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.

Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis

“…However, the blood glucose, measured in males, was decreased at all time-points in Cyp1b1-ko mice fed the LFD and HFD, relative to their WT counterparts, without significant decreases in the area under the curve (AUC) (Figure 3B). The AUC were, however, significantly decreased at this 11 week time point in our second study [38]. After 33 weeks, the glucose tolerance curves of the females on the LFD were similar to those of the 11 week males.…”

“…The detailed findings for mice from the 11 week studies have been recently described [38]. Interestingly, the 18:0 LPC parallels the cholesterol ester/obesity response, whereas the other major LPC, 16:0, is unaffected by these conditions.…”

Cyp1b1 deletion and retinol deficiency coordinately suppress mouse liver lipogenic genes and hepcidin expression during post-natal development

“…Cytochrome P450 1b1 ( Cyp1b1 ) is an atypical P450, demonstrating extra-hepatocyte expression and the capacity to metabolize endogenous substrates, such as estradiol, polyunsaturated fatty acids, and retinol (Chambers et al, 2007, Jennings et al, 2014, Larsen et al, 2015, Li et al, 2014). Cyp1b1 is expressed in many types of support cells, including mesenchymal progenitor cells, endothelia, pericytes, macrophage, and stellate cells (Choudhary et al, 2003, Piscaglia et al, 1999, Tang et al, 2009).…”

“…These clusters demonstrate functional links to [1] growth hormone signaling through HNF4α, [2] leptin suppression of fatty acid synthesis genes, including stearoyl-coenzyme A desaturase 1 ( Scd1 ), and [3] suppression of postprandial inflammation derived from a high carbohydrate diet (Bushkofsky et al, 2016, Larsen et al, 2015). Overexpression of Scd1 in Cyp1b1−/− mice restores adiposity and DIO on a post-weaning high fat diet (Li et al, 2014). …”

Syndrome de Bardet-Biedl : cils et obésité

“…À cet égard, l'étude des BBS, qui a permis de révéler un rôle direct du tissu adipeux, complémentaire de celui de l'axe hypothalamique, est sans doute emblématique des futures recherches à mettre en oeuvre pour l'exploration de voies potentiellement associées au développement de l'obésité, et aussi pour l'identification de nouveaux biomarqueurs. L'obésité, maladie complexe et multifactorielle, a déjà été abordée via de nombreuses approches haut débit allant des études d'associations de type GWAS (genome wide association study) [52], des recherches de variants structuraux de type CNV (copy number variation) [53] ou des études de variations épigénétiques [54], jusqu'aux analyses basées sur des transcriptomes [55], protéomes [56], métabolomes [57] et récemment, des liposomes [58] ou des sécrétomes [59]. Cependant, au vu de nos résultats sur la biologie du tissu adipeux, ou des récents travaux sur la communication pancréas-tissu adipeux [60], seule une approche multi-niveaux, intégrant les différentes techniques haut débit pourra déchiffrer la variété des signaux et des communications interorganes (cross-talks) intervenant dans l'obésité ( Figure 1C).…”