Circadian clock mediates ER stress signaling in alcoholic fatty liver (1116.12)

Abstract

[Purpose] This is the first study to investigate how alcohol regulates ER stress and fatty liver through nuclear receptor SHP mediated liver circadian clock machinery.[Methods] The NIAAA EtOH binge model was established using 8 weeks old, male C57BL/6 (WT) and SHP‐/‐ (SKO) mice (Nat Protoc 2013; 8:627‐637). In brief, the mice were acclimatized to a control liquid diet for 5 days, then fed with 5% Lieber‐DeCarli diet or pair‐fed for 10 days. By day 11, the mice were gavaged maltose (control) or EtOH solutions at zeitgeber time (ZT) 3 (9 am) and sacrificed at ZT12, 18, 0, and 6.[Results] Metabolomics by GC/MS revealed a global alteration by alcohol in the oscillation of serum intermediate metabolites in pathways of glucose, lipid and amino acid metabolism in SKO mice. The rhythmic expression of core clock genes (Clock, Bmal1, Npas2) and nuclear receptors (Rorα, Rorγ, Rev‐erbα) were disturbed by alcohol. Hepatic lipid metabolic genes and ER stress markers exhibited strong oscillations which were perturbed by alcohol. Chop was a clock controlled gene through the Rorα/Rorγ/Rev‐erbα/SHP regulatory cascade. Liver SREBP‐1c protein cleavage and TG content were drastically induced in control SKO livers, which was markedly decreased by alcohol in both WT and SKO mice.[Conclusions] SHP mediated clock machinery is significantly disrupted by alcohol, which in turn perturbs ER stress to control AFL.Grant Funding Source: Supported by AHA and NIDDK