Regulation of hepatic circadian metabolism by the E3 ubiquitin ligase HRD1-controlled CREBH/PPARα transcriptional program

Feb 16, 2021Molecular metabolism

How the liver's daily metabolism is controlled by HRD1 through the CREBH and PPARα gene program

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Hepatic HRD1 and Sel1L expression shows circadian rhythmicity influenced by CREBH, PPARα, and BMAL1.

HRD1/Sel1L is involved in the process of tagging the CREBH protein for degradation, which affects the expression of key genes in metabolic pathways.
Liver-specific knockout of HRD1 leads to increased expression of genes related to lipid and glucose metabolism, indicating its role in metabolic regulation.
Impaired circadian rhythms of circulating triglycerides, fatty acids, and glucose were observed in HRD1 knockout mice due to elevated levels of CREBH.
The circadian metabolic patterns in HRD1 knockout mice were found to be opposite to those in CREBH knockout mice.
Restoration of normal levels of circulating triglycerides and fatty acids in HRD1 knockout mice occurred when CREBH overproduction was suppressed.

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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.

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Regulation of hepatic circadian metabolism by the E3 ubiquitin ligase HRD1-controlled CREBH/PPARα transcriptional program

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