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

• Published in: Biochimica et biophysica acta Vol. 1851; no. 1; pp. 19 - 29
• Main Authors: Qi, Yunpeng, Jiang, Changtao, Cheng, Jie, Krausz, Kristopher W., Li, Tiangang, Ferrell, Jessica M., Gonzalez, Frank J., Chiang, John Y.L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2015
• Subjects: Animals; antagonists; bile acid metabolism; Bile Acids and Salts - genetics; Bile Acids and Salts - metabolism; biochemical pathways; blood serum; ceramides; cholesterol; Cholesterol 7-alpha-Hydroxylase - genetics; Cholesterol 7-alpha-Hydroxylase - metabolism; cholesterol 7alpha-monooxygenase; CYP7A1; diabetes; Diabetes Mellitus - genetics; Diabetes Mellitus - metabolism; Diet, High-Fat - methods; energy metabolism; farnesoid X receptor (FXR); fatty liver; Female; gene overexpression; glucose; Glucose - genetics; Glucose - metabolism; high fat diet; Homeostasis; Insulin Resistance; intestines; Intestines - metabolism; ionization; lipid metabolism; Lipid Metabolism - physiology; lipidomics; liver; Liver - metabolism; lysophosphatidylcholine; Male; mass spectrometry; metabolites; Metabolome - genetics; metabolomics; Metabolomics - methods; Mice; Mice, Inbred C57BL; Mice, Transgenic; multivariate analysis; obesity; Obesity - genetics; Obesity - metabolism; Rats; Signal Transduction; sphingomyelins; tauro-β-muricholic acid; taurocholic acid; Taurocholic Acid - analogs & derivatives; Taurocholic Acid - genetics; Taurocholic Acid - metabolism; transgenic animals; FXR; tauro-β-muricholic acid; HFD; UPLC-ESI-QTOFMS; UDCA; CYP7A1; α-MCA; SM; bile acid metabolism; CA; CDCA; DCA; farnesoid X receptor (FXR); OPLS-DA; TDCA; T-β-MCA; PLS-DA; TCDCA; PCA; CER; PC; TCA; CYP7A1-tg mice; β-MCA; LPC; lipidomics
• ISSN: 1388-1981; 0006-3002; 1879-2618
• DOI: 10.1016/j.bbalip.2014.04.008

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. •Lipidomics identified 7 lipid markers decreased in HFD-fed CYP7A1-tg mice.•Metabolomics identified 13 bile acid metabolites that were altered in CYP7A1-tg mice.•Bile acids protect against HDF-induced obesity and insulin resistance.