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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.
- 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.)
- Subjects :
- Animals
Anticholesteremic Agents pharmacology
Cholesterol Ester Transfer Proteins metabolism
Fatty Liver metabolism
Mice
Mice, Transgenic
Oxazolidinones pharmacology
Cholesterol Ester Transfer Proteins antagonists & inhibitors
Cholesterol Ester Transfer Proteins genetics
Cholesterol, HDL blood
Diet, High-Fat
Fatty Liver genetics
Insulin Resistance physiology
Subjects
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