The research was led by Kezhong Zhang, Ph.D., Professor at the Center for Molecular Medicine and Genetics and the Department of Biochemistry, Microbiology, and Immunology of Wayne State University School of Medicine.
The hepatokine, named CREBH-C, is a fragment derived from the endoplasmic reticulum (ER) protein CREBH. CREBH is a stress sensor that is activated in response to increased energy demands or hepatic stress. In the current study, the researchers showed that CREBH is cleaved to form CREBH-C, which is then secreted from the liver.
CREBH-C has two main functions. First, it blocks the formation of a complex between angiopoietin-like (ANGPTL) 3 and ANGPTL8. This complex inhibits lipoprotein lipase (LPL), an enzyme that breaks down triglycerides in the blood. By blocking the formation of this complex, CREBH-C increases LPL activity and promotes triglyceride clearance from the blood.
Second, CREBH-C promotes the partitioning of triglycerides into peripheral tissues. This is important because it helps to prevent the accumulation of triglycerides in the liver and blood stream, which can lead to fatty liver disease and hypertriglyceridemia.
The researchers found that CREBH-C levels are higher in people with obesity and in individuals after fasting or exercise. This suggests that CREBH-C may be present as a marker for the conditions of severe obesity and other metabolic disorders while it plays a beneficial role in counteracting metabolic diseases associated with hypertriglyceridemia.
Therapeutic Potential of CREBH-C
The researchers are currently investigating the potential of CREBH-C as a therapeutic agent for the treatment of hypertriglyceridemia and the associated cardiovascular and metabolic complications. They are using a variety of approaches to study the effects of CREBH-C in mice, including:
- Administration of CREBH-C protein to mice with hypertriglyceridemia: This has been shown to reduce triglyceride levels in the blood and improve the functions of liver, skeletal muscle, and adipose tissues.
- Gene therapy to increase CREBH-C levels in mice: This has also been shown to reduce triglyceride levels and improve the functions and morphologies of liver, skeletal muscle, heart, kidney, and fat tissues.
- Development of small molecules that mimic the effects of CREBH-C: This could lead to the development of new drugs for the treatment of hypertriglyceridemia.
The researchers are hopeful that their work will lead to the development of new treatments for cardiovascular and metabolic diseases. They believe that CREBH-C is a promising new therapeutic target, and they are excited to continue their research in this area.
About the Author
Kezhong Zhang, Ph.D., is Professor of Molecular Medicine and Genetics and of Biochemistry, Microbiology and Immunology at Wayne State University School of Medicine. He is a leading expert in the fields of cell stress response and lipid metabolism and has published over 160 papers in peer-reviewed journals. Dr. Zhang’s research has focused on understanding the molecular mechanisms underlying the regulation of lipid and glucose metabolism by ER- or mitochondria- originated stress responses. He is also interested in the development of new therapeutic strategies for the treatment of metabolic diseases.
In Conclusion
The research by Dr. Zhang and his colleagues has identified a new hepatokine that has the potential to be a therapeutic target for the treatment of hypertriglyceridemia and other cardiovascular and metabolic diseases. Further studies are needed to confirm the efficacy and safety of CREBH-C as a therapeutic agent. However, the results of this study provide a promising new avenue for the development of treatments for these common human complex diseases.
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