Abstract
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.
Highlights
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 organspecific physiological functions remain largely undefined
The expression of Hrd[1] was not affected by high-fat diet (HFD) because Hrd[1] mRNA levels are comparable between mice fed with normal chew and HFD (Supplementary Fig. 1a), implying that liver HRD1 expression is regulated by food intake and that HRD1 likely plays an important role in metabolic regulation
We confirmed the elevation of Fgf[21] mRNA by reverse transcriptase–quantitative PCR (qPCR) methods, and we found that the fibroblast growth factor 21 (FGF21) protein levels in the serum were increased after hepatic HRD1 deletion (Supplementary Fig. 10a, b)
Summary
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 organspecific physiological functions remain largely undefined. 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. The contribution of proteolysis leading to key metabolic enzyme turnover, as well as the specific role of ubiquitin E3 ligases, to the regulation metabolic enzyme activity remains to be defined[10]. HMG-CoA reductase degradation protein 1 (HRD1) was identified as an E3 ligase to control cholesterol production through regulation of rate-limiting enzyme HMGCR (HMG-CoA reductase) turnover in yeast[11,12,13]. Consequent studies have shown that HRD1 plays a critical role in endoplasmic reticulum (ER)associated degradation of misfolded/unfolded proteins and protects cells from ER stress-induced cell death[14]. Genetic HRD1 suppression in the liver protected mice from high-fat diet (HFD)-induced obesity, hyperlipidemia, NAFLD, and insulin resistance. We further demonstrated that HRD1 serves as a positive effector of metabolism through direct binding and increase of the ubiquitination of key metabolic enzymes
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