Cholesteryl ester transfer protein protects against insulin resistance in obese female mice

Cappel, David A.; Palmisano, Brian T.; Emfinger, Christopher H.; Martinez, Mélissa; McGuinness, Owen P.; Stafford, John M.

doi:10.1016/j.molmet.2013.08.007

Cited by 25 publications

(48 citation statements)

References 45 publications

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“…Interestingly, CETP expression also results in a significant increase in fecal bile acids in vehicle treated animals (Supplemental Figure VIID). Increased bile acid synthesis has previously been reported in CETP transgenic mice 57, 58 . Little or no difference was observed in hepatic 3 H-cholesterol levels among the groups (data not shown).…”

Section: Resultsmentioning

confidence: 63%

Macrophage-Independent Regulation of Reverse Cholesterol Transport by Liver X Receptors

Breevoort

Angdisen

Schulman

2014

ATVB

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Objective The ability of high density lipoprotein (HDL) particles to accept cholesterol from peripheral cells such as lipid-laden macrophages and to transport cholesterol to the liver for catabolism and excretion in a process termed reverse cholesterol transport (RCT) is believed to underlie the beneficial cardiovascular effects of elevated HDL. The liver X receptors (LXRα and LXRβ) regulate RCT by controlling the efflux of cholesterol from macrophages to HDL and the excretion, catabolism and absorption of cholesterol in the liver and intestine. Importantly, treatment with LXR agonists increases RCT and decreases atherosclerosis in animal models. Nevertheless, LXRs are expressed in multiple tissues involved in RCT and their tissue specific contributions to RCT are still not well defined. Approach and Results Utilizing tissue-specific LXR deletions together with in vitro and in vivo assays of cholesterol efflux and fecal cholesterol excretion we demonstrate that macrophage LXR activity is neither necessary nor sufficient for LXR agonist-stimulated RCT. In contrast, the ability of LXR agonists primarily acting in the intestine to increase HDL mass and HDL function appears to underlie the ability of LXR agonists to stimulate RCT in vivo. Conclusions We demonstrate that activation of LXR in macrophages makes little or no contribution to LXR agonist-stimulated RCT. Unexpectedly our studies suggest that the ability of macrophages to efflux cholesterol to HDL in vivo is not regulated by macrophage activity but is primarily determined by the quantity and functional activity of HDL.

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Section: Resultsmentioning

confidence: 63%

Macrophage-Independent Regulation of Reverse Cholesterol Transport by Liver X Receptors

Breevoort

Angdisen

Schulman

2014

ATVB

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“…Previously, CETP was shown to improve HDL function in women, but not men (15). Additionally, we have shown that transgenic expression of CETP protected against insulin resistance in females (16), recapitulating how estrogen increases insulin sensitivity in women. This suggests that CETP may facilitate estrogen-specific functions.…”

Section: Estrogen Treatment Raises Tg Production In Cetp Femalesmentioning

confidence: 57%

“…Because liver ER was not required to raise TG production in response to estrogen treatment in CETP mice, we sought to determine additional factors required for this effect in CETP mice. Previously, we showed that CETP expression enhanced bile acid signaling to the nuclear receptor SHP in females (16). SHP regulates a number of metabolic pathways, including VLDL-TG production (26) and estrogen signaling (27,28).…”

Section: Cetp Requires Liver Shp To Increase Tg Production With Estromentioning

confidence: 99%

Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice

Palmisano

Zhu

et al. 2016

Journal of Lipid Research

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Elevated plasma TGs increase risk of cardiovascular disease in women. Estrogen treatment raises plasma TGs in women, but molecular mechanisms remain poorly understood. Here we explore the role of cholesteryl ester transfer protein (CETP) in the regulation of TG metabolism in female mice, which naturally lack CETP. In transgenic CETP females, acute estrogen treatment raised plasma TGs 50%, increased TG production, and increased expression of genes involved in VLDL synthesis, but not in nontransgenic littermate females. In CETP females, estrogen enhanced expression of small heterodimer partner (SHP), a nuclear receptor regulating VLDL production. Deletion of liver SHP prevented increases in TG production and expression of genes involved in VLDL synthesis in CETP mice with estrogen treatment. We also examined whether CETP expression had effects on TG metabolism independent of estrogen treatment. CETP increased liver β-oxidation and reduced liver TG content by 60%. Liver estrogen receptor α (ERα) was required for CETP expression to enhance β-oxidation and reduce liver TG content. Thus, CETP alters at least two networks governing TG metabolism, one involving SHP to increase VLDL-TG production in response to estrogen, and another involving ERα to enhance β-oxidation and lower liver TG content. These findings demonstrate a novel role for CETP in estrogen-mediated increases in TG production and a broader role for CETP in TG metabolism.

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“…Our analysis of CETP expression in several databases across cell line, BC tissue and patient gene expression data also provides evidence for the implication of CETP in BC as it was found commonly overexpressed in BC cases, correlated with poor relapse free and overall survival and a significant probability of poor long-term survival for ER+ BC patients. These observations may be crucial in light of the evidence that CETP : is elevated in BC; increases cholesterol uptake in BC cells; mediates the transfer of free cholesterol between lipoproteins and membranes; shuttles estradiol (E2) between HDL and LDL; and augments estradiol delivery to tissues, potentially enhancing estrogen signalling [24]. Furthermore, AP significantly decreased estrogen receptor– 1 (ESR-1) and elevated the CETP inhibitor APOF gene expression which further adds another level of regulation mediated by the therapeutic small molecule (AP) in the CETP pathway (Figure S6F and G).…”

Section: Discussionmentioning

confidence: 99%

“…The cholesteryl ester transfer protein (CETP) shuttles cholesteryl esters (CEs) and triglycerides between HDL and LDL to maintain cholesterol homeostasis both intracellularly and extracellularly [22]. CETP has been shown to prevent development of atherosclerotic lesions in ovariectomized hypercholesterolemic mice [23],and a link between CETP and estrogen has also been proposed [24]. Furthermore, CETP-deficient cells have been reported to have lower cholesterol content as CETP deficiency impeded CE transport from its site of synthesis to the storage droplet thereby reducing CE hydrolysis [25].…”

Section: Introductionmentioning

confidence: 99%

Identification of CETP as a molecular target for estrogen positive breast cancer cell death by cholesterol depleting agents

et al. 2016

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Cholesterol and its metabolites act as steroid hormone precursors, which promote estrogen receptor positive (ER+) breast cancer (BC) progression. Development of cholesterol targeting anticancer drugs has been hindered due to the lack of knowledge of viable molecular targets. Till now, Cholesteryl ester transfer protein (CETP) has been envisaged as a feasible molecular target in atherosclerosis, but for the first time, we show that CETP contributes to BC cell survival when challenged with cholesterol depleting agents. We show that MCF-7 CETP knockout BC cells pose less resistance towards cytotoxic compounds (Tamoxifen and Acetyl Plumbagin (AP)), and were more susceptible to intrinsic apoptosis. Analysis of differentially expressed genes using Ingenuity Pathway Analysis (IPA), in vivo tumor inhibition, and in vitro phenotypic responses to AP revealed a unique CETP-centric cholesterol pathway involved in sensitizing ER+ BC cells to intrinsic mitochondrial apoptosis. Furthermore, analysis of cell line, tissue and patient data available in publicly available databases linked elevated CETP expression to cancer, cancer relapse and overall poor survival. Overall, our findings highlight CETP as a pharmacologically relevant and unexploited cellular target in BC. The work also highlights AP as a promising chemical entity for preclinical investigations as a cholesterol depleting anticancer therapeutic agent.

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Cholesteryl ester transfer protein protects against insulin resistance in obese female mice

Cited by 25 publications

References 45 publications

Macrophage-Independent Regulation of Reverse Cholesterol Transport by Liver X Receptors

Macrophage-Independent Regulation of Reverse Cholesterol Transport by Liver X Receptors

Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice

Identification of CETP as a molecular target for estrogen positive breast cancer cell death by cholesterol depleting agents

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