Relationship between carboxylesterase 1 and carboxylesterase 2 gene expression levels and body mass index, and gene polymorphism analysis

doi:10.3969/j.issn.1006-7795.2023.01.003

Abstract

Abstract: Objective To explore the role of carboxylesterase 1(CES1) and carboxylesterase 2 (CES2) in metabolism by detecting gene polymorphisms and gene expression levels ofCES1 and CES2 in healthy volunteers. Methods The DNA was extracted from peripheral blood lymphocytes of 48 volunteers with written consent, and total genomic DNA was sequenced using a target sequencing strategy. The total RNA was extracted to determine gene expression levels. The multiple linear regression was used to analyze the relationship between CES1 and CES2 gene expression and sex, age and body mass index (BMI). Results The expression level of CES1 and CES2 was 141.8 (72.7, 237.8) and 74.4 (30.8, 133.6), respectively. The multiple linear regression analyses indicated that BMI (β = －28.83, P=0.048) had a significant effect on the expression level of CES2. Age, sex, or BMI were not associated with the expression level of CES1. The sequence variants were identified, and 10 of a total of 20 sequence variants of CES1 caused a change in the CES1 amino acid sequence and two of a total of six sequence variants of CES2 caused a change in the CES2 amino acid sequence. Conclusion In this study, we found that the expression level of CES2 was correlated with BMI, while the expression level of CES1 was not significantly correlated with BMI. The results of gene prediction suggested that the genetic variation of CES1 might affect its functional expression.

Key words: carboxylesterase, gene polymorphism, gene expression level, body mass index

CLC Number:

R394

Zhang Jianxiong, Li Dandan, Hu Mengmeng, Cheng Xuewei, Dong Ruihua. Relationship between carboxylesterase 1 and carboxylesterase 2 gene expression levels and body mass index, and gene polymorphism analysis[J]. Journal of Capital Medical University, 2023, 44(1): 13-19.

0
/ Save 0 / Recommend

Add to citation manager EndNote|Reference Manager|ProCite|BibTeX|RefWorks

URL: https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/10.3969/j.issn.1006-7795.2023.01.003

https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/Y2023/V44/I1/13

References

[1] Ryan A S, Serra M C, Goldberg A P. Metabolic benefits of prior weight loss with and without exercise on subsequent 6-month weight regain[J]. Obesity (Silver Spring), 2018, 26(1): 37－44.
[2] Boeing H. Obesity and cancer—the update 2013[J]. Best Pract Res Clin Endocrinol Metab, 2013, 27(2): 219－227.
[3] GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years[J]. N Engl J Med, 2017, 377(1): 13－27.
[4] Cohen J C, Horton J D, Hobbs H H. Human fatty liver disease: old questions and new insights[J]. Science, 2011, 332(6037): 1519－1523.
[5] Quiroga A D, Li L N, Trötzmüller M, et al. Deficiency of carboxylesterase 1/esterase-x results in obesity, hepatic steatosis, and hyperlipidemia[J]. Hepatology, 2012, 56(6): 2188－2198.
[6] Lian J H, Nelson R, Lehner R. Carboxylesterases in lipid metabolism: from mouse to human[J]. Protein Cell, 2018, 9(2): 178－195.
[7] Zou L W, Jin Q, Wang D D, et al. Carboxylesterase inhibitors: an update[J]. Curr Med Chem, 2018, 25(14): 1627－1649.
[8] Yang D F, Pearce R E, Wang X L, et al. Human carboxylesterases HCE1 and HCE2: ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin[J]. Biochem Pharmacol, 2009, 77(2): 238－247.
[9] Imai T, Taketani M, Shii M, et al. Substrate specificity of carboxylesterase isozymes and their contribution to hydrolase activity in human liver and small intestine[J]. Drug Metab Dispos, 2006, 34(10): 1734－1741.
[10] Rasmussen H B, Bjerre D, Linnet K, et al. Individualization of treatments with drugs metabolized by CES1: combining genetics and metabolomics[J]. Pharmacogenomics, 2015, 16(6): 649－665.
[11] Quiroga A D, Lehner R. Role of endoplasmic reticulum neutral lipid hydrolases[J]. Trends Endocrinol Metab, 2011, 22(6): 218－225.
[12] Xu J S, Yin L Y, Xu Y, et al. Hepatic carboxylesterase 1 is induced by glucose and regulates postprandial glucose levels[J]. PLoS One, 2014, 9(10): e109663.
[13] Jernås M, Olsson B, Arner P, et al. Regulation of carboxylesterase 1 (CES1) in human adipose tissue[J]. Biochem Biophys Res Commun, 2009, 383(1): 63－67.
[14] Friedrichsen M, Poulsen P, Wojtaszewski J, et al. Carboxylesterase 1 gene duplication and mRNA expression in adipose tissue are linked to obesity and metabolic function[J]. PLoS One, 2013, 8(2): e56861.
[15] Nagashima S, Yagyu H, Takahashi N, et al. Depot-specific expression of lipolytic genes in human adipose tissues—association among CES1 expression, triglyceride lipase activity and adiposity[J]. J Atheroscler Thromb, 2011, 18(3): 190－199.
[16] Merali Z, Ross S, Paré G. The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect[J]. Drug Metabol Drug Interact, 2014, 29(3): 143－151.
[17] Adzhubei I, Jordan D M, Sunyaev S R. Predicting functional effect of human missense mutations using PolyPhen-2[J]. Curr Protoc Hum Genet, 2013, Chapter 7: Unit7.20.
[18] Thomas P D, Campbell M J, Kejariwal A, et al. PANTHER: a library of protein families and subfamilies indexed by function[J]. Genome Res, 2003, 13(9): 2129－2141.
[19] Ng P C, Henikoff S. SIFT: predicting amino acid changes that affect protein function[J]. Nucleic Acids Res, 2003, 31(13): 3812－3814.
[20] Schwarz J M, Rödelsperger C, Schuelke M, et al. MutationTaster evaluates disease-causing potential of sequence alterations[J]. Nat Methods, 2010, 7(8): 575－576.
[21] Moon Y A, Liang G S, Xie X F, et al. The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals[J]. Cell Metab, 2012, 15(2): 240－246.
[22] Tang J J, Li J G, Qi W, et al. Inhibition of SREBP by a small molecule, betulin, improves hyperlipidemia and insulin resistance and reduces atherosclerotic plaques[J]. Cell Metab, 2011, 13(1): 44－56.
[23] Satoh T, Hosokawa M. Structure, function and regulation of carboxylesterases[J]. Chem Biol Interact, 2006, 162(3): 195－211.
[24] Satoh T, Taylor P, Bosron W F, et al. Current progress on esterases: from molecular structure to function[J]. Drug Metab Dispos, 2002, 30(5): 488－493.
[25] Holmes R S, Wright M W, Laulederkind S J F, et al. Recommended nomenclature for five mammalian carboxylesterase gene families: human, mouse, and rat genes and proteins[J]. Mamm Genome, 2010, 21(9/10): 427－441.
[26] Hosokawa M. Structure and catalytic properties of carboxylesterase isozymes involved in metabolic activation of prodrugs[J]. Molecules, 2008, 13(2): 412－431.
[27] Laizure S C, Herring V, Hu Z Y, et al. The role of human carboxylesterases in drug metabolism: have we overlooked their importance?[J]. Pharmacotherapy, 2013, 33(2): 210－222.
[28] Ross M K, Crow J A. Human carboxylesterases and their role in xenobiotic and endobiotic metabolism[J]. J Biochem Mol Toxicol, 2007, 21(4): 187－196.
[29] Lian J H, Nelson R, Lehner R. Carboxylesterases in lipid metabolism: from mouse to human[J]. Protein Cell, 2018, 9(2): 178－195.
[30] Potter P M, Wolverton J S, Morton C L, et al. Cellular localization domains of a rabbit and a human carboxylesterase: influence on irinotecan (CPT－11) metabolism by the rabbit enzyme[J]. Cancer Res, 1998, 58(16): 3627－3632.
[31] Imai T. Human carboxylesterase isozymes: catalytic properties and rational drug design[J]. Drug Metab Pharmacokinet, 2006, 21(3): 173－185.
[32] Crow J A, Middleton B L, Borazjani A, et al. Inhibition of carboxylesterase 1 is associated with cholesteryl ester retention in human THP-1 monocyte/macrophages[J]. Biochim Biophys Acta, 2008, 1781(10): 643－654.
[33] Bencharit S, Morton C L, Xue Y, et al. Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme[J]. Nat Struct Biol, 2003, 10(5): 349－356.
[34] Wei E H, Ali Y B, Lyon J, et al. Loss of TGH/Ces3 in mice decreases blood lipids, improves glucose tolerance, and increases energy expenditure[J]. Cell Metab, 2010, 11(3): 183－193.
[35] Bie J H, Wang J, Marqueen K E, et al. Liver-specific cholesteryl ester hydrolase deficiency attenuates sterol elimination in the feces and increases atherosclerosis in ldlr- mice[J]. Arterioscler Thromb Vasc Biol, 2013, 33(8): 1795－1802.
[36] Ghosh S. Cholesteryl ester hydrolase in human monocyte/macrophage: cloning, sequencing, and expression of full-length cDNA[J]. Physiol Genomics, 2000, 2(1): 1－8.
[37] Dominguez E, Galmozzi A, Chang J W, et al. Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes[J]. Nat Chem Biol, 2014, 10(2): 113－121.
[38] Li Y Y, Zalzala M, Jadhav K, et al. Carboxylesterase 2 prevents liver steatosis by modulating lipolysis, endoplasmic reticulum stress, and lipogenesis and is regulated by hepatocyte nuclear factor 4 alpha in mice[J]. Hepatology, 2016, 63(6): 1860－1874.
[39] Maresch L K, Benedikt P, Feiler U, et al. Intestine-specific overexpression of carboxylesterase 2c protects mice from diet-induced liver steatosis and obesity[J]. Hepatol Commun, 2019, 3(2): 227－245.
[40] Li Y Y, Zalzala M, Jadhav K, et al. Carboxylesterase 2 prevents liver steatosis by modulating lipolysis, endoplasmic reticulum stress, and lipogenesis and is regulated by hepatocyte nuclear factor 4 alpha in mice[J]. Hepatology, 2016, 63(6): 1860－1874.
[41] 闫建慧. 膳食脂肪酸及CES1基因拷贝数变异与非酒精性脂肪肝病的相关性研究[D]. 福州: 福建医科大学, 2018.
[42] 郑绪雅, 张琳, 张俊峰. 非瓣膜性心房颤动患者ABCB1和CES1基因多态性对达比加群酯抗凝疗效的影响[J]. 临床检验杂志, 2021, 39(12): 903－908.