REV-ERBα Activates C/EBP Homologous Protein to Control Small Heterodimer Partner-Mediated Oscillation of Alcoholic Fatty Liver.
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.
Department of Physiology and Neurobiology, and the Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.
Zhihong
Z
Yang
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Hiroyuki
H
Tsuchiya
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
Yuxia
Y
Zhang
Department of Physiology and Neurobiology, and the Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut.
Sangmin
S
Lee
Department of Physiology and Neurobiology, and the Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut.
Chune
C
Liu
Department of Physiology and Neurobiology, and the Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Yi
Y
Huang
Department of Physiology and Neurobiology, and the Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut.
Gymar M
GM
Vargas
Department of Physiology and Neurobiology, and the Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut. Electronic address: li.wang@uconn.edu.
Li
L
Wang
D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D000431:Ethanol / Q000009:adverse effects; D005235:Fatty Liver, Alcoholic / Q000209:etiology* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; C099713:nuclear receptor subfamily 0, group B, member 2; D051742:Transcription Factor CHOP; D000431:Ethanol
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