title: Hepatic carboxylesterase 1 is essential for both normal and farnesoid X receptor-controlled lipid homeostasis.
abstract: Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner.
  
  
  CONCLUSIONS
  Hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Jiesi
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.|Key laboratory of receptor-mediated gene regulation and drug discovery, School of Medicine, Henan University, Kaifeng, China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Chen
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Liya
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Ge
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Jadhav
authors.affiliation: Intercept Pharmaceuticals, 18 Desbrosses Street, New York, NY 10013, USA.
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Yanqiao
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000502:physiology*; D002784:Cholesterol / Q000097:blood; D005227:Fatty Acids / Q000378:metabolism; D006706:Homeostasis; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002265:Carboxylic Ester Hydrolases; D002784:Cholesterol; D005227:Fatty Acids; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C497388:Srebf1 protein, mouse; C545375:carboxylesterase 1, mouse
references.citation: Mol Cell. 2000 Sep;6(3):507-15
references.pmid: 11030331
references.citation: J Clin Invest. 2006 Apr;116(4):1102-9
references.pmid: 16557297
references.citation: J Lipid Res. 2010 Apr;51(4):771-84
references.pmid: 19783811
references.citation: Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H272-81
references.pmid: 19028791
references.citation: J Pharmacol Exp Ther. 2005 Aug;314(2):584-95
references.pmid: 15860571
references.citation: J Clin Invest. 2004 May;113(10):1408-18
references.pmid: 15146238
references.citation: J Biol Chem. 2000 Sep 29;275(39):30280-6
references.pmid: 10801800
references.citation: Biochem Biophys Res Commun. 2001 Sep 21;287(2):391-6
references.pmid: 11554740
references.citation: Mol Cell. 2000 Sep;6(3):517-26
references.pmid: 11030332
references.citation: J Biol Chem. 2000 Sep 15;275(37):28488-93
references.pmid: 10862772
references.citation: Can J Biochem Physiol. 1959 Aug;37(8):911-7
references.pmid: 13671378
references.citation: J Biol Chem. 2010 Jan 29;285(5):3035-43
references.pmid: 19996107
references.citation: J Biol Chem. 2006 Apr 21;281(16):11039-49
references.pmid: 16446356
references.citation: J Med Chem. 2000 Aug 10;43(16):2971-4
references.pmid: 10956205
references.citation: Hepatology. 2011 Jul;54(1):122-32
references.pmid: 21465509
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):1006-11
references.pmid: 16410358
references.citation: Am J Physiol Endocrinol Metab. 2006 Apr;290(4):E716-22
references.pmid: 16291572
references.citation: J Lipid Res. 2009 Aug;50(8):1621-9
references.pmid: 19304987
references.citation: EMBO J. 2005 Jul 20;24(14):2624-33
references.pmid: 15973435
references.citation: J Biol Chem. 2011 Jan 28;286(4):2425-32
references.pmid: 21081494
references.citation: J Biol Chem. 2000 Apr 28;275(17):12497-502
references.pmid: 10777536
references.citation: J Biol Chem. 1989 Dec 25;264(36):21824-9
references.pmid: 2557341
references.citation: Nat Rev Gastroenterol Hepatol. 2010 Apr;7(4):195-203
references.pmid: 20195271
references.citation: J Lipid Res. 2009 Jun;50(6):1090-100
references.pmid: 19174369
references.citation: PLoS One. 2012;7(11):e49515
references.pmid: 23145182
references.citation: J Hepatol. 2009 Aug;51(2):380-8
references.pmid: 19501927
references.citation: Biochem Biophys Res Commun. 2005 Oct 28;336(3):754-61
references.pmid: 16140264
references.citation: Hepatology. 2007 Jul;46(1):147-57
references.pmid: 17526026
references.citation: Biochim Biophys Acta. 2009 Dec;1791(12):1133-43
references.pmid: 19651238
references.citation: J Lipids. 2012;2012:934396
references.pmid: 22187656
references.citation: Diabetes Metab. 2008 Dec;34(6 Pt 2):685-91
references.pmid: 19195631
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11041-8
references.pmid: 10500120
references.citation: PLoS One. 2009 Aug 27;4(8):e6796
references.pmid: 19710929
references.citation: J Med Chem. 2002 Aug 15;45(17):3569-72
references.pmid: 12166927
references.citation: J Lipid Res. 2011 Aug;52(8):1561-8
references.pmid: 21642744
references.citation: Gastroenterology. 2008 Feb;134(2):556-67
references.pmid: 18242221
references.citation: Hepatology. 2012 Dec;56(6):2188-98
references.pmid: 22806626
references.citation: Hepatology. 2011 Jan;53(1):116-26
references.pmid: 20967758
references.citation: J Biol Chem. 2008 May 9;283(19):13087-99
references.pmid: 18337240
references.citation: J Clin Invest. 2007 Oct;117(10):2983-92
references.pmid: 17885686
references.citation: Cell Metab. 2005 Oct;2(4):227-38
references.pmid: 16213225
references.citation: Biochim Biophys Acta. 1994 Nov 17;1215(1-2):126-32
references.pmid: 7947994
references.citation: Drug Discov Today. 2012 Sep;17(17-18):988-97
references.pmid: 22652341
references.citation: J Lipid Res. 2006 Dec;47(12):2754-61
references.pmid: 16957179
references.citation: Biochim Biophys Acta. 1998 Apr 29;1397(2):175-9
references.pmid: 9565681
references.citation: Physiol Genomics. 2005 Nov 17;23(3):304-10
references.pmid: 16131527
references.citation: FEBS Lett. 2008 Jan 9;582(1):10-8
references.pmid: 18023284
references.citation: Diabetes. 2002 Feb;51(2):276-83
references.pmid: 11812733
references.citation: Science. 2004 Nov 19;306(5700):1383-6
references.pmid: 15550674