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

    Research output: Contribution to journalArticle

    3 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)2494-2506
    Number of pages13
    JournalDiabetes
    Volume67
    Issue number12
    DOIs
    StatePublished - Dec 1 2018

    ASJC Scopus subject areas

    • Internal Medicine
    • Endocrinology, Diabetes and Metabolism

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