ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes

The HMG-CoA reductase degradation protein 1 (HRD1) has been identified as a key enzyme for endoplasmic reticulum-associated degradation of misfolded proteins, but its organ-specific physiological functions remain largely undefined. Here we show that mice with HRD1 deletion specifically in the liver display increased energy expenditure and are resistant to HFD-induced obesity and liver steatosis and insulin resistance. Proteomic analysis identifies a HRD1 interactome, a large portion of which includes metabolic regulators. Loss of HRD1 results in elevated ENTPD5, CPT2, RMND1, and HSD17B4 protein levels and a consequent hyperactivation of both AMPK and AKT pathways. Genome-wide mRNA sequencing revealed that HRD1-deficiency reprograms liver metabolic gene expression profiles, including suppressing genes involved in glycogenesis and lipogenesis and upregulating genes involved in glycolysis and fatty acid oxidation. We propose HRD1 as a liver metabolic regulator and a potential drug target for obesity, fatty liver disease, and insulin resistance associated with the metabolic syndrome.Special Funds for Major State Basic Research of China [2014CBA02001]; National Institutes of Health (NIH) [AI079056, AI108634, AR006634]; NIH [DK090313, 5P01AG049665]Open access journal.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu