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Publication
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
Submitted By Submitted Externally on 12/12/2018
Status Published
Journal Diabetes
Year 2018
Date Published 12/1/2018
Volume : Pages 67 : 2494 - 2506
PubMed Reference 30213825
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.




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