title: Bile acid signaling in lipid metabolism: metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice.
abstract: Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7α-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-β-muricholic acid (T-β-MCA) that differed between CYP7A1-tg and wild-type mice. Notably, T-β-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12α-hydroxylated bile acids and increasing intestinal T-β-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.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Tiangang
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Ferrell
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA. Electronic address: jchiang@neomed.edu.
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chiang
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000235:genetics / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000379:methods; D005260:Female; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D055442:Metabolome / Q000235:genetics*; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013656:Taurocholic Acid / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; C037351:tauromuricholic acid; D013656:Taurocholic Acid; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D005947:Glucose
keywords: CYP7A1; bile acid metabolism; farnesoid X receptor (FXR); lipidomics; tauro-β-muricholic acid