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 language | English (US) |
|---|---|
| Pages (from-to) | 2494-2506 |
| Number of pages | 13 |
| Journal | Diabetes |
| Volume | 67 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2018 |
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ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
Cite this
CETP inhibition improves hdl function but leads to fatty liver and insulin resistance in CETP-expressing transgenic mice on a high-fat diet. / Zhu, Lin; Luu, Thao; Emfinger, Christopher H.; Parks, Bryan A.; Shi, Jeanne; Trefts, Elijah; Zeng, Fenghua; Kuklenyik, Zsuzsanna; Harris, Raymond C.; Wasserman, David H.; Fazio, Sergio; Stafford, John M.
In: Diabetes, Vol. 67, No. 12, 01.12.2018, p. 2494-2506.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - CETP inhibition improves hdl function but leads to fatty liver and insulin resistance in CETP-expressing transgenic mice on a high-fat diet
AU - Zhu, Lin
AU - Luu, Thao
AU - Emfinger, Christopher H.
AU - Parks, Bryan A.
AU - Shi, Jeanne
AU - Trefts, Elijah
AU - Zeng, Fenghua
AU - Kuklenyik, Zsuzsanna
AU - Harris, Raymond C.
AU - Wasserman, David H.
AU - Fazio, Sergio
AU - Stafford, John M.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056802989&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056802989&partnerID=8YFLogxK
U2 - 10.2337/db18-0474
DO - 10.2337/db18-0474
M3 - Article
C2 - 30213825
AN - SCOPUS:85056802989
VL - 67
SP - 2494
EP - 2506
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 12
ER -