REVIEW

Carboxylesterases in lipid metabolism: from mouse to human

  • Jihong Lian , 1,2 ,
  • Randal Nelson 1,2 ,
  • Richard Lehner 1,2,3
Expand
  • 1. Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
  • 2. Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
  • 3. Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada

Received date: 02 Mar 2017

Accepted date: 31 May 2017

Published date: 22 Mar 2018

Copyright

2017 The Author(s) 2017. This article is an open access publication

Abstract

Mammalian carboxylesterases hydrolyze a wide range of xenobiotic and endogenous compounds, including lipid esters. Physiological functions of carboxylesterases in lipid metabolism and energy homeostasis in vivo have been demonstrated by genetic manipulations and chemical inhibition in mice, and in vitro through (over)expression, knockdown of expression, and chemical inhibition in a variety of cells. Recent research advances have revealed the relevance of carboxylesterases to metabolic diseases such as obesity and fatty liver disease, suggesting these enzymes might be potential targets for treatment of metabolic disorders. In order to translate pre-clinical studies in cellular and mouse models to humans, differences and similarities of carboxylesterases between mice and human need to be elucidated. This review presents and discusses the research progress in structure and function of mouse and human carboxylesterases, and the role of these enzymes in lipid metabolism and metabolic disorders.

Cite this article

Jihong Lian , Randal Nelson , Richard Lehner . Carboxylesterases in lipid metabolism: from mouse to human[J]. Protein & Cell, 2018 , 9(2) : 178 -195 . DOI: 10.1007/s13238-017-0437-z

1
Aida K, Moore R, Negishi M (1993) Cloning and nucleotide sequence of a novel, male-predominant carboxylesterase in mouse liver . Biochim Biophys Acta 1174:72–74

DOI

2
Aizawa Y, Seki N, Nagano T, Abe H (2015) Chronic hepatitis C virus infection and lipoprotein metabolism . World J Gastroenterol 21:10299–10313

DOI

3
Alam M, Ho S, Vance DE, Lehner R (2002a) Heterologous expression, purification, and characterization of human triacylglycerol hydrolase . Protein Expr Purif 24:33–42

DOI

4
Alam M, Vance DE, Lehner R (2002b) Structure-function analysis of human triacylglycerol hydrolase by site-directed mutagenesis: identification of the catalytic triad and a glycosylation site . Biochemistry 41:6679–6687

DOI

5
Alam M, Gilham D, Vance DE, Lehner R (2006) Mutation of F417 but not of L418 or L420 in the lipid binding domain decreases the activity of triacylglycerol hydrolase . J Lipid Res 47:375–383

DOI

6
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr, International Diabetes Federation Task Force on Epidemiology and Prevention, Hational Heart, Lung, and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity . Circulation 120:1640–1645

DOI

7
Alexander CA, Hamilton RL, Havel RJ (1976) Subcellular localization of B apoprotein of plasma lipoproteins in rat liver . J Cell Biol 69:241–263

DOI

8
Alikhani N, Ferguson RD, Novosyadlyy R, Gallagher EJ, Scheinman EJ, Yakar S, LeRoith D (2013) Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model . Oncogene 32:961–967

DOI

9
Bahar FG, Ohura K, Ogihara T, Imai T (2012) Species difference of esterase expression and hydrolase activity in plasma . J Pharm Sci 101:3979–3988

DOI

10
Bahitham W, Watts R, Nelson R, Lian J, Lehner R (2016) Liverspecific expression of carboxylesterase 1g/esterase-x reduces hepatic steatosis, counteracts dyslipidemia and improves insulin signaling . Biochim Biophys Acta 1861:482–490

DOI

11
Basen-Engquist K, Chang M (2011) Obesity and cancer risk: recent review and evidence . Curr Oncol Rep 13:71–76

DOI

12
Beloribi-Djefaflia S, Vasseur S, Guillaumond F (2016) Lipid metabolic reprogramming in cancer cells . Oncogenesis 5:e189

DOI

13
Bencharit S, Morton CL, Howard-Williams EL, Danks MK, Potter PM, Redinbo MR (2002) Structural insights into CPT-11 activation by mammalian carboxylesterases . Nat Struct Biol 9:337–342

DOI

14
Bencharit S, Morton CL, Hyatt JL, Kuhn P, Danks MK, Potter PM, Redinbo MR (2003a) Crystal structure of human carboxylesterase 1 complexed with the Alzheimer’s drug tacrine: from binding promiscuity to selective inhibition . Chem Biol 10:341–349

DOI

15
Bencharit S, Morton CL, Xue Y, Potter PM, Redinbo MR (2003b) Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme . Nat Struct Biol 10:349–356

DOI

16
Bie J, Wang J, Marqueen KE, Osborne R, Kakiyama G, Korzun W, Ghosh SS, Ghosh S (2013) Liver-specific cholesteryl ester hydrolase deficiency attenuates sterol elimination in the feces and increases atherosclerosis in ldlr−/− mice . Arterioscler Thromb Vasc Biol 33:1795–1802

DOI

17
Bilz S, Samuel V, Morino K, Savage D, Choi CS, Shulman GI (2006) Activation of the farnesoid X receptor improves lipid metabolism in combined hyperlipidemic hamsters . Am J Physiol Endocrinol Metab 290:E716–722

DOI

18
Birner-Gruenberger R, Susani-Etzerodt H, Waldhuber M, Riesenhuber G, Schmidinger H, Rechberger G, Kollroser M, Strauss JG, Lass A, Zimmermann R, Haemmerle G, Zechner R, Hermetter A (2005) The lipolytic proteome of mouse adipose tissue . Mol Cell Proteomics 4:1710–1717

DOI

19
Blais DR, Lyn RK, Joyce MA, Rouleau Y, Steenbergen R, Barsby N, Zhu LF, Pegoraro AF, Stolow A, Tyrrell DL, Pezacki JP (2010) Activity-based protein profiling identifies a host enzyme, carboxylesterase 1, which is differentially active during hepatitis C virus replication . J Biol Chem 285:25602–25612

DOI

20
Brasaemle DL, Dolios G, Shapiro L, Wang R (2004) Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes . J Biol Chem 279:46835–46842

DOI

21
Breitling J, Aebi M (2013) N-linked protein glycosylation in the endoplasmic reticulum . Cold Spring Harb Perspect Biol 5: a013359

DOI

22
Brenneman DE, Mathur SN, Spector AA (1975) Characterization of the hyperlipidemia in mice bearing the Ehrlich ascites tumor . Eur J Cancer 11:225–230

DOI

23
Brocca S, Secundo F, Ossola M, Alberghina L, Carrea G, Lotti M (2003) Sequence of the lid affects activity and specificity of Candida rugosa lipase isoenzymes . Protein Sci 12:2312–2319

DOI

24
Buchebner M, Pfeifer T, Rathke N, Chandak PG, Lass A, Schreiber R, Kratzer A, Zimmermann R, Sattler W, Koefeler H, Frohlich E, Kostner GM, Birner-Gruenberger R, Chiang KP, Haemmerle G, Zechner R, Levak-Frank S, Cravatt B, Kratky D (2010) Cholesteryl ester hydrolase activity is abolished in HSL−/−macrophages but unchanged in macrophages lacking KIAA1363 . J Lipid Res 51:2896–2908

DOI

25
Bulleid NJ (2012) Disulfide bond formation in the mammalian endoplasmic reticulum . Cold Spring Harb Perspect Biol 4: a013219

DOI

26
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults . N Engl J Med 348:1625–1638

DOI

27
Carr RM, Reid AE (2015) FXR agonists as therapeutic agents for non-alcoholic fatty liver disease . Curr Atheroscler Rep 17:500

DOI

28
Carriere F, Withers-Martinez C, van Tilbeurgh H, Roussel A, Cambillau C, Verger R (1998) Structural basis for the substrate selectivity of pancreatic lipases and some related proteins . Biochim Biophys Acta 1376:417–432

DOI

29
Cohen JC, Horton JD, Hobbs HH (2011) Human fatty liver disease: old questions and new insights . Science 332:1519–1523

DOI

30
Crow JA, Herring KL, Xie S, Borazjani A, Potter PM, Ross MK (2010) Inhibition of carboxylesterase activity of THP1 monocytes/macrophages and recombinant human carboxylesterase 1 by oxysterols and fatty acids . Biochim Biophys Acta 1801:31–41

DOI

31
Deng X, Cagen LM, Wilcox HG, Park EA, Raghow R, Elam MB (2002) Regulation of the rat SREBP-1c promoter in primary rat hepatocytes . Biochem Biophys Res Commun 290:256–262

DOI

32
Dolinsky VW, Sipione S, Lehner R, Vance DE (2001) The cloning and expression of a murine triacylglycerol hydrolase cDNA and the structure of its corresponding gene . Biochim Biophys Acta 1532:162–172

DOI

33
Dolinsky VW, Gilham D, Hatch GM, Agellon LB, Lehner R, Vance DE (2003) Regulation of triacylglycerol hydrolase expression by dietary fatty acids and peroxisomal proliferator-activated receptors . Biochim Biophys Acta 1635:20–28

DOI

34
Dolinsky VW, Gilham D, Alam M, Vance DE, Lehner R (2004) Triacylglycerol hydrolase: role in intracellular lipid metabolism . Cell Mol Life Sci 61:1633–1651

DOI

35
Dominguez E, Galmozzi A, Chang JW, Hsu KL, Pawlak J, Li W, Godio C, Thomas J, Partida D, Niessen S, O’Brien PE, Russell AP, Watt MJ, Nomura DK, Cravatt BF, Saez E (2014) Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes . Nat Chem Biol 10:113–121

DOI

36
Dugi KA, Dichek HL, Santamarina-Fojo S (1995) Human hepatic and lipoprotein lipase: the loop covering the catalytic site mediates lipase substrate specificity . J Biol Chem 270:25396–25401

DOI

37
Ellinghaus P, Seedorf U, Assmann G (1998) Cloning and sequencing of a novel murine liver carboxylesterase cDNA . Biochim Biophys Acta 1397:175–179

DOI

38
Faulds MH, Dahlman-Wright K (2012) Metabolic diseases and cancer risk . Curr Opin Oncol 24:58–61

DOI

39
Fu ZD, Selwyn FP, Cui JY, Klaassen CD (2016) RNA sequencing quantification of xenobiotic-processing genes in various sections of the intestine in comparison to the liver of male mice . Drug Metab Dispos 44:842–856

DOI

40
Fukami T, Kariya M, Kurokawa T, Iida A, Nakajima M (2015) Comparison of substrate specificity among human arylacetamide deacetylase and carboxylesterases . Eur J Pharm Sci 78:47–53

DOI

41
Fulcher GR, Walker M, Catalano C, Agius L, Alberti KG (1992) Metabolic effects of suppression of nonesterified fatty acid levels with acipimox in obese NIDDM subjects . Diabetes 41:1400–1408

DOI

42
Furihata T, Hosokawa M, Nakata F, Satoh T, Chiba K (2003) Purification, molecular cloning, and functional expression of inducible liver acylcarnitine hydrolase in C57BL/6 mouse, belonging to the carboxylesterase multigene family . Arch Biochem Biophys 416:101–109

DOI

43
Furihata T, Hosokawa M, Koyano N, Nakamura T, Satoh T, Chiba K(2004) Identification of di-(2-ethylhexyl) phthalate-induced carboxylesterase 1 in C57BL/6 mouse liver microsomes: purification, cDNA cloning, and baculovirus-mediated expression . Drug Metab Dispos 32:1170–1177

DOI

44
Gastaminza P, Cheng G, Wieland S, Zhong J, Liao W, Chisari FV (2008) Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion . J Virol 82:2120–2129

DOI

45
Genetta TL, D’Eustachio P, Kadner SS, Finlay TH (1988) cDNA cloning of esterase 1, the major esterase activity in mouse plasma . Biochem Biophys Res Commun 151:1364–1370

DOI

46
Geshi E, Kimura T, Yoshimura M, Suzuki H, Koba S, Sakai T, Saito T, Koga A, Muramatsu M, Katagiri T (2005) A single nucleotide polymorphism in the carboxylesterase gene is associated with the responsiveness to imidapril medication and the promoter activity . Hypertens Res 28:719–725

DOI

47
Ghosh S (2000) Cholesteryl ester hydrolase in human monocyte/macrophage: cloning, sequencing, and expression of fulllength cDNA . Physiol Genomics 2:1–8

DOI

48
Ghosh S, Mallonee DH, Hylemon PB, Grogan WM (1995) Molecular cloning and expression of rat hepatic neutral cholesteryl ester hydrolase . Biochim Biophys Acta 1259:305–312

DOI

49
Ghosh S, St Clair RW, Rudel LL (2003) Mobilization of cytoplasmic CE droplets by overexpression of human macrophage cholesteryl ester hydrolase . J Lipid Res 44:1833–1840

DOI

50
Gibbons GF, Wiggins D, Brown AM, Hebbachi AM (2004) Synthesis and function of hepatic very-low-density lipoprotein . Biochem Soc Trans 32:59–64

DOI

51
Gilham D, Ho S, Rasouli M, Martres P, Vance DE, Lehner R (2003) Inhibitors of hepatic microsomal triacylglycerol hydrolase decrease very low density lipoprotein secretion . FASEB J 17:1685–1687

DOI

52
Gilham D, Alam M, Gao W, Vance DE, Lehner R (2005) Triacylglycerol hydrolase is localized to the endoplasmic reticulum by an unusual retrieval sequence where it participates in VLDL assembly without utilizing VLDL lipids as substrates . Mol Biol Cell 16:984–996

DOI

53
Griffon N, Budreck EC, Long CJ, Broedl UC, Marchadier DH, Glick JM, Rader DJ (2006) Substrate specificity of lipoprotein lipase and endothelial lipase: studies of lid chimeras . J Lipid Res 47:1803–1811

DOI

54
Grimble RF, Howell WM, O’Reilly G, Turner SJ, Markovic O, Hirrell S, East JM, Calder PC (2002) The ability of fish oil to suppress tumor necrosis factor alpha production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes that influence tumor necrosis factor alpha production . Am J Clin Nutr 76:454–459

DOI

55
Harrison EH, Gad MZ, Ross AC (1995) Hepatic uptake and metabolism of chylomicron retinyl esters: probable role of plasma membrane/endosomal retinyl ester hydrolases . J Lipid Res 36:1498–1506

56
Hatfield MJ, Umans RA, Hyatt JL, Edwards CC, Wierdl M, Tsurkan L, Taylor MR, Potter PM(2016) Carboxylesterases: general detoxifying enzymes . Chem Biol Interact 259:327–331

DOI

57
Ho SC, Rajagopalan S, Chaudhuri S, Shieh CC, Brenner MB, Pillai S (1999) Membrane anchoring of calnexin facilitates its interaction with its targets . Mol Immunol 36:1–12

DOI

58
Holmes RS, Cox LA, Vandeberg JL (2009a) A new class of mammalian carboxylesterase CES6 . Comp Biochem Physiol Part D Genomics Proteomics 4:209–217

DOI

59
Holmes RS, Glenn JP, VandeBerg JL, Cox LA (2009b) Baboon carboxylesterases 1 and 2: sequences, structures and phylogenetic relationships with human and other primate carboxylesterases . J Med Primatol 38:27–38

DOI

60
Holmes RS, Wright MW, Laulederkind SJ, Cox LA, Hosokawa M, Imai T, Ishibashi S, Lehner R, Miyazaki M, Perkins EJ, Potter PM, Redinbo MR, Robert J, Satoh T, Yamashita T, Yan B, Yokoi T, Zechner R, Maltais LJ (2010a) Recommended nomenclature for five mammalian carboxylesterase gene families: human, mouse, and rat genes and proteins . Mamm Genome 21:427–441

DOI

61
Holmes RS, Cox LA, VandeBerg JL (2010b) Mammalian carboxylesterase 3: comparative genomics and proteomics . Genetica 138:695–708

DOI

62
Hosokawa M (2008) Structure and catalytic properties of carboxylesterase isozymes involved in metabolic activation of prodrugs . Molecules 13:412–431

DOI

63
Hosokawa M, Maki T, Satoh T (1990) Characterization of molecular species of liver microsomal carboxylesterases of several animal species and humans . Arch Biochem Biophys 277:219–227

DOI

64
Hosokawa M, Endo T, Fujisawa M, Hara S, Iwata N, Sato Y, Satoh T (1995) Interindividual variation in carboxylesterase levels in human liver microsomes. Drug Metab Dispos 23:1022–1027

65
Huang H, Sun F, Owen DM, Li W, Chen Y, Gale M Jr, Ye J (2007) Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins . Proc Natl Acad Sci USA 104:5848–5853

DOI

66
Huang J, Li L, Lian J, Schauer S, Vesely PW, Kratky D, Hoefler G, Lehner R (2016) Tumor-induced hyperlipidemia contributes to tumor growth . Cell Rep 15:336–348

DOI

67
Igarashi M, Osuga J, Uozaki H, Sekiya M, Nagashima S, Takahashi M, Takase S, Takanashi M, Li Y, Ohta K, Kumagai M, Nishi M, Hosokawa M, Fledelius C, Jacobsen P, Yagyu H, Fukayama M, Nagai R, Kadowaki T, Ohashi K, Ishibashi S (2010) The critical role of neutral cholesterol ester hydrolase 1 in cholesterol removal from human macrophages . Circ Res 107:1387–1395

DOI

68
Imai T (2006) Human carboxylesterase isozymes: catalytic properties and rational drug design . Drug Metab Pharmacokinet 21:173–185

DOI

69
Imai T, Taketani M, Shii M, Hosokawa M, Chiba K (2006) Substrate specificity of carboxylesterase isozymes and their contribution to hydrolase activity in human liver and small intestine . Drug Metab Dispos 34:1734–1741

DOI

70
Innerarity TL, Boren J, Yamanaka S, Olofsson SO (1996) Biosynthesis of apolipoprotein B48-containing lipoproteins. Regulation by novel post-transcriptional mechanisms . J Biol Chem 271:2353–2356

DOI

71
Jernas M, Olsson B, Arner P, Jacobson P, Sjostrom L, Walley A, Froguel P, McTernan PG, Hoffstedt J, Carlsson LM (2009) Regulation of carboxylesterase 1 (CES1) in human adipose tissue . Biochem Biophys Res Commun 383:63–67

DOI

72
Jones RD, Taylor AM, Tong EY, Repa JJ (2013) Carboxylesterases are uniquely expressed among tissues and regulated by nuclear hormone receptors in the mouse . Drug Metab Dispos 41:40–49

DOI

73
Karpe F, Dickmann JR, Frayn KN (2011) Fatty acids, obesity, and insulin resistance: time for a reevaluation . Diabetes 60:2441–2449

DOI

74
Kim SR, Nakamura T, Saito Y, Sai K, Nakajima T, Saito H, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Ozawa S, Sawada J (2003) Twelve novel single nucleotide polymorphisms in the CES2 gene encoding human carboxylesterase 2 (hCE-2) . Drug Metab Pharmacokinet 18:327–332

DOI

75
Ko KW, Erickson B, Lehner R (2009) Es-x/Ces1 prevents triacylglycerol accumulation in McArdle-RH7777 hepatocytes . Biochim Biophys Acta 1791:1133–1143

DOI

76
Kroetz DL, McBride OW, Gonzalez FJ (1993) Glycosylation-dependent activity of baculovirus-expressed human liver carboxylesterases: cDNA cloning and characterization of two highly similar enzyme forms . Biochemistry 32:11606–11617

DOI

77
Kubo T, Kim SR, Sai K, Saito Y, Nakajima T, Matsumoto K, Saito H, Shirao K, Yamamoto N, Minami H, Ohtsu A, Yoshida T, Saijo N, Ohno Y, Ozawa S, Sawada J (2005) Functional characterization of three naturally occurring single nucleotide polymorphisms in the CES2 gene encoding carboxylesterase 2 (HCE-2) . Drug Metab Dispos 33:1482–1487

DOI

78
Laizure SC, Herring V, Hu Z, Witbrodt K, Parker RB (2013) The role of human carboxylesterases in drug metabolism: have we overlooked their importance ? Pharmacotherapy 33:210–222

DOI

79
Larsson SC, Kumlin M, Ingelman-Sundberg M, Wolk A (2004) Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms . Am J Clin Nutr 79:935–945

DOI

80
Lee JN, Zhang X, Feramisco JD, Gong Y, Ye J (2008) Unsaturated fatty acids inhibit proteasomal degradation of Insig-1 at a postubiquitination step . J Biol Chem 283:33772–33783

DOI

81
Lehner R, Vance DE (1999) Cloning and expression of a cDNA encoding a hepatic microsomal lipase that mobilizes stored triacylglycerol . Biochem J 343(Pt 1):1–10

DOI

82
Lehner R, Lian J, Quiroga AD (2012) Lumenal lipid metabolism: implications for lipoprotein assembly . Arterioscler Thromb Vasc Biol 32:1087–1093

DOI

83
Li G, Janecka JE, Murphy WJ (2011) Accelerated evolution of CES7, a gene encoding a novel major urinary protein in the cat family . Mol Biol Evol 28:911–920

DOI

84
Li Y, Zalzala M, Jadhav K, Xu Y, Kasumov T, Yin L, Zhang Y (2016) Carboxylesterase 2 prevents liver steatosis by modulating lipolysis, endoplasmic reticulum stress, and lipogenesis and is regulated by hepatocyte nuclear factor 4 alpha in mice . Hepatology 63:1860–1874

DOI

85
Lian J, Wei E, Wang SP, Quiroga AD, Li L, Di Pardo A, van der Veen J, Sipione S, Mitchell GA, Lehner R (2012a) Liver specific inactivation of carboxylesterase 3/triacylglycerol hydrolase decreases blood lipids without causing severe steatosis in mice . Hepatology 56:2154–2162

DOI

86
Lian J, Quiroga AD, Li L, Lehner R (2012b) Ces3/TGH deficiency improves dyslipidemia and reduces atherosclerosis in Ldlr(−/−) mice . Circ Res 111:982–990

DOI

87
Lian J, Wei E, Groenendyk J, Das SK, Hermansson M, Li L, Watts R, Thiesen A, Oudit GY, Michalak M, Lehner R (2016) Ces3/TGH deficiency attenuates steatohepatitis . Sci Rep 6:25747

DOI

88
Lin X, Jia J, Du T, Li W, Wang X, Wei J, Lin X, Zeng H, Yao L, Chen X, Zhuang J, Weng J, Liu Y, Lin J, Wu Q, Wang W, Yao K, Xu K, Xiao D (2015) Overexpression of miR-155 in the liver of transgenic mice alters the expression profiling of hepatic genes associated with lipid metabolism . PLoS ONE 10:e0118417

DOI

89
Linke T, Dawson H, Harrison EH (2005) Isolation and characterization of a microsomal acid retinyl ester hydrolase . J Biol Chem 280:23287–23294

DOI

90
Liu P, Ying Y, Zhao Y, Mundy DI, Zhu M, Anderson RG (2004) Chinese hamster ovary K2 cell lipid droplets appear to be metabolic organelles involved in membrane traffic . J Biol Chem 279:3787–3792

DOI

91
Lord CC, Ferguson D, Thomas G, Brown AL, Schugar RC, Burrows A, Gromovsky AD, Betters J, Neumann C, Sacks J, Marshall S, Watts R, Schweiger M, Lee RG, Crooke RM, Graham MJ, Lathia JD, Sakaguchi TF, Lehner R, Haemmerle G, Zechner R, Brown JM (2016) Regulation of hepatic triacylglycerol metabolism by CGI-58 does not require ATGL co-activation . Cell Rep 16:939–949

DOI

92
Maki T, Hosokawa M, Satoh T, Sato K (1991) Changes in carboxylesterase isoenzymes of rat liver microsomes during hepatocarcinogenesis . Jpn J Cancer Res 82:800–806

DOI

93
Marrades MP, Gonzalez-Muniesa P, Martinez JA, Moreno-Aliaga MJ (2010) A dysregulation in CES1, APOE and other lipid metabolism-related genes is associated to cardiovascular risk factors linked to obesity . Obes Facts 3:312–318

DOI

94
Marsh S, Xiao M, Yu J, Ahluwalia R, Minton M, Freimuth RR, Kwok PY, McLeod HL (2004) Pharmacogenomic assessment of carboxylesterases 1 and 2 . Genomics 84:661–668

DOI

95
Martin S, Parton RG (2006) Lipid droplets: a unified view of a dynamic organelle . Nat Rev Mol Cell Biol 7:373–378

DOI

96
McQuaid SE, Hodson L, Neville MJ, Dennis AL, Cheeseman J, Humphreys SM, Ruge T, Gilbert M, Fielding BA, Frayn KN, Karpe F (2011) Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition ? Diabetes 60:47–55

DOI

97
Mentlein R, Heymann E (1987) Hydrolysis of retinyl esters by nonspecific carboxylesterases from rat liver endoplasmic reticulum . Biochem J 245:863–867

DOI

98
Mishra S, Khaddaj R, Cottier S, Stradalova V, Jacob C, Schneiter R (2016) Mature lipid droplets are accessible to ER luminal proteins . J Cell Sci 129:3803–3815

DOI

99
Miyanari Y, Atsuzawa K, Usuda N, Watashi K, Hishiki T, Zayas M, Bartenschlager R, Wakita T, Hijikata M, Shimotohno K (2007) The lipid droplet is an important organelle for hepatitis C virus production . Nat Cell Biol 9:1089–1097

DOI

100
Miyazaki M, Yamashita T, Hosokawa M, Taira H, Suzuki A (2006) Species-, sex-, and age-dependent urinary excretion of cauxin, a mammalian carboxylesterase . Comp Biochem Physiol B 145:270–277

DOI

101
Morgan EW, Yan B, Greenway D, Parkinson A (1994) Regulation of two rat liver microsomal carboxylesterase isozymes: species differences, tissue distribution, and the effects of age, sex, and xenobiotic treatment of rats . Arch Biochem Biophys 315:513–526

DOI

102
Mori M, Hosokawa M, Ogasawara Y, Tsukada E, Chiba K (1999) cDNA cloning, characterization and stable expression of novel human brain carboxylesterase . FEBS Lett 458:17–22

DOI

103
Munro S, Pelham HR (1987) A C-terminal signal prevents secretion of luminal ER proteins . Cell 48:899–907

DOI

104
Nagashima S, Yagyu H, Takahashi N, Kurashina T, Takahashi M, Tsuchita T, Tazoe F, Wang XL, Bayasgalan T, Sato N, Okada K, Nagasaka S, Gotoh T, Kojima M, Hyodo M, Horie H, Hosoya Y, Okada M, Yasuda Y, Fujiwara H, Ohwada M, Iwamoto S, Suzuki M, Nagai H, Ishibashi S (2011) Depot-specific expression of lipolytic genes in human adipose tissues-association among CES1 expression, triglyceride lipase activity and adiposity . J Atheroscler Thromb 18:190–199

DOI

105
Okazaki H, Igarashi M, Nishi M, Tajima M, Sekiya M, Okazaki S, Yahagi N, Ohashi K, Tsukamoto K, Amemiya-Kudo M, Matsuzaka T, Shimano H, Yamada N, Aoki J, Morikawa R, Takanezawa Y, Arai H, Nagai R, Kadowaki T, Osuga J, Ishibashi S (2006) Identification of a novel member of the carboxylesterase family that hydrolyzes triacylglycerol: a potential role in adipocyte lipolysis . Diabetes 55:2091–2097

DOI

106
Okazaki H, Igarashi M, Nishi M, Sekiya M, Tajima M, Takase S, Takanashi M, Ohta K, Tamura Y, Okazaki S, Yahagi N, Ohashi K, Amemiya-Kudo M, Nakagawa Y, Nagai R, Kadowaki T, Osuga J, Ishibashi S (2008) Identification of neutral cholesterol ester hydrolase, a key enzyme removing cholesterol from macrophages . J Biol Chem 283:33357–33364

DOI

107
Olofsson SO, Stillemark-Billton P, Asp L (2000) Intracellular assembly of VLDL: two major steps in separate cell compartments . Trends Cardiovasc Med 10:338–345

DOI

108
Ovnic M, Swank RT, Fletcher C, Zhen L, Novak EK, Baumann H, Heintz N, Ganschow RE (1991) Characterization and functional expression of a cDNA encoding egasyn (esterase-22): the endoplasmic reticulum-targeting protein of beta-glucuronidase . Genomics 11:956–967

DOI

109
Pelham HR (1991) Recycling of proteins between the endoplasmic reticulum and Golgi complex . Curr Opin Cell Biol 3:585–591

DOI

110
Pindel EV, Kedishvili NY, Abraham TL, Brzezinski MR, Zhang J, Dean RA, Bosron WF (1997) Purification and cloning of a broad substrate specificity human liver carboxylesterase that catalyzes the hydrolysis of cocaine and heroin . J Biol Chem 272:14769–14775

DOI

111
Potter PM, Wolverton JS, Morton CL, Wierdl M, Danks MK (1998) Cellular localization domains of a rabbit and a human carboxylesterase: influence on irinotecan (CPT-11) metabolism by the rabbit enzyme . Cancer Res 58:3627–3632

112
Quiroga AD, Li L, Trotzmuller M, Nelson R, Proctor SD, Kofeler H, Lehner R (2012a) Deficiency of carboxylesterase 1/esterase-x results in obesity, hepatic steatosis, and hyperlipidemia . Hepatology 56:2188–2198

DOI

113
Quiroga AD, Lian J, Lehner R (2012b) Carboxylesterase1/Esterasex regulates chylomicron production in mice . PLoS ONE 7:e49515

DOI

114
Quiroga AD, Ceballos MP, Parody JP, Comanzo CG, Lorenzetti F, Pisani GB, Ronco MT, Alvarez ML, Carrillo MC (2016) Hepatic carboxylesterase 3 (Ces3/Tgh) is downregulated in the early stages of liver cancer development in the rat . Biochim Biophys Acta 1862:2043–2053

DOI

115
Riddles PW, Richards LJ, Bowles MR, Pond SM (1991) Cloning and analysis of a cDNA encoding a human liver carboxylesterase . Gene 108:289–292

DOI

116
Robbi M, Beaufay H (1991) The COOH terminus of several liver carboxylesterases targets these enzymes to the lumen of the endoplasmic reticulum . J Biol Chem 266:20498–20503

117
Robbi M, Beaufay H, Octave JN (1990) Nucleotide sequence of cDNA coding for rat liver pI 6.1 esterase (ES-10), a carboxylesterase located in the lumen of the endoplasmic reticulum . Biochem J 269:451–458

DOI

118
Ross MK, Borazjani A, Wang R, Crow JA, Xie S (2012) Examination of the carboxylesterase phenotype in human liver . Arch Biochem Biophys 522:44–56

DOI

119
Ruby MA, Massart J, Hunerdosse DM, Schonke M, Correia JC, Louie SM, Ruas JL, Naslund E, Nomura DK, Zierath JR (2017) Human carboxylesterase 2 reverses obesity-induced diacylglycerol accumulation and glucose intolerance . Cell Rep 18:636–646

DOI

120
Saito S, Iida A, Sekine A, Kawauchi S, Higuchi S, Ogawa C, Nakamura Y (2003) Catalog of 680 variations among eight cytochrome p450 (CYP) genes, nine esterase genes, and two other genes in the Japanese population . J Hum Genet 48:249–270

DOI

121
Sanghani SP, Davis WI, Dumaual NG, Mahrenholz A, Bosron WF (2002) Identification of microsomal rat liver carboxylesterases and their activity with retinyl palmitate . Eur J Biochem 269:4387–4398

DOI

122
Sanghani SP, Quinney SK, Fredenburg TB, Davis WI, Murry DJ, Bosron WF (2004) Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin, by human carboxylesterases CES1A1, CES2, and a newly expressed carboxylesterase isoenzyme, CES3 . Drug Metab Dispos 32:505–511

DOI

123
Sanghani SP, Sanghani PC, Schiel MA, Bosron WF (2009) Human carboxylesterases: an update on CES1, CES2 and CES3 . Protein Pept Lett 16:1207–1214

DOI

124
Satoh T, Taylor P, Bosron WF, Sanghani SP, Hosokawa M, La Du BN (2002) Current progress on esterases: from molecular structure to function . Drug Metab Dispos 30:488–493

DOI

125
Schreiber R, Taschler U, Wolinski H, Seper A, Tamegger SN, Graf M, Kohlwein SD, Haemmerle G, Zimmermann R, Zechner R, Lass A (2009) Esterase 22 and beta-glucuronidase hydrolyze retinoids in mouse liver . J Lipid Res 50:2514–2523

DOI

126
Schweiger M, Schreiber R, Haemmerle G, Lass A, Fledelius C, Jacobsen P, Tornqvist H, Zechner R, Zimmermann R (2006) Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism . J Biol Chem 281:40236–40241

DOI

127
Schwer H, Langmann T, Daig R, Becker A, Aslanidis C, Schmitz G (1997) Molecular cloning and characterization of a novel putative carboxylesterase, present in human intestine and liver . Biochem Biophys Res Commun 233:117–120

DOI

128
Shelness GS, Sellers JA (2001) Very-low-density lipoprotein assembly and secretion . Curr Opin Lipidol 12:151–157

DOI

129
Shimizu M, Fukami T, Nakajima M, Yokoi T (2014) Screening of specific inhibitors for human carboxylesterases or arylacetamide deacetylase . Drug Metab Dispos 42:1103–1109

DOI

130
So JS, Hur KY, Tarrio M, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Lichtman AH, Iwawaki T, Glimcher LH, Lee AH (2012) Silencing of lipid metabolism genes through IRE1alphamediated mRNA decay lowers plasma lipids in mice . Cell Metab 16:487–499

DOI

131
Soni KG, Lehner R, Metalnikov P, O’Donnell P, Semache M, Gao W, Ashman K, Pshezhetsky AV, Mitchell GA (2004) Carboxylesterase 3 (EC 3.1.1.1) is a major adipocyte lipase . J Biol Chem 279:40683–40689

DOI

132
Staudinger JL, Xu C, Cui YJ, Klaassen CD (2010) Nuclear receptormediated regulation of carboxylesterase expression and activity . Expert Opin Drug Metab Toxicol 6:261–271

DOI

133
Steinberg GR, Kemp BE, Watt MJ (2007) Adipocyte triglyceride lipase expression in human obesity . Am J Physiol Endocrinol Metab 293:E958–964

DOI

134
Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA, Mammalian T (2002) Gene Collection Program, Generation and initial analysis of more than 15,000 fulllength human and mouse cDNA sequences . Proc Natl Acad Sci USA 99:16899–16903

DOI

135
Sun G, Alexson SE, Harrison EH (1997) Purification and characterization of a neutral, bile salt-independent retinyl ester hydrolase from rat liver microsomes. Relationship to rat carboxylesterase ES-2. J Biol Chem 272:24488–24493

DOI

136
Szafran B, Borazjani A, Lee JH, Ross MK, Kaplan BL (2015) Lipopolysaccharide suppresses carboxylesterase 2g activity and 2-arachidonoylglycerol hydrolysis: a possible mechanism to regulate inflammation. Prostaglandins Other Lipid Mediat 121:199–206

DOI

137
Thomsen R, Rasmussen HB, Linnet K, Consortium I (2014) In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors. Drug Metab Dispos 42:126–133

DOI

138
Tiniakos DG, Vos MB, Brunt EM (2010) Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol 5:145–171

DOI

139
Townsley FM, Wilson DW, Pelham HR (1993) Mutational analysis of the human KDEL receptor: distinct structural requirements for Golgi retention, ligand binding and retrograde transport. EMBO J 12:2821–2829

140
Walther TC, Farese RV Jr (2009) The life of lipid droplets. Biochim Biophys Acta 1791:459–466

DOI

141
Walther TC, Farese RV Jr(2012) Lipid droplets and cellular lipid metabolism. Annu Rev Biochem 81:687–714

DOI

142
Wang H, Gilham D, Lehner R (2007) Proteomic and lipid characterization of apolipoprotein B-free luminal lipid droplets from mouse liver microsomes: implications for very low density lipoprotein assembly. J Biol Chem 282:33218–33226

DOI

143
Wang H, Wei E, Quiroga AD, Sun X, Touret N, Lehner R (2010) Altered lipid droplet dynamics in hepatocytes lacking triacylglycerol hydrolase expression. Mol Biol Cell 21:1991–2000

DOI

144
Wang R, Borazjani A, Matthews AT, Mangum LC, Edelmann MJ, Ross MK (2013) Identification of palmitoyl protein thioesterase 1 in human THP1 monocytes and macrophages and characterization of unique biochemical activities for this enzyme. Biochemistry 52:7559–7574

DOI

145
Wei E, Lehner R, Vance DE (2005) C/EBPalpha activates the transcription of triacylglycerol hydrolase in 3T3-L1 adipocytes. Biochem J 388:959–966

DOI

146
Wei E, Alam M, Sun F, Agellon LB, Vance DE, Lehner R (2007a) Apolipoprotein B and triacylglycerol secretion in human triacylglycerol hydrolase transgenic mice. J Lipid Res 48:2597–2606

DOI

147
Wei E, Gao W, Lehner R (2007b) Attenuation of adipocyte triacylglycerol hydrolase activity decreases basal fatty acid efflux. J Biol Chem 282:8027–8035

DOI

148
Wei E, Ben Ali Y, Lyon J, Wang H, Nelson R, Dolinsky VW, Dyck JR, Mitchell G, Korbutt GS, Lehner R (2010) Loss of TGH/Ces3 in mice decreases blood lipids, improves glucose tolerance, and increases energy expenditure. Cell Metab 11:183–193

DOI

149
Wiggins D, Gibbons GF (1992) The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density lipoprotein and its response to hormones and sulphonylureas. Biochem J 284(Pt 2):457–462

DOI

150
Wilfling F, Thiam AR, Olarte MJ, Wang J, Beck R, Gould TJ, Allgeyer ES, Pincet F, Bewersdorf J, Farese RV Jr, Walther TC (2014) Arf1/COPI machinery acts directly on lipid droplets and enables their connection to the ER for protein targeting. Elife 3:e01607

DOI

151
Williams ET, Wang H, Wrighton SA, Qian YW, Perkins EJ (2010) Genomic analysis of the carboxylesterases: identification and classification of novel forms. Mol Phylogenet Evol 57:23–34

DOI

152
Wu MH, Chen P, Wu X, Liu W, Strom S, Das S, Cook EH Jr, Rosner GL, Dolan ME (2004) Determination and analysis of single nucleotide polymorphisms and haplotype structure of the human carboxylesterase 2 gene. Pharmacogenetics 14:595–605

DOI

153
Xie S, Borazjani A, Hatfield MJ, Edwards CC, Potter PM, Ross MK (2010) Inactivation of lipid glyceryl ester metabolism in human THP1 monocytes/macrophages by activated organophosphorus insecticides: role of carboxylesterases 1 and 2. Chem Res Toxicol 23:1890–1904

DOI

154
Xie C, Ding X, Gao J, Wang H, Hang Y, Zhang H, Zhang J, Jiang B, Miao L (2014) The effects of CES1A2 A(-816)C and CYP2C19 loss-of-function polymorphisms on clopidogrel response variability among Chinese patients with coronary heart disease. Pharmacogenet Genomics 24:204–210

DOI

155
Xu J, Teran-Garcia M, Park JH, Nakamura MT, Clarke SD (2001) Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay. J Biol Chem 276:9800–9807

DOI

156
Xu J, Li Y, Chen WD, Xu Y, Yin L, Ge X, Jadhav K, Adorini L, Zhang Y (2014a) Hepatic carboxylesterase 1 is essential for both normal and farnesoid X receptor-controlled lipid homeostasis. Hepatology 59:1761–1771

DOI

157
Xu J, Yin L, Xu Y, Li Y, Zalzala M, Cheng G, Zhang Y (2014b) Hepatic carboxylesterase 1 is induced by glucose and regulates postprandial glucose levels. PLoS ONE 9:e109663

DOI

158
Xu J, Xu Y, Li Y, Jadhav K, You M, Yin L, Zhang Y (2016) Carboxylesterase 1 Is regulated by hepatocyte nuclear factor 4alpha and protects against alcohol- and MCD diet-induced liver injury. Sci Rep 6:24277

DOI

159
Yamada S, Richardson K, Tang M, Halaschek-Wiener J, Cook VJ, Fitzgerald JM, Elwood K, Marra F, Brooks-Wilson A (2010) Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity. Pharmacogenomics J 10:524–536

DOI

160
Yan B, Yang D, Bullock P, Parkinson A (1995) Rat serum carboxylesterase. Cloning, expression, regulation, and evidence of secretion from liver. J Biol Chem 270:19128–19134

DOI

161
Yan B, Matoney L, Yang D (1999) Human carboxylesterases in term placentae: enzymatic characterization, molecular cloning and evidence for the existence of multiple forms. Placenta 20:599–607

DOI

162
Young SG, Parthasarathy S (1994) Why are low-density lipoproteins atherogenic? West J Med 160:153–164

163
Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, Willson TM, Edwards PA (2006) Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci USA 103:1006–1011

DOI

164
Zhao B, Fisher BJ, St Clair RW, Rudel LL, Ghosh S (2005) Redistribution of macrophage cholesteryl ester hydrolase from cytoplasm to lipid droplets upon lipid loading. J Lipid Res 46:2114–2121

DOI

165
Zhao B, Song J, Chow WN, St Clair RW, Rudel LL, Ghosh S (2007) Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr mice. J Clin Invest 117:2983–2992

DOI

166
Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, DeVane CL, Malcolm R, Johnson JA, Youngblood GL, Sweet DH, Langaee TY, Markowitz JS (2008) Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet 82:1241–1248

DOI

Outlines

/