The controversy over the use of cholesteryl ester transfer protein inhibitors: is there some light at the end of the tunnel?

Quintão, E.C.R.

doi:10.1111/eci.12626

Cited by 5 publications

(10 citation statements)

References 85 publications

(152 reference statements)

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“…CETP is synthesized in the liver and secreted into the plasma, and its activity influences the atherogenicity of the lipoprotein profile and cholesterol efflux in macrophages (Tall et al, 2008). In humans, CETP deficiency characteristically exhibits high HDL and low LDL levels (Brown et al, 1989;Inazu et al, 1994), but the correlation of plasma CETP level with atherosclerosis remains controversial and has not yet been clearly demonstrated in studies involving human populations (Dullaart et al, 2007;Quintao, 2016). Some species, such as rats and mice, do not express CETP, and transfer of cholesterol and CE to the liver mainly via HDL (Kingwell et al, 2014).…”

Section: Cholesteryl Ester Transfer Protein (Cetp)mentioning

confidence: 99%

“…Therefore, CETP-containing species, such as hamsters, monkeys, and ApoB/CETP double-transgenic mice, have been used to evaluate the effects of CETP expression on lipid metabolism and atherosclerosis development (Honzumi et al, 2010;Kingwell et al, 2014). Numerous studies suggest that CETP may have pro-or antiatherogenic properties depending upon the pathophysiological settings, and whether the CETP inhibition-induced lipoprotein changes exert anti-atherogenic activities remains a matter of debate (Dullaart et al, 2007;Ghosh and Ghosh, 2012;Quintao, 2016). LXRα has an essential role in the induction of CETP, whereas LXRβ activation has only a minor effect (Honzumi et al, 2010).…”

Section: Cholesteryl Ester Transfer Protein (Cetp)mentioning

confidence: 99%

See 1 more Smart Citation

Liver X Receptors and their Agonists: Targeting for Cholesterol Homeostasis and Cardiovascular Diseases

Ma¹,

Deng²,

Hu³

et al. 2017

Current Issues in Molecular Biology

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Liver X receptors α (LXRα) and β (LXRβ) are essential for protection against cardiovascular diseases. LXRs are members of the nuclear receptor superfamily of DNA-binding transcription factors and act as sensors of cholesterol homeostasis. In this review, we introduce LXRs and briefly describe the roles of LXRs in reverse cholesterol transport and trans-intestinal cholesterol efflux. We discuss LXR agonists and the downstream genes of LXRs that are involved in the regulation of cholesterol transport. In addition, we describe the cardioprotective effects of LXRs against atherosclerosis, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, and myocardial hypertrophy. Finally, we expand our discussion to the actions of LXRs in atherosclerosis and suggest several potential research avenues that may be of interest to clinicians and basic scientists. The information included herein may be useful for the design of future experimental research studies and may advance the investigation of LXRs as therapeutic targets.

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Section: Cholesteryl Ester Transfer Protein (Cetp)mentioning

confidence: 99%

Section: Cholesteryl Ester Transfer Protein (Cetp)mentioning

confidence: 99%

Liver X Receptors and their Agonists: Targeting for Cholesterol Homeostasis and Cardiovascular Diseases

Ma¹,

Deng²,

Hu³

et al. 2017

Current Issues in Molecular Biology

View full text Add to dashboard Cite

show abstract

“…In animal models, CETP inhibition protected transgenic mice expressing human CETP ( 1 ) as well as rabbits naturally expressing CETP against atherosclerosis ( 3 , 4 ). The CETP link with atherosclerosis and infection has been reviewed in humans ( 5 ), and lower plasma CETP concentrations occurred in patients who did not survive sepsis compared to survivors. Additionally, a positive correlation between plasma CETP concentration and sepsis survival rate was reported ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, a positive correlation between plasma CETP concentration and sepsis survival rate was reported ( 6 ). CETP is involved in the inflammatory response in mice expressing the human CETP gene (huCETP), which is more resistant to endotoxemia and experimental sepsis than in wild type mice ( 5 , 7 , 8 ). However, these results diverge from more recent results concluding that human CETP worsens inflammation and sepsis in mice ( 9 ), with CETP inhibition improving the survival rate in human sepsis ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

Cholesterol-Ester Transfer Protein Alters M1 and M2 Macrophage Polarization and Worsens Experimental Elastase-Induced Pulmonary Emphysema

et al. 2021

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Cholesterol-ester transfer protein (CETP) plays a role in atherosclerosis, the inflammatory response to endotoxemia and in experimental and human sepsis. Functional alterations in lipoprotein (LP) metabolism and immune cell populations, including macrophages, occur during sepsis and may be related to comorbidities such as chronic obstructive pulmonary disease (COPD). Macrophages are significantly associated with pulmonary emphysema, and depending on the microenvironment, might exhibit an M1 or M2 phenotype. Macrophages derived from the peritoneum and bone marrow reveal CETP that contributes to its plasma concentration. Here, we evaluated the role of CETP in macrophage polarization and elastase-induced pulmonary emphysema (ELA) in human CETP-expressing transgenic (huCETP) (line 5203, C57BL6/J background) male mice and compared it to their wild type littermates. We showed that bone marrow-derived macrophages from huCETP mice reduce polarization toward the M1 phenotype, but with increased IL-10. Compared to WT, huCETP mice exposed to elastase showed worsened lung function with an increased mean linear intercept (Lm), reflecting airspace enlargement resulting from parenchymal destruction with increased expression of arginase-1 and IL-10, which are M2 markers. The cytokine profile revealed increased IL-6 in plasma and TNF, and IL-10 in bronchoalveolar lavage (BAL), corroborating with the lung immunohistochemistry in the huCETP-ELA group compared to WT-ELA. Elastase treatment in the huCETP group increased VLDL-C and reduced HDL-C. Elastase-induced pulmonary emphysema in huCETP mice promotes lung M2-like phenotype with a deleterious effect in experimental COPD, corroborating the in vitro result in which CETP promoted M2 macrophage polarization. Our results suggest that CETP is associated with inflammatory response and influences the role of macrophages in COPD.

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“…High plasma concentrations of CETP are associated with low HDL-C which led to the development of CETP inhibitors that raise HDL-C levels and reduce atherosclerosis in experimental animals [ 17 – 20 ]. However, trials in humans using CETP inhibitors failed to protect against cardiovascular diseases [ 17 , 20 – 22 ] and one of them (torcetrapib) increased the incidence of cancer and infection [ 20 , 22 ]. In addition, recent in vivo experiments and human studies have suggested that CETP may have beneficial actions during acute inflammatory states [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

CETP Lowers TLR4 Expression Which Attenuates the Inflammatory Response Induced by LPS and Polymicrobial Sepsis

Venancio

Machado

Castoldi

et al. 2016

Mediators of Inflammation

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Sepsis is a systemic inflammatory response to infection eliciting high mortality rate which is a serious health problem. Despite numerous studies seeking for therapeutic alternatives, the mechanisms involved in this disease remain elusive. In this study we evaluated the influence of cholesteryl ester transfer protein (CETP), a glycoprotein that promotes the transfer of lipids between lipoproteins, on the inflammatory response in mice. Human CETP transgenic mice were compared to control mice (wild type, WT) after polymicrobial sepsis induced by cecal ligation and puncture (CLP), aiming at investigating their survival rate and inflammatory profiles. Macrophages from the peritoneal cavity were stimulated with LPS in the presence or absence of recombinant CETP for phenotypic and functional studies. In comparison to WT mice, CETP mice showed higher survival rate, lower IL-6 plasma concentration, and decreased liver toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH) protein. Moreover, macrophages from WT mice to which recombinant human CETP was added decreased LPS uptake, TLR4 expression, NF-κB activation and IL-6 secretion. This raises the possibility for new therapeutic tools in sepsis while suggesting that lowering CETP by pharmacological inhibitors should be inconvenient in the context of sepsis and infectious diseases.

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The controversy over the use of cholesteryl ester transfer protein inhibitors: is there some light at the end of the tunnel?

Cited by 5 publications

References 85 publications

Liver X Receptors and their Agonists: Targeting for Cholesterol Homeostasis and Cardiovascular Diseases

Liver X Receptors and their Agonists: Targeting for Cholesterol Homeostasis and Cardiovascular Diseases

Cholesterol-Ester Transfer Protein Alters M1 and M2 Macrophage Polarization and Worsens Experimental Elastase-Induced Pulmonary Emphysema

CETP Lowers TLR4 Expression Which Attenuates the Inflammatory Response Induced by LPS and Polymicrobial Sepsis

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