期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
卷 1851, 期 1, 页码 19-29出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2014.04.008
关键词
CYP7A1; lipidomics; tauro-beta-muricholic acid; farnesoid X receptor (FXR); bile acid metabolism
资金
- National Cancer Institute Intramural Research Program
- NIDDK, NIH [R37DK058379, R01DK044442]
- NATIONAL CANCER INSTITUTE [ZIABC005708] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R37DK058379, R01DK044442] Funding Source: NIH RePORTER
Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7 alpha-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-beta-muricholic acid (T-beta-MCA) that differed between CYP7A1-tg and wild-type mice. Notably, T-beta-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12 alpha-hydroxylated bile acids and increasing intestinal T-beta-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. (C) 2014 Elsevier B.V. All rights reserved.
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