| Author |
Cheng, Jie Krausz, Kristopher W. Gonzalez, Frank J. Jiang, Changtao Li, Tiangang Qi, Yunpeng Chiang, John Y. L. Ferrell, Jessica M. |
| Description |
Author Affiliation: Qi Y ( Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA); Jiang C ( Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.); Cheng J ( Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA); Krausz KW ( Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.); Li T ( Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.); Ferrell JM ( Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.); Gonzalez FJ ( Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.); Chiang JY ( Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA. Electronic address: jchiang@neomed.edu.) |
| Abstract |
Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7 -hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway in the liver and plays an important role in regulating lipid, glucose and energy metabolism. Transgenic mice overexpressing CYP7A1 (CYP7A1-tg mice) were resistant to high-fat diet (HFD)-induced obesity, fatty liver, and diabetes. However the mechanism of resistance to HFD-induced obesity of CYP7A1-tg mice has not been determined. In this study, metabolomic and lipidomic profiles of CYP7A1-tg mice were analyzed to explore the metabolic alterations in CYP7A1-tg mice that govern the protection against obesity and insulin resistance by using ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry combined with multivariate analyses. Lipidomics analysis identified seven lipid markers including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides that were significantly decreased in serum of HFD-fed CYP7A1-tg mice. Metabolomics analysis identified 13 metabolites in bile acid synthesis including taurochenodeoxycholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, taurocholic acid, and tauro-ß-muricholic acid (T-ß-MCA) that differed between CYP7A1-tg and wild-type mice. Notably, T-ß-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12 -hydroxylated bile acids and increasing intestinal T-ß-MCA may reduce high fat diet-induced increase of phospholipids, sphingomyelins and ceramides, and ameliorate diabetes and obesity. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. |
| Subject Keyword |
Bile Acids And Salts Metabolism Diabetes Mellitus Lipid Metabolism Physiology Metabolome Genetics Obesity Animals Cholesterol 7-alpha-Hydroxylase Diet, High-Fat Glucose Homeostasis Insulin Resistance Intestines Liver Metabolomics Mice Mice, Inbred C57BL Mice, Transgenic Signal Transduction Taurocholic Acid Analogs & Derivatives Research Support, N.I.H., Intramural Biochemistry |
