Lipidomics Reveals a Link between CYP1B1 and SCD1 in Promoting Obesity

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.

[1]  James B. Mitchell,et al.  Stable isotope- and mass spectrometry-based metabolomics as tools in drug metabolism: a study expanding tempol pharmacology. , 2013, Journal of proteome research.

[2]  C. Jefcoate,et al.  Stimulation of mouse Cyp1b1 during adipogenesis: characterization of promoter activation by the transcription factor Pax6. , 2013, Archives of biochemistry and biophysics.

[3]  Svati H Shah,et al.  A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. , 2009, Cell metabolism.

[4]  R. Vasan,et al.  Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations , 2006, Circulation.

[5]  R. Hargreaves,et al.  Clinical biomarkers in drug discovery and development , 2003, Nature Reviews Drug Discovery.

[6]  V. Vasiliou,et al.  Role of CYP1B1 in glaucoma. , 2008, Annual review of pharmacology and toxicology.

[7]  J. Ntambi,et al.  Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism , 2008, Current opinion in lipidology.

[8]  B. Monia,et al.  Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance. , 2006, The Journal of clinical investigation.

[9]  J. Ntambi,et al.  Regulation of Stearoyl-CoA Desaturase 1 mRNA Stability by Polyunsaturated Fatty Acids in 3T3-L1 Adipocytes* , 1996, The Journal of Biological Chemistry.

[10]  G. De Pergola,et al.  Obesity as a Major Risk Factor for Cancer , 2013, Journal of obesity.

[11]  M. Miyazaki,et al.  Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis. , 2007, Cell metabolism.

[12]  Christian Gieger,et al.  Novel biomarkers for pre-diabetes identified by metabolomics , 2012, Molecular systems biology.

[13]  M. Kleber,et al.  Childhood Obesity Is Associated with Changes in the Serum Metabolite Profile , 2012, Obesity Facts.

[14]  H. Sampath,et al.  Role of Stearoyl-CoA Desaturase-1 in Skin Integrity and Whole Body Energy Balance , 2013, The Journal of Biological Chemistry.

[15]  M. Miyazaki,et al.  Stearoyl-CoA desaturase-1 deficiency attenuates obesity and insulin resistance in leptin-resistant obese mice. , 2009, Biochemical and biophysical research communications.

[16]  J. Lindon,et al.  Metabonomics: a platform for studying drug toxicity and gene function , 2002, Nature Reviews Drug Discovery.

[17]  J. Ward,et al.  Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Ralf Tautenhahn,et al.  Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin. , 2012, Nature chemical biology.

[19]  W. F. Greenlee,et al.  Regulation, function, and tissue-specific expression of cytochrome P450 CYP1B1. , 2001, Annual review of pharmacology and toxicology.

[20]  T. A. Richardson,et al.  Metabolomics reveals that hepatic stearoyl-CoA desaturase 1 downregulation exacerbates inflammation and acute colitis. , 2008, Cell metabolism.

[21]  Jie Lu,et al.  Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co–therapy , 2013, Nature Medicine.

[22]  Svati H Shah,et al.  Differential Metabolic Impact of Gastric Bypass Surgery Versus Dietary Intervention in Obese Diabetic Subjects Despite Identical Weight Loss , 2011, Science Translational Medicine.

[23]  F. Gonzalez.  Cytochrome P450 humanised mice , 2004, Human Genomics.

[24]  X. Wang,et al.  Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes. , 2013, Gastroenterology.

[25]  C. Griffin,et al.  Isolation and Characterization of the Human Cytochrome P450 CYP1B1 Gene* , 1996, The Journal of Biological Chemistry.

[26]  James B. Mitchell,et al.  Metabolomics Reveals That Tumor Xenografts Induce Liver Dysfunction* , 2013, Molecular & Cellular Proteomics.

[27]  M. Nashed.  Role of Stearoyl-CoA desaturase-1 (SCD1) in the activation of epidermal growth factor receptor (EGFR) in lung cancer cells , 2011 .

[28]  C. Jefcoate,et al.  Differentiation of pluripotent C3H10T1/2 cells rapidly elevates CYP1B1 through a novel process that overcomes a loss of Ah Receptor. , 2005, Archives of biochemistry and biophysics.

[29]  J. Schenkman,et al.  Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P450 1b1. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[30]  T. Brüning,et al.  Cytochrome P450 1B1, a new keystone in gene–environment interactions related to human head and neck cancer? , 2002, Archives of Toxicology.

[31]  D. Kardassis,et al.  A Dominant Negative Form of the Transcription Factor c-Jun Affects Genes That Have Opposing Effects on Lipid Homeostasis in Mice* , 2007, Journal of Biological Chemistry.

[32]  D. Oxley,et al.  Disease Biomarkers in Cerebrospinal Fluid of Patients with First-Onset Psychosis , 2006, PLoS medicine.

[33]  B. Spiegelman,et al.  Molecular mechanisms of cancer development in obesity , 2011, Nature Reviews Cancer.

[34]  Marko Sysi-Aho,et al.  Acquired Obesity Is Associated with Changes in the Serum Lipidomic Profile Independent of Genetic Effects – A Monozygotic Twin Study , 2007, PloS one.

[35]  Donald,et al.  Metabolomic Profiling of Fatty Acid and Amino AcidMetabolism in YouthWith Obesity and Type 2 Diabetes Evidence for enhanced mitochondrial oxidation , 2012 .

[36]  G. Bray,et al.  Dietary fat intake does affect obesity! , 1998, The American journal of clinical nutrition.

[37]  S. Imaoka,et al.  Selective deficiency of debrisoquine 4-hydroxylase activity in mouse liver microsomes. , 1997, The Journal of pharmacology and experimental therapeutics.

[38]  Jae Ho Park,et al.  Metabolomic analysis of livers and serum from high-fat diet induced obese mice. , 2011, Journal of proteome research.

[39]  D. Fairlie,et al.  Inflammatory lipid mediators in adipocyte function and obesity , 2010, Nature Reviews Endocrinology.

[40]  B. Miller,et al.  Lipidomic analysis of human plasma reveals ether-linked lipids that are elevated in morbidly obese humans compared to lean , 2013, Diabetology & Metabolic Syndrome.

[41]  Choon Nam Ong,et al.  Metabolic signature shift in type 2 diabetes mellitus revealed by mass spectrometry-based metabolomics. , 2013, The Journal of clinical endocrinology and metabolism.

[42]  F. Gonzalez,et al.  Cytochrome P450 and xenobiotic receptor humanized mice. , 2006, Annual review of pharmacology and toxicology.