January 19, 2023

WSU scientists discover new stress hormone that counteracts metabolic disorders

The research team included, pictured from left, Hyunbae Kim, Ph.D., Kezhong Zhang, Ph.D., and Zhenfeng Song, Ph.D.

A research team led by Professor Kezhong Zhang, Ph.D., at the Wayne State University School of Medicine’s Center for Molecular Medicine and Genetics and the Department of Biochemistry, Microbiology and Immunology, has made a key discovery in a stress-induced hormone produced by the liver called hepatokine. The finding could be used to counteract hyperlipidemia and the associated cardiovascular and metabolic diseases. Hyperlipidemia is a metabolic disorder in which the blood contains too many lipids, or fats, such as triglycerides and cholesterol, stuck in the circulation. One type, hypertriglyceridemia, a condition in which circulating triglyceride levels are elevated, is a common health problem in the United States, Dr. Zhang said.

Hypertriglyceridemia, often caused by an excessive intake of nutrition, abnormal lifestyles or environmental stress, increases the risk of stroke, heart attack and type-2 diabetes. Metabolic disorder researchers like Dr. Zhang are seeking effective ways to counteract hyperlipidemia by safely decreasing or depositing blood triglycerides.

Dr. Zhang and colleagues discovered the novel hepatokine, a hormone derived from a membrane protein called CREBH, in response to increased energy demands or stress challenges, such as those induced by fasting. The hepatokine, named “CREBH-C,” can stimulate triglyceride breakdown and promote blood triglyceride and fatty acid clearance.

“Treating animals under a high-fat diet with CREBH-C decreased circulating lipid amounts and increased triglyceride and fatty acid uptake by fat-burning muscle or fat storage tissues, thereby reversing the condition of hyperlipidemia,” Dr. Zhang said.

The related discoveries were published in “A hepatokine derived from the ER protein CREBH promotes triglyceride metabolism by stimulating lipoprotein lipase activity,” and featured as a cover story in the journal Science Signaling.

“Our discovery reveals a new paradigm that a metabolic hormone can be derived from a cell organelle membrane protein under stress conditions. This will have high impact on many areas of biomedical research.” Dr. Zhang said. "As shown by our work, CREBH-C acts as a physiological booster of blood lipid clearance and uptake. CREBH-C may be utilized for drug intervention to control hyperlipidemia and the associated cardiovascular and metabolic disorders, such as atherosclerosis, type-2 diabetes and non-alcoholic fatty liver disease.”

Dr. Zhang’s laboratory has long studied mechanisms and impacts of stress responses in health and disease. His team at Wayne State conducted a series of projects defining the functions and mechanisms of cell stress sensors and signaling pathways in metabolism and metabolic disease. The discovery of the new stress hormone CREBH-C may provide an effective avenue to modulating lipid metabolism for therapeutic benefit for cardiovascular and metabolic diseases, he added.

Wayne State University researchers, including Assistant Professor Hyunbae Kim, Ph.D., Research Associate Zhenfeng Song, Ph.D., and Associate Professor Ren Zhang, Ph.D., M.D., contributed to the work. University of Iowa Associate Professor Brandon Davies, Ph.D., collaborated with the WSU team.

The work was partially supported by the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases (grant Nos. DK090313, DK126908, DK132065), National Heart, Lung and Blood Institute (grant Nos. HL130146, HL134787), and a Pilot and Feasibility Grant from the Michigan Diabetes Research Center (NIH P30-DK020572).

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