CRT to the membrane, where it acts as a DAMP, instigating immunogenicity. Shc inhibition could be a novel treatment strategy in AH.

View details for DOI 10.1016/j.jcmgh.2022.09.005

View details for PubMedID 36122677