title: Lipidomics reveals a link between CYP1B1 and SCD1 in promoting obesity.
abstract: Cytochrome P450 1B1 (CYP1B1) is involved in the metabolism of xenobiotic compounds and endogenous metabolites. Disruption of Cyp1b1 in mice results in suppression of high-fat diet (HFD)-induced obesity and an extensive change in hepatic energy regulation despite minimal constitutive expression of CYP1B1 in hepatocytes. Lack of CYP1B1 is correlated with altered lipid metabolism, especially lysophosphatidylcholines, contributing to protection against obesity. Ultraperformance liquid chromatography coupled to electrospray ionization quadrupole mass spectrometry (UPLC-ESI-QTOFMS)-based metabolomics revealed lysophosphatidylcholine 18:0 (LPC 18:0) as a biomarker positively related to HFD-induced obesity. The increased serum LPC 18:0 in wild-type mice is reduced in Cyp1b1-null mice on a HFD, which is reversed in CYP1B1-humanized mice. CYP1B1-humanized mice show higher diet-induced obesity compared with Cyp1b1-null mice, suggesting that human CYP1B1 shows a similar response to HFD as mouse Cyp1b1. In addition, hepatic stearoyl-CoA desaturase 1 (SCD1) expression was decreased in Cyp1b1-null mice, and the attenuated diet-induced obesity and lower serum LPC 18:0 in the Cyp1b1-null mice is elevated after SCD1 overexpression, suggesting that SCD1 is correlated with CYP1B1-induced obesity. These studies establish a biochemical link between cytochromes P450, lipids, and metabolic disorders and suggest that inhibition of CYP1B1 could be target for antiobesity drugs.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.forename: Michele C
authors.initials: MC
authors.lastname: Larsen
authors.forename: Justin
authors.initials: J
authors.lastname: Bushkofsky
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Colin R
authors.initials: CR
authors.lastname: Jefcoate
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D002853:Chromatography, Liquid / Q000379:methods; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D015870:Gene Expression; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000097:blood; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D055432:Metabolomics / Q000379:methods; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D008244:Lysophosphatidylcholines; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase