Dr. Kezhong Zhang recently discovered CREBH-C, a new hepatokine that helps control triglyceride levels  

Kezhong Zhang, PhD

Dr. Kezhong Zhang, Ph.D., Professor of Molecular Medicine and Genetics and of Biochemistry, Microbiology, and Immunology


CREBH, a stress-sensing protein tethered to the cell's endoplasmic reticulum, was discovered more than 10 years ago by Dr. Kezhong Zhang (Professor of Molecular Medicine and Genetics and of Biochemistry, Microbiology and Immunology). Recently, he and his colleagues made the surprising discovery that CREBH can be processed to release a fragment from the carboxy terminus (CREBH-C) that acts as a secreted liver hormone (hepatokine) that regulates an enzyme called lipoprotein lipase. Lipoprotein lipase is the enzyme that primarily clears triglycerides from plasma. How it functions and how its function is regulated are of major importance in seeking to control elevated triglyceride levels and associated metabolic disorders. CREBH-C production is stimulated by fasting or hepatic stress. 


The new work is part of Dr. Zhang's long-time focus on the cellular stress responses originating from the endoplasmic reticulum and/or mitochondria, which are associated with metabolic diseases, autoimmune diseases, and cancer. He will specifically study the role of CREBH-C in regulating lipid metabolism in the whole body. CREBH, as noted above, is a protein factor localized to the ER-membrane that is stress-inducible and implicated in lipid metabolism. It is cleaved into two fragments, one of which, from the amino terminus end of the protein, is sent to the nucleus as a transcription factor for enzymes acting in lipid and glucose metabolism. The other fragment derived from CREBH is the CREBH-C protein that is secreted as a hepatokine. For example, during exercise or fasting, CREBH can be activated to release CREBH-C to increase lipid metabolization to provide energy to the muscles exerting energy. This hormone functions to prevent hyperlipidemia, a condition caused by overnutrition or genetic susceptibility. “With this hormone, hyperlipidemia can be significantly attenuated,” said Dr. Zhang, thus having “very promising potential in the treatment of cardiovascular and metabolic disorders. 


The CREBH-C work is funded by a renewal of Dr. Zhang's grant from the NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases). The CREBH project has been continuously funded by the NIH for the past 15 years and is his fourth successful NIH R01 grant in the last two years. 

Dr. Zhang's collaborators on this project include another Center faculty member, Dr. Ren Zhang (no relation), Associate Professor of Molecular Medicine and Genetics and of Internal Medicine), whose interest in lipid metabolism catalyzed the collaboration. Dr. R. Zhang is a co-investigator on the new NIH grant as well as a coauthor on the recent publication describing the identification of CREBH-C (https://pubmed.ncbi.nlm.nih.gov/36649378/).