The American journal of pathology 2016 9 21() pii 10.1016/j.ajpath.2016.07.014
The small heterodimer partner (SHP) nuclear receptor is an important regulator of nonalcoholic fatty liver disease. However, the molecular mechanisms that underline alcoholic fatty liver controlled by SHP remain elusive. In the present study, we used a modified Gao-binge model of advanced liver disease to examine cyclic alterations of lipid metabolism in wild-type (WT) and Shp(-/-) mice over a 24-hour period after binge. The serum and hepatic lipid profiles, as well as the expression levels of lipid synthesis genes and markers of endoplasmic reticulum stress, exhibited distinct variations in WT and Shp(-/-) mice in response to ethanol diet plus ethanol binge (ED+E) and control diet plus maltose binge. ED+E induced steatosis in WT mice, which correlated with a marked up-regulation of activating transcription factor 4 protein levels but down-regulation of C/EBP homologous protein (CHOP) and sterol regulatory element-binding transcription factor 1c protein levels. On the contrary, the control diet plus maltose binge caused lipid accumulation in Shp(-/-) mice, which was accompanied by a sharp elevation of CHOP, sterol regulatory element-binding transcription factor 1c, and REV-ERBα proteins but diminished levels of activating transcription factor 4 protein. REV-ERBα activated CHOP promoter activity and gene transcription, which were inhibited by SHP. Knockdown of REV-ERBα in Shp(-/-) mice prevented steatosis induced by ED+E. Overall, our study revealed a new regulatory role of SHP and REV-ERBα in the control of rhythmic CHOP expression in alcoholic fatty liver.