REV-ERBα Activates C/EBP Homologous Protein to Control Small Heterodimer Partner–Mediated Oscillation of Alcoholic Fatty Liver

Abstract

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 Shp mice 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 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 (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 Shp mice, 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 Shp mice 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.

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

“…The small heterodimer partner (SHP, NROB2) is a member of the nuclear receptor superfamily that functions as a transcriptional repressor and is a critical regulator of lipid metabolism 81 . The role of SHP in the pathogenesis of ALD has been extensively investigated in the chronic-plus-binge ethanol feeding model by several groups 82–85 . The data from these studies suggest that SHP plays a complex role in the pathogenesis of ALD via the regulation of ER stress, homocysteine metabolism, hepatic circadian clock, and ethanol catabolism 82–85 .…”

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

“…SHP has been shown to be involved in BA synthesis, lipid and cholesterol metabolism, glucose homeostasis, apoptosis, and cell invasion 36, 37, 38, 39, 40, 41, 42, 43. SHP has also been identified as a mediating factor in the metabolic circadian clock 44, 45, 46, 47, 48. In addition, SHP acts as a transcriptional repressor of microRNA expression and function through interaction with other nuclear receptors 49, 50, 51, 52.…”

Loss of miR-141/200c ameliorates hepatic steatosis and inflammation by reprogramming multiple signaling pathways in NASH

“…Livers were lysed in radio-immunoprecipitation assay buffer (RIPA) containing phosphatase and proteasome cocktail inhibitors as previously described (43). Equal amounts of protein from 5 livers in each group (n = 5 per group) were pooled.…”

“…A piece of liver was fixed in 10% formalin overnight, processed, and embedded in paraffin wax. Approximately 4-μm thick sections were deparaffinized and then stained with H&E and Masson's trichrome (43). Livers embedded in Tissue-Tek OCT compound were cut at 10 μm for F4/80 IHC and Oil Red O staining (35).…”

“…Total RNA was extracted from mouse and human livers using Trizol reagent (MilliporeSigma) according to manufacturer's instructions and then reverse transcribed with the iScript cDNA Synthesis Kit (Bio-Rad). Quantitative PCR (qPCR) was carried out using SYBR Green assay in Bio-Rad Cycler detection system (43). A PCR master mix containing specific primers was used, and HPRT (mouse) or U6 (human) was used as the internal control.…”