TY - JOUR
T1 - Regulation of hepatic circadian metabolism by the E3 ubiquitin ligase HRD1-controlled CREBH/PPARα transcriptional program
AU - Kim, Hyunbae
AU - Wei, Juncheng
AU - Song, Zhenfeng
AU - Mottillo, Emilio
AU - Samavati, Lobelia
AU - Zhang, Ren
AU - Li, Li
AU - Chen, Xuequn
AU - Jena, Bhanu P.
AU - Lin, Jiandie D.
AU - Fang, Deyu
AU - Zhang, Kezhong
N1 - Funding Information:
Portions of this work were supported by National Institutes of Health (NIH) grants DK090313 and ES017829 (to KZ), AR066634 (to DF and KZ), DK120330 (to DF), DK110314 (to XC), American Heart Association Grants 0635423Z and 09GRNT2280479 (to KZ), and a Pilot and Feasibility Grant (to HK) from the Michigan Diabetes Research Center (NIH Grant P30-DK020572).
Publisher Copyright:
© 2021 The Authors
PY - 2021/7
Y1 - 2021/7
N2 - Objective: The endoplasmic reticulum (ER)-resident E3 ligase HRD1 and its co-activator Sel1L are major components of ER-associated degradation (ERAD) machinery. Here, we investigated the molecular mechanism and functional significance underlying the circadian regulation of HRD1/Sel1L-mediated protein degradation program in hepatic energy metabolism. Methods: Genetically engineered animal models as well as gain- and loss-of-function studies were employed to address the circadian regulatory mechanism and functional significance. Gene expression, transcriptional activation, protein–protein interaction, and animal metabolic phenotyping analyses were performed to dissect the molecular network and metabolic pathways. Results: Hepatic HRD1 and Sel1L expression exhibits circadian rhythmicity that is controlled by the ER-tethered transcriptional activator CREBH, the nuclear receptor peroxisome proliferator-activated receptor α (PPARα), and the core clock oscillator BMAL1 in mouse livers. HRD1/Sel1L mediates polyubiquitination and degradation of the CREBH protein across the circadian cycle to modulate rhythmic expression of the genes encoding the rate-limiting enzymes or regulators in fatty acid (FA) oxidation, triglyceride (TG) lipolysis, lipophagy, and gluconeogenesis. HRD1 liver-specific knockout (LKO) mice displayed increased expression of the genes involved in lipid and glucose metabolism and impaired circadian profiles of circulating TG, FA, and glucose due to overproduction of CREBH. The circadian metabolic activities of HRD1 LKO mice were inversely correlated with those of CREBH KO mice. Suppressing CREBH overproduction in the livers of HRD1 LKO mice restored the diurnal levels of circulating TG and FA of HRD1 LKO mice. Conclusion: Our work revealed a key circadian-regulated molecular network through which the E3 ubiquitin ligase HRD1 and its co-activator Sel1L regulate hepatic circadian metabolism.
AB - Objective: The endoplasmic reticulum (ER)-resident E3 ligase HRD1 and its co-activator Sel1L are major components of ER-associated degradation (ERAD) machinery. Here, we investigated the molecular mechanism and functional significance underlying the circadian regulation of HRD1/Sel1L-mediated protein degradation program in hepatic energy metabolism. Methods: Genetically engineered animal models as well as gain- and loss-of-function studies were employed to address the circadian regulatory mechanism and functional significance. Gene expression, transcriptional activation, protein–protein interaction, and animal metabolic phenotyping analyses were performed to dissect the molecular network and metabolic pathways. Results: Hepatic HRD1 and Sel1L expression exhibits circadian rhythmicity that is controlled by the ER-tethered transcriptional activator CREBH, the nuclear receptor peroxisome proliferator-activated receptor α (PPARα), and the core clock oscillator BMAL1 in mouse livers. HRD1/Sel1L mediates polyubiquitination and degradation of the CREBH protein across the circadian cycle to modulate rhythmic expression of the genes encoding the rate-limiting enzymes or regulators in fatty acid (FA) oxidation, triglyceride (TG) lipolysis, lipophagy, and gluconeogenesis. HRD1 liver-specific knockout (LKO) mice displayed increased expression of the genes involved in lipid and glucose metabolism and impaired circadian profiles of circulating TG, FA, and glucose due to overproduction of CREBH. The circadian metabolic activities of HRD1 LKO mice were inversely correlated with those of CREBH KO mice. Suppressing CREBH overproduction in the livers of HRD1 LKO mice restored the diurnal levels of circulating TG and FA of HRD1 LKO mice. Conclusion: Our work revealed a key circadian-regulated molecular network through which the E3 ubiquitin ligase HRD1 and its co-activator Sel1L regulate hepatic circadian metabolism.
KW - Circadian metabolism
KW - ER-associated degradation
KW - Endoplasmic reticulum
KW - Lipid metabolism
KW - Transcriptional regulation
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UR - http://www.scopus.com/inward/citedby.url?scp=85102295379&partnerID=8YFLogxK
U2 - 10.1016/j.molmet.2021.101192
DO - 10.1016/j.molmet.2021.101192
M3 - Article
C2 - 33592335
AN - SCOPUS:85102295379
VL - 49
JO - Molecular Metabolism
JF - Molecular Metabolism
SN - 2212-8778
M1 - 101192
ER -