CYP2A6 is associated with obesity: studies in human samples and a high fat diet mouse model

Wang, Kesheng; Chen, Xue; Ward, Stephen; Liu, Ying; Ouédraogo, Youssoufou; Chun, Xu; Cederbaum, Arthur I.; Lu, Yongke

doi:10.1038/s41366-018-0037-x

Cited by 15 publications

(21 citation statements)

References 47 publications

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“…Elevated proinflammatory cytokines in NAFLD have been reported, and this may partially explain the downregulation of CYP1A2 and CYP3A4 activity and protein observed in our study (Liptrott et al, 2009). In contrast to other reports of significant upregulation of CYP2A6 in NAFLD, we found a marginal decrease in the protein expression of the enzyme (Wang et al, 2018). The coumarin hydroxylation activity of the enzyme was similar between control and NAFLD livers.…”

Section: Discussioncontrasting

confidence: 70%

Effect of Non-Alcoholic Fatty Liver Disease (Nafld) on Hepatic Drug Metabolism Enzymes in Human

Jamwal¹

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Significant changes in dietary habits have led to a rampant increase in metabolic disorders. Non-alcoholic fatty liver disease (NAFLD) is one such disorder characterized by the excess buildup of fat in hepatocytes of people who drink little or no alcohol. If not managed, NAFL (simple steatosis) progress into nonalcoholic steatohepatitis (NASH) and further deteriorate to cirrhosis leading to severe illness or even death. Drug disposition proteins (enzymes and transporters) in liver control the systemic exposure of drugs and xenobiotics in human and drive the efficacy as well as adverse events in the body. Therefore, it is critical to address the effect of NAFLD on the abundance of these proteins. A variation would result in an altered pharmacokinetic and/or pharmacodynamic profile of substrate drugs in patients with NAFLD. Most studies were performed in preclinical species (rat, mice) and only a few reports are available in human. The primary objective of this doctoral project was to investigate the effect of NALFD on the abundance of hepatic drug disposition proteins (DDP) in a human liver-bank. The levels of proteins were determined using an LC-MS/MS based label-free, global proteomics method. In addition, CYP3A4 enzyme kinetics parameters were determined using midazolam as a probe substrate. Considerable changes in the protein expression and activity of CYP3A4 and CYP1A2 were found in NAFL and NASH. Only marginal alterations were observed for other cytochrome P450 enzymes in this study. Levels of uridine 5'-diphosphoglucuronosyltransferases (UGT) and sulfotransferases (SULT) in NAFLD were mostly unaltered. Dysregulation of mitochondrial proteins involved in lipid metabolism (ACADSB, ACSM3/5, CPS1) was also observed. A significant downregulation of CYP3A4 protein and activity but not mRNA in NAFLD was observed suggesting that post-transcriptional changes may play a more significant role in the observed phenotypic perturbations for the isoform. Overall, enzyme kinetics and quantitative protein abundance data from this project will be important in the development of physiologically based pharmacokinetic (PBPK) models for prediction of drug disposition in the NAFLD population iv ACKNOWLEDGMENTS First and foremost, I would like to thank and extend my gratitude to my doctoral research advisor, Prof. Fatemeh Akhlaghi. Through this journey of completing my dissertation, she has supported and contributed to my development and growth as a researcher and a person. I am especially indebted to you for believing in me and giving me an opportunity to be a part of your lab. Thank you, Dr. Akhlaghi. I thank my committee member Professors Navindra Seeram and Ingrid Lofgren for their continuous support throughout this process. I also want to acknowledge Prof. Sara Rosenbaum and others who guided and supported me. I would be amiss not to thank Kathleen Hayes for help throughout this journey. I am grateful to my colleagues and friends without whom I couldn't have made it this far. Sravani, thank you for your friendship and support....

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Section: Discussioncontrasting

confidence: 70%

Effect of Non-Alcoholic Fatty Liver Disease (Nafld) on Hepatic Drug Metabolism Enzymes in Human

Jamwal¹

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“…A substantial number of preclinical ( 47 , 96 , 156 – 163 ) and epidemiological ( 164 – 170 ) studies have shown the impact of diets, that result in obesity, with different macronutrient compositions on BC development and disease outcomes. For example, several studies have demonstrated the negative impacts on overall health from diets high in fat content, including cancer outcomes from consumption of Western -style diets, high in poor quality carbohydrates (refined and simple sugars) and saturated fats ( 171 – 176 ).…”

Section: Discussion On Challenges and Gaps For Nutritionally Relevantmentioning

confidence: 99%

“…This communication, which also includes other stromal components (i.e., fibroblasts and tumor-adjacent normal tissue), creates a milieu promoting genetic instability that enhances every aspect of BC progression from increasing proliferation, reducing apoptosis, and facilitating angiogenesis, migration, and ultimately metastasis ( 94 ). In obese women, systemic abnormalities can also include comorbidities like nonalcoholic fatty liver disease, shown to interfere with expression of several cytochrome P450 genes involved in drug metabolism, contributing to obesity-associated reductions chemotherapeutic efficacy ( 95 , 96 ).…”

Section: Mediators Of Inflammation and Immunosuppression In Obesity–bmentioning

confidence: 99%

Mechanistic Targets and Nutritionally Relevant Intervention Strategies to Break Obesity–Breast Cancer Links

et al. 2021

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The worldwide prevalence of overweight and obesity has tripled since 1975. In the United States, the percentage of adults who are obese exceeds 42.5%. Individuals with obesity often display multiple metabolic perturbations, such as insulin resistance and persistent inflammation, which can suppress the immune system. These alterations in homeostatic mechanisms underlie the clinical parameters of metabolic syndrome, an established risk factor for many cancers, including breast cancer. Within the growth-promoting, proinflammatory milieu of the obese state, crosstalk between adipocytes, immune cells and breast epithelial cells occurs via obesity-associated hormones, angiogenic factors, cytokines, and other mediators that can enhance breast cancer risk and/or progression. This review synthesizes evidence on the biological mechanisms underlying obesity-breast cancer links, with emphasis on emerging mechanism-based interventions in the context of nutrition, using modifiable elements of diet alone or paired with physical activity, to reduce the burden of obesity on breast cancer.

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“…Previously when we studied cytochrome P-450 2A6 (CYP2A6) and its mouse ortholog CYP2A5 in the development of alcoholassociated fatty liver disease (ALD), we found that alcohol feeding induces CYP2A5 in mouse liver (21,23), and ALD was more severe in cyp2a5 knockout (cyp2a5 À/À ) mice than in wild-type (WT) mice, suggesting that CYP2A5 protects against ALD (4,12). The protective effects of CYP2A5 are also observed in NAFLD, i.e., HFD-induced obesity and hepatic steatosis are also more severe in cyp2a5 À/À mice than in WT mice (39). Interestingly, the basal level of peroxisome proliferator-activated receptor a (PPARa) was elevated in the cyp2a5 À/À mice (4,12,39).…”

Section: Introductionmentioning

confidence: 98%

“…The protective effects of CYP2A5 are also observed in NAFLD, i.e., HFD-induced obesity and hepatic steatosis are also more severe in cyp2a5 À/À mice than in WT mice (39). Interestingly, the basal level of peroxisome proliferator-activated receptor a (PPARa) was elevated in the cyp2a5 À/À mice (4,12,39). PPARa is a well-known lipid metabolism regulator.…”

Section: Introductionmentioning

confidence: 99%

High-fat diet induces fibrosis in mice lacking CYP2A5 and PPARα: a new model for steatohepatitis-associated fibrosis

Chen

Acquaah‐Mensah

Denning

et al. 2020

American Journal of Physiology-Gastrointestinal and Liver Physi

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Obesity is linked to non-alcoholic steatohepatitis. PPARα regulates lipid metabolism. CYP2A5 is a potential antioxidant and CYP2A5 induction by ethanol is CYP2E1-dependent. High fat diet (HFD)-induced obesity and steatosis are more severe in CYP2A5 knockout (cyp2a5-/-) mice than in wild-type mice although PPARα is elevated in cyp2a5-/- mice. To examine why the up-regulated PPARα failed to prevent the enhanced steatosis in cyp2a5-/- mice, we abrogate the up-regulated PPARα in cyp2a5-/- mice by cross-breeding cyp2a5-/- mice with PPARα knockout (pparα-/-) mice to create pparα-/-/cyp2a5-/- mice. The pparα-/-/cyp2a5-/- mice, pparα-/- mice, and cyp2a5-/- mice were fed HFD to induce steatosis. After HFD feeding, more severe steatosis was developed in pparα-/-/cyp2a5-/- mice than in pparα-/- mice and cyp2a5-/- mice. The pparα-/-/cyp2a5-/- mice and pparα-/-mice exhibited comparable and impaired lipid metabolism. Elevated serum ALT and liver IL-1β, liver inflammatory cell infiltration, foci of hepatocellular ballooning were observed in pparα-/-/cyp2a5-/- mice but not in pparα-/- mice and cyp2a5-/- mice. In pparα-/-/cyp2a5-/- mice, although redox sensitive transcription factor Nrf2 and its target antioxidant genes were upregulated as a compensation, thioredoxin was suppressed, and phosphorylation of JNK and formation of nitrotyrosine adduct were increased. liver glutathione was decreased, and lipid peroxidation was increased. Interestingly, inflammation and fibrosis were all observed within the clusters of lipid droplets, and these lipid droplet clusters were all located inside the area with CYP2E1 positive staining. These results suggest that HFD-induced fibrosis in pparα-/-/cyp2a5-/- mice is associated with steatosis, and CYP2A5 interacts with PPARα to participate in regulating steatohepatitis-associated fibrosis.

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CYP2A6 is associated with obesity: studies in human samples and a high fat diet mouse model

Abstract: 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.

Cited by 15 publications

References 47 publications

Effect of Non-Alcoholic Fatty Liver Disease (Nafld) on Hepatic Drug Metabolism Enzymes in Human

Effect of Non-Alcoholic Fatty Liver Disease (Nafld) on Hepatic Drug Metabolism Enzymes in Human

Mechanistic Targets and Nutritionally Relevant Intervention Strategies to Break Obesity–Breast Cancer Links

High-fat diet induces fibrosis in mice lacking CYP2A5 and PPARα: a new model for steatohepatitis-associated fibrosis

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