CYP2A6 (CYP2A5 in mice) is mainly expressed in the liver. Hepatic CYP2A6 expression is increased in patients with non-alcoholic fatty liver disease (NAFLD). In mice, hepatic CYP2A5 is induced by high fat diet (HFD) feeding. Hepatic CYP2A5 is also increased in monosodium glutamate-induced obese mice. NAFLD is associated with obesity. In this study, we examined whether obesity is related to CYP2A6.
Obesity genetic association study: The SAGE is a comprehensive genome-wide association study (GWAS) with case subjects having a lifetime history of alcohol dependence and control subjects never addicted to alcohol. We used 1030 control individuals with self-reported height and weight. A total of 12 single nucleotide polymorphisms (SNP) within the CYP2A6 gene were available. Obesity was determined as a BMI ≥30: 30–34.9 (Class I obesity) and ≥35 (Class II and III obesity). Animal experiment study: CYP2A5 knockout (cyp2a5−/−) mice and wild type (cyp2a5+/+) mice were fed HFD for 14 weeks. Body weight was measured weekly. After an overnight fast, the mice were sacrificed. Liver and blood were collected for biochemical assays.
Single marker analysis showed that three SNPs (rs8192729, rs7256108, and rs7255443) were associated with class I obesity (p < 0.05). The most significant SNP for obesity was rs8192729 (odds ratio (OR) = 1.94, 95% confidence intervals = 1.21–3.10, p = 0.00582). After HFD feeding, body weight was increased in cyp2a5−/− mice to a greater extent than in cyp2a5+/+ mice, and fatty liver was more pronounced in cyp2a5−/− mice than in cyp2a5+/+ mice. PPARα deficiency in cyp2a5−/− mice developed more severe fatty liver, but body weight was not increased significantly.
CYP2A6 is associated with human obesity; CYP2A5 protects against obesity and NAFLD in mice. PPARα contributes to the CYP2A5 protective effects on fatty liver but it opposes to the protective effects on obesity.
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Funding support for the SAGE was provided through the NIH Genes, Environment and Health Initiative (GEI) Grant U01 HG004422. SAGE is one of the GWAS funded as part of the GENEVA under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (Grant U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples were provided by COGA (Grant U10 AA008401), COGEND (Grant P01 CA089392), and FSCD (Grant R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by NIH GEI Grant U01HG004438, NIAAA, NIDA, and the NIH contract “High throughput genotyping for studying the genetic contributions to human disease” (HHSN268200782096C). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi study_id = phs000092.v1.p1 through dbGaP accession number phs000092.v1.p.1. We thank Dr. Xinxin Ding for the cyp2a5−/− mice, Dr. Jerome Lasker for anti-CYP2E1 IgG, and Dr. Risto Juvonen for anti-CYP2A5 IgG.
This study is partially supported by USPHS grants AA-024723 from the National Institute on Alcohol Abuse and Alcoholism and National Institute of Health grant C06RR0306551.
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The authors declare that they have no conflict of interest.
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Wang, K., Chen, X., Ward, S.C. et al. CYP2A6 is associated with obesity: studies in human samples and a high fat diet mouse model. Int J Obes 43, 475–486 (2019). https://doi.org/10.1038/s41366-018-0037-x