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Carboxylesterase 1 plays a protective role against metabolic disease

Xu, Jiesi
http://orcid.org/0000-0001-5112-3025
http://rave.ohiolink.edu/etdc/view?acc_num=kent1461012669

Abstract Details

2016, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Carboxylesterase 1 (CES1) is a phase I drug metabolizing enzyme which is shown to hydrolyze ester and amide-containing drugs and prodrugs. It also hydrolyzes triglyceride and cholesteryl ester. The present studies show that glucose induces CES1 expression, and that the induction of CES1 expression, in turn, reduces plasma glucose level, likely through increasing insulin sensitivity. We then demonstrate that over-expression of hepatic CES1 reduces hepatic triglyceride level and promotes fatty acid oxidation. In contrast, loss of hepatic CES1 induces hepatic steatosis by increasing sterol regulatory-element binding protein (SREBP) processing and lipogenesis. We also find that CES1 is a farnesoid X receptor (FXR) target gene, and that activation of FXR reduces hepatic and plasma triglyceride levels through, at least in part, inducing CES1. These results suggest that CES1 plays a protective role against non-alcoholic fatty liver disease (NAFLD). We further show that CES1 is inhibited by alcohol, and is a hepatocyte nuclear factor 4a (HNF4a) direct target. Using liver specific Ces1 deficient and Ces1-/- mice together with chronic-binge alcohol feeding, we find that CES1 deficiency exacerbates alcohol-induced liver inflammation. CES1 deficiency also results in increased hepatic acetaldehyde level, elevated reactive oxygen species (ROS) level and enhanced lipid peroxidation, suggesting that CES1 plays a protective role against alcoholic liver disease (ALD). Lastly, we demonstrate that loss of hepatic CES1 aggravates western diet-induced atherosclerosis in ApoE-/- mice. These exciting results lead us to conclude that CES1 plays an essential role in lipid and carbohydrate metabolism, and that it also protects against NAFLD, ALD and atherosclerosis. Targeting CES1 may be a plausible strategy for treating metabolic disease.
Yanqiao Zhang (Committee Chair)
John Chiang (Committee Member)
Novak Colleen (Committee Member)
Eric Mintz (Committee Member)
Min You (Committee Member)
146 p.
Biochemistry

Recommended Citations

Citations

  • Xu, J. (2016). Carboxylesterase 1 plays a protective role against metabolic disease [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1461012669

    APA Style (7th edition)

  • Xu, Jiesi . Carboxylesterase 1 plays a protective role against metabolic disease . 2016. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1461012669.

    MLA Style (8th edition)

  • Xu, Jiesi . "Carboxylesterase 1 plays a protective role against metabolic disease ." Doctoral dissertation, Kent State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1461012669

    Chicago Manual of Style (17th edition)

kent1461012669
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© 2016, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.