Ncb5or in Fatty Acid Desaturation and Metabolic Diseases
I discovered the human Ncb5or gene during my postdoctoral training at Harvard Medical School by mining the genome database. Ncb5or, or NADH-cytochrome b5 oxidoreductase, is a novel redox enzyme, and the Ncb5or gene has been found to be conserved in all other animals studied. The biological relevance of Ncb5or became apparent after the gene was knocked out in mice through gene-specific targeting. The Ncb5or knockout mice develop both lipodystrophy (fat loss) and diabetes early in life. All males develop diabetes, while penetrance in females varies depending on diet composition and feeding behavior. The Ncb5or knockout mice also display dry fur, lactation problems and osteoporosis.
We are studying how Ncb5or functions in cells, in tissues and in the whole organism. Our focuses are fatty acid desaturation, triglyceride synthesis and utilization, glucose metabolism, pancreatic beta-cell function, and the impact of the overall signaling process on energy balance. We are employing techniques from biochemistry, cell biology, physiology and histology to analyze these processes in various tissues, including adipose tissues, liver and pancreas. The goal is to understand all the steps during development of lipodystrophy and diabetes in Ncb5or knockout mice. We hope these studies will provide new insights into the prevention and treatment of obesity and diabetes.
New concept in fatty acid desaturation
Earlier biochemical studies on stearoyl-CoA desaturation in isolated liver microsomes suggested that three components are necessary to reconstitute the enzymatic activity: stearoyl-CoA desaturase (SCD), cytochrome b5 (b5), and cytochrome b5 reductase (b5R). The latter two are thought to serve as electron donors to SCD, which converts saturated (stearoyl-CoA) into monounsaturated (oleoyl-CoA) fatty acids. Our in vivo and in vitro experiments and analysis of Ncb5or knockout mice demonstrate for the first time that Ncb5or, a natural fusion of b5 and b5R domains, substitutes for the classical counterparts in the SCD reaction. This concept shifts the paradigm of how stearoyl-CoA desaturation works.
Understanding the physiological roles of saturated and unsaturated fatty acids
While both saturated and unsaturated fatty acids can be used as energy sources in animals, little is known about their physiological differences and impact. Since the Ncb5or knockout mice lack de novo synthesis of oleic acid, a crucial monounsaturated fatty acid, this animal model can help us understand the biochemical and physiological importance of monounsaturated fatty acids in lipid synthesis and energy homeostasis.
Intervention through diet and exercise
Deficiency in stearoyl-CoA desaturation leads to both lipodystrophy and diabetes in Ncb5or knockout mice. We will test the possibility of rescuing these phenotypes by supplementing their diet with monounsaturated lipids. In addition, Ncb5or knockout mice eat significantly more than the normal littermates, and this feeding behavior is linked to the penetrance of diabetes in females. We will test whether caloric restriction or exercise can decrease the extra circulating lipids and delay or even alleviate diabetes in these mice.
This work is supported by the National Institutes of Health and the School of Health Professions, KU Medical Center.
For more information, please contact:
Hao Zhu, PhD, Diabetes Research Group
2146 W. 39th Avenue
Kansas City, KS 66160