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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.

Authors :
Zhu L
Luu T
Emfinger CH
Parks BA
Shi J
Trefts E
Zeng F
Kuklenyik Z
Harris RC
Wasserman DH
Fazio S
Stafford JM
Source :
Diabetes [Diabetes] 2018 Dec; Vol. 67 (12), pp. 2494-2506. Date of Electronic Publication: 2018 Sep 13.
Publication Year :
2018

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.<br /> (© 2018 by the American Diabetes Association.)

Details

Language :
English
ISSN :
1939-327X
Volume :
67
Issue :
12
Database :
MEDLINE
Journal :
Diabetes
Publication Type :
Academic Journal
Accession number :
30213825
Full Text :
https://doi.org/10.2337/db18-0474