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Metabolism

CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet

  1. Lin Zhu1,2,
  2. Thao Luu2,
  3. Christopher H. Emfinger1,2,
  4. Bryan A. Parks3,
  5. Jeanne Shi2,4,
  6. Elijah Trefts5,
  7. Fenghua Zeng6,
  8. Zsuzsanna Kuklenyik3,
  9. Raymond C. Harris6,
  10. David H. Wasserman5,
  11. Sergio Fazio7 and
  12. John M. Stafford1,2,5⇑
  1. 1Veterans Administration Tennessee Valley Healthcare System, Vanderbilt University School of Medicine, Nashville, TN
  2. 2Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine, Nashville, TN
  3. 3Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA
  4. 4Trinity College of Art and Science, Duke University, Durham, NC
  5. 5Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
  6. 6Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, TN
  7. 7The Center for Preventive Cardiology at the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR
  1. Corresponding author: John M. Stafford, john.stafford{at}vanderbilt.edu.
Diabetes 2018 Dec; 67(12): 2494-2506. https://doi.org/10.2337/db18-0474
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Abstract

In clinical trials, inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels but does not robustly improve cardiovascular outcomes. Approximately two-thirds of trial participants are obese. Lower plasma CETP activity is associated with increased cardiovascular risk in human studies, and protective aspects of CETP have been observed in mice fed a high-fat diet (HFD) with regard to metabolic outcomes. To define whether CETP inhibition has different effects depending on the presence of obesity, we performed short-term anacetrapib treatment in chow- and HFD-fed CETP transgenic mice. Anacetrapib raised HDL cholesterol and improved aspects of HDL functionality, including reverse cholesterol transport, and HDL’s antioxidative capacity in HFD-fed mice was better than in chow-fed mice. Anacetrapib worsened the anti-inflammatory capacity of HDL in HFD-fed mice. The HDL proteome was markedly different with anacetrapib treatment in HFD- versus chow-fed mice. Despite benefits on HDL, anacetrapib led to liver triglyceride accumulation and insulin resistance in HFD-fed mice. Overall, our results support a physiologic importance of CETP in protecting from fatty liver and demonstrate context selectivity of CETP inhibition that might be important in obese subjects.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-0474/-/DC1.

  • Received April 26, 2018.
  • Accepted September 5, 2018.
  • © 2018 by the American Diabetes Association.
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CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet
Lin Zhu, Thao Luu, Christopher H. Emfinger, Bryan A. Parks, Jeanne Shi, Elijah Trefts, Fenghua Zeng, Zsuzsanna Kuklenyik, Raymond C. Harris, David H. Wasserman, Sergio Fazio, John M. Stafford
Diabetes Dec 2018, 67 (12) 2494-2506; DOI: 10.2337/db18-0474

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CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet
Lin Zhu, Thao Luu, Christopher H. Emfinger, Bryan A. Parks, Jeanne Shi, Elijah Trefts, Fenghua Zeng, Zsuzsanna Kuklenyik, Raymond C. Harris, David H. Wasserman, Sergio Fazio, John M. Stafford
Diabetes Dec 2018, 67 (12) 2494-2506; DOI: 10.2337/db18-0474
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