The ER-Associated E3 Ligase HRD1 Is a Therapeutic Target for High-Fat Diet-Induced Metabolic Syndrome

Presentation Number: MON 513
Date of Presentation: April 3rd, 2017

Juncheng Wei*
Northwestern University, IL

Abstract

The ER-associated E3 ligase HRD1 is a therapeutic target for high-fat diet-induced metabolic syndrome

Juncheng Wei, Deyu Fang

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

The endoplasmic reticulum (ER) resident ubiquitin ligase HRD1 has been identified as a key enzyme for ER-associated degradation (ERAD) of misfolded proteins, but its organ-specific physiological functions remain largely undefined. Here we showed that mice with targeted HRD1 deletion specifically in the liver display increased energy expenditure and are resistant to HFD-induced obesity and fatty liver disease, even with increased food and water intake. Proteomic analysis identified a HRD1 interactome, a large portion of which includes metabolic regulators. Further biochemical studies demonstrated that HRD1 functions as a ubiquitin ligase of metabolic enzymes including ENTPD5, HSD17B4, and CPT2, all of which are important for hepaticr glucose and lipid metabolism. Loss of HRD1 resulted in elevated expression of ENTPD5, HSD17B4, and CPT2, and a consequent hyperactivation of both AMPK and AKT pathways in the liver. Genome-wide mRNA sequence analysis revealed that HRD1 deletion reprograms liver metabolic gene expression profiles, suppressing both glycogenesis and lipogenesis but facilitating glycolysis and fatty acid oxidation. Finally, we showed that induction of liver-specific HRD1 deletion after 6 weeks of high-fat diet (HFD) efficiently protected against the development of HFD-induced obesity, fatty liver disease, and insulin resistance. Our studies identified HRD1 as a liver metabolic regulator and a potential drug target for obesity, fatty liver disease, and insulin resistance associated with the metabolic syndrome.

 

Nothing to Disclose: JW