Original articles
Pei Wang, Xueyan Shao, Yifan Bao, Junjie Zhu, Liming Chen, Lirong Zhang, Xiaochao Ma, Xiao-bo Zhong. Impact of obese levels on the hepatic expression of nuclear receptors and drug-metabolizing enzymes in adult and offspring mice[J]. Acta Pharmaceutica Sinica B, 2020, 10(1): 171-185

Impact of obese levels on the hepatic expression of nuclear receptors and drug-metabolizing enzymes in adult and offspring mice
Pei Wanga,b, Xueyan Shaob, Yifan Baob, Junjie Zhuc, Liming Chenb, Lirong Zhanga, Xiaochao Mac, Xiao-bo Zhongb
a Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China;
b Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA;
c Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
The prevalence of obesity-associated conditions raises new challenges in clinical medication. Although altered expression of drug-metabolizing enzymes (DMEs) has been shown in obesity, the impacts of obese levels (overweight, obesity, and severe obesity) on the expression of DMEs have not been elucidated. Especially, limited information is available on whether parental obese levels affect ontogenic expression of DMEs in children. Here, a high-fat diet (HFD) and three feeding durations were used to mimic different obese levels in C57BL/6 mice. The hepatic expression of five nuclear receptors (NRs) and nine DMEs was examined. In general, a trend of induced expression of NRs and DMEs (except for Cyp2c29 and 3a11) was observed in HFD groups compared to low-fat diet (LFD) groups. Differential effects of HFD on the hepatic expression of DMEs were found in adult mice at different obese levels. Family-based dietary style of an HFD altered the ontogenic expression of DMEs in the offspring older than 15 days. Furthermore, obese levels of parental mice affected the hepatic expression of DMEs in offspring. Overall, the results indicate that obese levels affected expression of the DMEs in adult individuals and that of their children. Drug dosage might need to be optimized based on the obese levels.
Key words:    Diet-induced obesity    Overweight    High-fat diet    Drug-metabolizing enzymes    Nuclear receptors    Ontogenic expression   
Received: 2019-06-19     Revised: 2019-08-30
DOI: 10.1016/j.apsb.2019.10.009
Funds: This work was supported by the National Institutes of Health (Grant R01GM118367 to Xiao-bo Zhong, USA). Pei Wang was supported by the China Scholarship Council (Grant 201707040007).
Corresponding author: Xiao-bo Zhong     Email:xiaobo.zhong@uconn.edu
Author description:
PDF(KB) Free
Pei Wang
Xueyan Shao
Yifan Bao
Junjie Zhu
Liming Chen
Lirong Zhang
Xiaochao Ma
Xiao-bo Zhong

1. World Health Organization. reportObesity: preventing and managing the global epidemic. Report of a WHO consultation (WHO Technical Report Series 894). Available from: https://www.who.int/nutrition/publications/obesity/WHO_TRS_894/en/.
2. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet 2017;390:2627-42.
3. Liu JX, Wang YT, Lin LG. Small molecules for fat combustion: targeting obesity. Acta Pharm Sin B 2019;9:220-36.
4. World Health Organization. Fact sheets: obesity and overweight. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.
5. Zhang YX, Wang ZX, Zhao JS, Chu ZH. The current prevalence and regional disparities in general and central obesity among children and adolescents in Shandong, China. Int J Cardiol 2017;227:89-93.
6. Stokes A, Collins JM, Grant BF, Hsiao CW, Johnston SS, Ammann EM, et al. Prevalence and determinants of engagement with obesity care in the United States. Obesity 2018;26:814-8.
7. Ahirwar R, Mondal PR. Prevalence of obesity in India: a systematic review. Diabetes Metab Syndr 2019;13:318-21.
8. GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377: 13-27.
9. Hurt RT, Kulisek C, Buchanan LA, McClave SA. The obesity epidemic: challenges, health initiatives, and implications for gastroenterologists. Gastroenterol Hepatol 2010;6:780-92.
10. Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis 2010;28:155-61.
11. Temple JL, Cordero P, Li JW, Nguyen V, Oben JA. A guide to nonalcoholic fatty liver disease in childhood and adolescence. Int J Mol Sci 2016;17:E947.
12. Fromenty B. Drug-induced liver injury in obesity. J Hepatol 2013;58: 824-6.
13. Ghoneim RH, Ngo Sock ET, Lavoie JM, Piquette-Miller M. Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition. Br J Nutr 2015;113: 507-16.
14. Natale S, Bradley J, Nguyen WH, Tran T, Ny P, La K, et al. Pediatric obesity: pharmacokinetic alterations and effects on antimicrobial dosing. Pharmacotherapy 2017;37:361-78.
15. Chomchai S, Chomchai C. Being overweight or obese as a risk factor for acute liver injury secondary to acute acetaminophen overdose. Pharmacoepidemiol Drug Saf 2018;27:19-24.
16. Gade C, Dalhoff K, Petersen TS, Riis T, Schmeltz C, Chabanova E, et al. Higher chlorzoxazone clearance in obese children compared with nonobese peers. Br J Clin Pharmacol 2018;84:1738-47.
17. Sun P, Zhu JJ, Wang T, Huang Q, Zhou YR, Yu BW, et al. Benzbromarone aggravates hepatic steatosis in obese individuals. Biochim Biophys Acta Mol Basis Dis 2018;1864:2067-77.
18. Emond C, DeVito MJ, Diliberto JJ, Birnbaum LS. The influence of obesity on the pharmacokinetics of dioxin in mice: an assessment using classical and PBPK modeling. Toxicol Sci 2018;164:218-28.
19. Brill MJE, Diepstraten J, van Rongen A, van Kralingen S, van den Anker JN, Knibbe CAJ. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet 2012;51: 277-304.
20. Brill MJE, van Rongen A, Houwink API, Burggraaf J, van Ramshorst B, Wiezer RJ, et al. Midazolam pharmacokinetics in morbidly obese patients following semi-simultaneous oral and intravenous administration: a comparison with healthy volunteers. Clin Pharmacokinet 2014;53:931-41.
21. Ulvestad M, Skottheim IB, Jakobsen GS, Bremer S, Molden E, Asberg A, et al. Impact of OATP1B1, MDR1, and CYP3A4 expression in liver and intestine on interpatient pharmacokinetic variability of atorvastatin in obese subjects. Clin Pharmacol Ther 2013;93:275-82.
22. van Rongen A, Välitalo PAJ, Peeters MYM, Boerma D, Huisman FW, van Ramshorst B, et al. Morbidly obese patients exhibit increased CYP2-1-mediated oxidation of acetaminophen. Clin Pharmacokinet 2016;55:833-47.
23. Mittwede PN, Clemmer JS, Bergin PF, Xiang L. Obesity and critical illness: insights from animal models. Shock 2016;45:349-58.
24. Kleinert M, Clemmensen C, Hofmann SM, Moore MC, Renner S, Woods SC, et al. Animal models of obesity and diabetes mellitus. Nat Rev Endocrinol 2018;14:140-62.
25. Kanasaki K, Koya D. Biology of obesity: lessons from animal models of obesity. J Biomed Biotechnol 2011;2011:197636.
26. Lutz TA, Woods SC. Overview of animal models of obesity. Curr Protoc Pharmacol 2012;58:5.61.1-5.61.18.
27. Chu DT, Malinowska E, Jura M, Kozak LP. C57BL/6J mice as a polygenic developmental model of diet-induced obesity. Physiol Rep 2017;5:e13093.
28. Ning M, Jeong H. High-fat diet feeding alters expression of hepatic drug-metabolizing enzymes in mice. Drug Metab Dispos 2017;45: 707-11.
29. Tomankova V, Anzenbacher P, Anzenbacherova E. Effects of obesity on liver cytochromes P450 in various animal models. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2017;161:144-51.
30. Zhang L, Xu PP, Cheng Y, Wang PL, Ma XR, Liu MY, et al. Dietinduced obese alters the expression and function of hepatic drugmetabolizing enzymes and transporters in rats. Biochem Pharmacol 2019;164:368-76.
31. Morgan K, Uyuni A, Nandgiri G, Mao L, Castaneda L, Kathirvel E, et al. Altered expression of transcription factors and genes regulating lipogenesis in liver and adipose tissue of mice with high fat dietinduced obesity and nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2008;20:843-54.
32. Sahoo K, Sahoo B, Choudhury AK, Sofi NY, Kumar R, Bhadoria AS. Childhood obesity: causes and consequences. J Fam Med Prim Care 2015;4:187-92.
33. Kumar S, Kelly AS. Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment. Mayo Clin Proc 2017;92:251-65.
34. Piekos SC, Chen LM, Wang PC, Shi J, Yaqoob S, Zhu HJ, et al. Consequences of phenytoin exposure on hepatic cytochrome P450 expression during postnatal liver maturation in mice. Drug Metab Dispos 2018;46:1241-50.
35. Schlezinger JJ, Struntz WDJ, Goldstone JV, Stegeman JJ. Uncoupling of cytochrome P450 1A and stimulation of reactive oxygen species production by co-planar polychlorinated biphenyl congeners. Aquat Toxicol 2006;77:422-32.
36. Gao N, Zou D, Qiao HL. Concentration-dependent inhibitory effect of Baicalin on the plasma protein binding and metabolism of chlorzoxazone, a CYP2-1 probe substrate, in rats in vitro and in vivo. PLoS One 2013;8:e53038.
37. Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 2003;306:287-300.
38. Lam JL, Jiang Y, Zhang T, Zhang EY, Smith BJ. Expression and functional analysis of hepatic cytochromes P450, nuclear receptors, and membrane transporters in 10-and 25-week-old db/db mice. Drug Metab Dispos 2010;38:2252-8.
39. Peng L, Yoo B, Gunewardena SS, Lu H, Klaassen CD, Zhong XB. RNA sequencing reveals dynamic changes of mRNA abundance of cytochromes P450 and their alternative transcripts during mouse liver development. Drug Metab Dispos 2012;40:1198-209.
40. Lu H, Gunewardena S, Cui JY, Yoo B, Zhong XB, Klaassen CD. RNA-sequencing quantification of hepatic ontogeny and tissue distribution of mRNAs of phase II enzymes in mice. Drug Metab Dispos 2013;41:844-57.
41. Fan WM, Xu YL, Liu Y, Zhang ZQ, Lu LM, Ding ZD. Obesity or overweight, a chronic inflammatory status in male reproductive system, leads to mice and human subfertility. Front Physiol 2017;8: 1117.
42. Fan Y, Liu Y, Xue K, Gu GB, Fan WM, Xu YL, et al. Diet-induced obesity in male C57BL/6 mice decreases fertility as a consequence of disrupted blood-testis barrier. PLoS One 2015;10:e0120775.
43. Pantasri T, Norman RJ. The effects of being overweight and obese on female reproduction: a review. Gynecol Endocrinol 2014;30:90-4.
44. Hohos NM, Skaznik-Wikiel ME. High-fat diet and female fertility. Endocrinology 2017;158:2407-19.
45. Hariri N, Thibault L. High-fat diet-induced obesity in animal models. Nutr Res Rev 2010;23:270-99.
46. Eshima H, Tamura Y, Kakehi S, Kurebayashi N, Murayama T, Nakamura K, et al. Long-term, but not short-term high-fat diet induces fiber composition changes and impaired contractile force in mouse fast-twitch skeletal muscle. Physiol Rep 2017;5:e13250.
47. Le JM, Zhang XY, Jia WP, Zhang Y, Luo JT, Sun YN, et al. Regulation of microbiotaeGLP1 axis by sennoside A in diet-induced obese mice. Acta Pharm Sin B 2019;9:758-68.
48. Shang Y, Khafipour E, Derakhshani H, Sarna LK, Woo CW, Siow YL, et al. Short term high fat diet induces obesity-enhancing changes in mouse gut microbiota that are partially reversed by cessation of the high fat diet. Lipids 2017;52:499-511.
49. Kim KA, Gu W, Lee IA, Joh EH, Kim DH. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One 2012;7:e47713.
50. Kawasaki N, Asada R, Saito A, Kanemoto S, Imaizumi K. Obesityinduced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Sci Rep 2012;2:799.
51. Williams LM, Campbell FM, Drew JE, Koch C, Hoggard N, Rees WD, et al. The development of diet-induced obesity and glucose intolerance in C57BL/6 mice on a high-fat diet consists of distinct phases. PLoS One 2014;9:e106159.
52. Long RT, Zeng WS, Chen LY, Guo J, Lin YZ, Huang QS, et al. Bifidobacterium as an oral delivery carrier of oxyntomodulin for obesity therapy: inhibitory effects on food intake and body weight in overweight mice. Int J Obes 2010;34:712-9.
53. Jia JB, Li FF, Zhou HY, Bai YH, Liu SJ, Jiang YG, et al. Oral exposure to silver nanoparticles or silver ions may aggravate fatty liver disease in overweight mice. Environ Sci Technol 2017;51:9334-43.
54. Hussain MA, Abogresha NM, Hassan R, Tamany DA, Lotfy M. Effect of feeding a high-fat diet independently of caloric intake on reproductive function in diet-induced obese female rats. Arch Med Sci 2016; 12:906-14.
55. Peyot ML, Pepin E, Lamontagne J, Latour MG, Zarrouki B, Lussier R, et al. Beta-cell failure in diet-induced obese mice stratified according to body weight gain: secretory dysfunction and altered islet lipid metabolism without steatosis or reduced beta-cell mass. Diabetes 2010;59:2178-87.
56. Lee HJ, Jo SB, Romer AI, Lim HJ, Kim MJ, Koo SH, et al. Overweight in mice and enhanced adipogenesis in vitro are associated with lack of the hedgehog coreceptor boc. Diabetes 2015;64:2092-103.
57. Tomankova V, Liskova B, Skalova L, Bartikova H, Bousova I, Jourova L, et al. Altered cytochrome P450 activities and expression levels in the liver and intestines of the monosodium glutamate-induced mouse model of human obesity. Life Sci 2015;133:15-20.
58. Ghose R, Omoluabi O, Gandhi A, Shah P, Strohacker K, Carpenter KC, et al. Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters. Life Sci 2011;89:57-64.
59. Yoshinari K, Takagi S, Yoshimasa T, Sugatani J, Miwa M. Hepatic CYP3A expression is attenuated in obese mice fed a high-fat diet. Pharm Res 2006;23:1188-200.
60. Yang L, Li Y, Hong HX, Chang CW, Guo LW, Lyn-Cook B, et al. Sex differences in the expression of drug-metabolizing and transporter genes in human liver. J Drug Metab Toxicol 2012;3:1000119.
61. Perl K, Ushakov K, Pozniak Y, Yizhar-Barnea O, Bhonker Y, Shivatzki S, et al. Reduced changes in protein compared to mRNA levels across non-proliferating tissues. BMC Genom 2017;18:305.
62. Maier T, Gu ëll M, Serrano L. Correlation of mRNA and protein in complex biological samples. FEBS Lett 2009;583:3966-73.
63. Xu K, Sun Y, Sheng B, Zheng Y, Wu X, Xu K. Role of identified RNA N6-methyladenosine methylation in liver. Anal Biochem 2019;578: 45-50.
64. Wang P, Nie YL, Wang SJ, Yang LL, Yang WH, Li JF, et al. Regulation of UGT1A expression by miR-298 in human livers from the Han Chinese population and in human cell lines. Epigenomics 2018; 10:43-57.
65. Smutny T, Mani S, Pavek P. Post-translational and post-transcriptional modifications of pregnane X receptor (PXR) in regulation of the cytochrome P450 superfamily. Curr Drug Metab 2013;14:1059-69.
66. Rigano D, Sirignano C, Taglialatela-Scafati O. The potential of natural products for targeting PPARa. Acta Pharm Sin B 2017;7:427-38.
67. Tanaka N, Aoyama T, Kimura S, Gonzalez FJ. Targeting nuclear receptors for the treatment of fatty liver disease. Pharmacol Ther 2017; 179:142-57.
68. Li XL, Wang ZM, Klaunig JE. Modulation of xenobiotic nuclear receptors in high-fat diet induced non-alcoholic fatty liver disease. Toxicology 2018;410:199-213.
69. Larsen MC, Bushkofsky JR, Gorman T, Adhami V, Mukhtar H, Wang SQ, et al. Cytochrome P450 1B1: an unexpected modulator of liver fatty acid homeostasis. Arch Biochem Biophys 2015;571: 21-39.
70. Yoshinari K, Takagi S, Sugatani J, Miwa M. Changes in the expression of cytochromes P450 and nuclear receptors in the liver of genetically diabetic db/db mice. Biol Pharm Bull 2006;29:1634-8.
71. Tajima M, Ikarashi N, Okaniwa T, Imahori Y, Saruta K, Toda T, et al. Consumption of a high-fat diet during pregnancy changes the expression of cytochrome P450 in the livers of infant male mice. Biol Pharm Bull 2013;36:649-57.
72. Platt KM, Charnigo RJ, Pearson KJ. Adult offspring of high-fat dietfed dams can have normal glucose tolerance and body composition. J Dev Orig Health Dis 2014;5:229-39.
73. DuBois BN, O’Tierney-Ginn P, Pearson J, Friedman JE, Thornburg K, Cherala G. Maternal obesity alters feto-placental cytochrome P4501A1 activity. Placenta 2012;33:1045-51.
74. Fuemmeler BF, Lovelady CA, Zucker NL, Østbye T. Parental obesity moderates the relationship between childhood appetitive traits and weight. Obesity 2013;21:815-23.