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Diabetes. 2018 Dec;67(12):2494-2506. doi: 10.2337/db18-0474. Epub 2018 Sep 13.

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

Author information

1
Veterans Administration Tennessee Valley Healthcare System, Vanderbilt University School of Medicine, Nashville, TN.
2
Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine, Nashville, TN.
3
Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA.
4
Trinity College of Art and Science, Duke University, Durham, NC.
5
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
6
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, TN.
7
The Center for Preventive Cardiology at the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR.
8
Veterans Administration Tennessee Valley Healthcare System, Vanderbilt University School of Medicine, Nashville, TN john.stafford@vanderbilt.edu.

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.

PMID:
30213825
PMCID:
PMC6245220
[Available on 2019-12-01]
DOI:
10.2337/db18-0474
[Indexed for MEDLINE]

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