Liver specific inactivation of carboxylesterase 3/triacylglycerol hydrolase decreases blood lipids without causing severe steatosis in mice

Authors

  • Jihong Lian,

    1. Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
    2. Departments of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
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    • These authors contributed equally to the work.

  • Enhui Wei,

    1. Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
    2. Departments of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
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    • These authors contributed equally to the work.

  • Shu Pei Wang,

    1. Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montreal, Quebec, Canada
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  • Ariel D. Quiroga,

    1. Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
    2. Departments of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
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  • Lena Li,

    1. Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
    2. Departments of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
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  • Alba Di Pardo,

    1. Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
    2. Departments of Pharmacology, University of Alberta, Edmonton, Alberta, Canada
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  • Jelske van der Veen,

    1. Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
    2. Departments of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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  • Simonetta Sipione,

    1. Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
    2. Departments of Pharmacology, University of Alberta, Edmonton, Alberta, Canada
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  • Grant A. Mitchell,

    1. Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montreal, Quebec, Canada
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  • Richard Lehner

    Corresponding author
    1. Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
    2. Departments of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
    3. Departments of Cell Biology, University of Alberta, Edmonton, Alberta, Canada
    • Group on Molecular and Cell Biology of Lipids, University of Alberta, 328 Heritage Medical Research Centre, Edmonton, Alberta, Canada T6G 2S2 fax: 780-492-3383

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    • fax: 780-492-3383


  • Potential conflict of interest: Nothing to report.

  • The Lipid Analysis Core received financial support from the Women and Children Health Research Institute. A. D. P. was supported by a studentship from the Alberta Heritage Foundation for Medical Research. A. D. Q. was supported by a fellowship from the Heart and Stroke Foundation of Canada. S. S. and R.L. are a Scholar and a Scientist, respectively, of the Alberta Heritage Foundation for Medical Research. S. S. is a Canada Research Chair in Neurobiology of Huntington Disease. This work was supported by operating grants from the Canadian Institutes of Health Research (69043 to R. L., 111219 to S. S., and 221920 to G. A. M.) and the Canadian Diabetes Association (to J. v. d. V.) and a Pfizer CardioVascular Award (to R. L.).

Abstract

Carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH) participates in hepatic very low-density lipoprotein (VLDL) assembly and in adipose tissue basal lipolysis. Global ablation of Ces3/Tgh expression decreases serum triacylglycerol (TG) and nonesterified fatty acid levels and improves insulin sensitivity. To understand the tissue-specific role of Ces3/TGH in lipid and glucose homeostasis, we generated mice with a liver-specific deletion of Ces3/Tgh expression (L-TGH knockout [KO]). Elimination of hepatic Ces3/Tgh expression dramatically decreased plasma VLDL TG and VLDL cholesterol concentrations but only moderately increased liver TG levels in mice fed a standard chow diet. Significantly reduced plasma TG and cholesterol without hepatic steatosis were also observed in L-TGH KO mice challenged with a high-fat, high-cholesterol diet. L-TGH KO mice presented with increased plasma ketone bodies and hepatic fatty acid oxidation. Intrahepatic TG in L-TGH KO mice was stored in significantly smaller lipid droplets. Augmented hepatic TG levels in chow-fed L-TGH KO mice did not affect glucose tolerance or glucose production from hepatocytes, but impaired insulin tolerance was observed in female mice. Conclusion: Our data suggest that ablation of hepatic Ces3/Tgh expression decreases plasma lipid levels without causing severe hepatic steatosis. (HEPATOLOGY 2012;56:2154–2162)

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