Northwestern Medicine scientists have demonstrated that a protein called HRD1 is a novel regulator of liver metabolism and could serve as a potential therapeutic target for obesity, type 2 diabetes and related conditions.
The study, published in Nature Communications, was led by Deyu Fang, PhD, the Hosmer Allen Johnson Professor of Pathology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Metabolic syndrome is a group of conditions — including hypertension, excessive abdominal fat and insulin resistance — that increases the risk of heart disease and diabetes. An estimated one in four Americans have metabolic syndrome, and its prevalence is increasing.
Metabolic syndrome is associated with the dysregulation of metabolic enzymes involved in the synthesis of glucose, lipid and proteins in the liver. But while many areas of metabolic enzyme regulation have been extensively studied, the role of protein degradation — and specific proteins in the process called ubiquitin E3 ligases — has been largely undefined.
In the current study, scientists demonstrated that a ubiquitin E3 ligase called HRD1 serves as a critical metabolic regulator in the liver, controlling the expression levels of metabolic enzymes.
“We demonstrated that HRD1 catalyzes a cascade of critical metabolic enzymes for ubiquitination to mediate their degradation,” Fang explained.
The scientists further found that when HRD1 was genetically suppressed in the liver of mice, the turnover of metabolic enzymes was inhibited — leading to decreased lipid and glycogen synthesis and increased energy expenditure.
As a result, mice without HRD1 in the liver who were fed a high-fat diet were resistant to developing obesity, fatty liver disease and insulin resistance — hallmarks of metabolic syndrome.
“Our discovery that HRD1 suppression promotes energy expenditure and decreases lipid synthesis provides a rationale for the therapeutic targeting of HRD1 to prevent or treat metabolic disorders,” Fang said.
Still, the authors note that it is too early to conclude that systemically inhibiting HRD1 would be an ideal therapy to treat metabolic disease, and much more research is needed.
Fang’s laboratory is currently analyzing HRD1 expression in patients with obesity and type 2 diabetes, as well as in healthy controls. The team is also screening small molecules to inhibit HRD1 enzyme activity and testing its therapeutic potentials in treating metabolic syndrome.
In a separate study published recently in The Embo Journal, Fang’s laboratory demonstrated that HRD1 in the liver suppresses production of a metabolic regulator called FGF21, through degradation of the transcription factor CREBH. Through this pathway, HRD1 plays a role in regulating growth, circadian behavior and female fertility in mice.
Juncheng Wei, PhD, a postdoctoral fellow, was a first author of both studies.
Other Northwestern authors of the Nature Communications paper include Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care and Cell and Molecular Biology; Clara Peek, PhD, assistant professor of Biochemistry and Molecular Genetics and of Medicine in the Division of Endocrinology, Metabolism and Molecular Medicine; Yuanming Xu and Johanna Melo-Cardenas, doctoral students in the Fang laboratory; Yajun Wang; Yi Yang; and Beixue Gao.
The study, a collaboration between scientists at Northwestern and the Beijing Institute of Lifeomics in China, was supported by grants from the Special Funds for Major State Basic Research of China (2014CBA02001), the National Institutes of Health (NIH) R01 grants (AI079056, AI108634, and AR006634), and NIH grant DK090313 and 5P01AG049665.