The American journal of pathologySep 25, 2016

REV-ERBα triggers a stress protein to regulate small heterodimer partner-driven cycles in alcoholic fatty liver

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Updated Mar 31, 2026

Abstract

ED+E induced steatosis in wild-type mice, marked by increased ATF4 and decreased CHOP and SREBP-1c.

Distinct variations in serum and liver lipid profiles were observed in wild-type and Shpmice after ethanol exposure.
Wild-type mice showed steatosis with increased expression of ATF4 and decreased levels of CHOP and SREBP-1c.
In contrast, Shpmice exhibited lipid accumulation after a control diet, marked by elevated CHOP, SREBP-1c, and REV-ERBα, but reduced ATF4.
REV-ERBα was found to activate the CHOP promoter and gene transcription, a process inhibited by SHP.
Knockdown of Rev-Erbα in Shpmice prevented steatosis associated with ethanol exposure.

Simplified

The small heterodimer partner (SHP) nuclear receptor is an important regulator of nonalcoholic fatty liver disease. However, little is known about the role of SHP in alcoholic fatty liver. In this study, we used a modified chronic ethanol-binge model to examine cyclic alterations of lipid metabolism in wild-type (WT) and Shpmice over a 24-hour period after binge. The serum and hepatic lipid profiles, as well as the expression of lipid synthesis genes and markers of endoplasmic reticulum stress, exhibited distinct variations in WT and Shpmice 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 (ATF4) but down-regulation of C/EBP homologous protein (CHOP) and sterol regulatory element-binding transcription factor 1c protein (SREBP-1c). On the contrary, the control diet plus maltose binge caused lipid accumulation in Shpmice, which was accompanied by a sharp elevation of CHOP, SREBP-1c, and REV-ERBα proteins but a diminished ATF4. REV-ERBα activated CHOP promoter activity and gene transcription, which were inhibited by SHP. Knockdown Rev-Erbα in Shpmice prevented steatosis induced by ED+E. Our study revealed a critical role of SHP and REV-ERBα in controlling rhythmic CHOP expression in alcoholic fatty liver. -/--/--/--/-

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REV-ERBα triggers a stress protein to regulate small heterodimer partner-driven cycles in alcoholic fatty liver

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