scholarly journals The lipid transfer properties of CETP define the concentration and composition of plasma lipoproteins

2020 ◽  
Vol 61 (8) ◽  
pp. 1168-1179 ◽  
Author(s):  
Richard E. Morton ◽  
Yan Liu
Keyword(s):  
Substrate Preference ◽  
Plasma Lipoproteins ◽  
Lipid Transfer ◽  
Hepatic Expression ◽  
Transfer Protein ◽  
Novel Approach ◽  
Human Ortholog ◽  
Low Levels ◽  
Transfer Properties

Cholesteryl ester transfer protein (CETP) facilitates the net transfer of cholesteryl esters (CEs) and TGs between lipoproteins, impacting the metabolic fate of these lipoproteins. Previous studies have shown that a CETP antibody can alter CETP’s preference for CE versus TG as transfer substrate, suggesting that CETP substrate preference can be manipulated in vivo. Hamster and human CETPs have very different preferences for CE and TG. To assess the effect of altering CETP’s substrate preference on lipoproteins in vivo, here, we expressed human CETP in hamsters. Chow-fed hamsters received adenoviruses expressing no CETP, hamster CETP, or human CETP. Plasma CETP mass increased 2-fold in both the hamster and human CETP groups. Although the animals expressing human CETP still had low levels of hamster CETP, the CE versus TG preference of their plasma CETP was similar to that of the human ortholog. Hamster CETP overexpression had little impact on lipoproteins. However, expression of human CETP reduced HDL up to 50% and increased VLDL cholesterol 2.5-fold. LDL contained 20% more CE, whereas HDL CE was reduced 40%, and TG increased 6-fold. The HDL3:HDL2 ratio increased from 0.32 to 0.60. Hepatic expression of three cholesterol-related genes (LDLR, SCARB1, and CYP7A1) was reduced up to 40%. However, HDL-associated CE excretion into feces was unchanged. We conclude that expression of human CETP in hamsters humanizes their lipoprotein profile with respect to the relative concentrations of VLDL, LDL, HDL, and the HDL3:HDL2 ratio. Altering the lipid substrate preference of CETP provides a novel approach for modifying plasma lipoproteins.

Abstract 319: Dalcetrapib-Mediated Modulation of Cholesteryl Ester Transfer Protein Activity Increases HDL-Cholesterol, Apolipoprotein A-I Levels and Cholesterol Efflux Capacity in Chow-Fed Rabbits

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Mathieu R Brodeur ◽  
David Rhainds ◽  
Daniel Charpentier ◽  
Téodora Mihalache-Avram ◽  
Cyrille Maugeais ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Cholesterol Efflux ◽  
Hdl Cholesterol ◽  
Lipid Transfer ◽  
Protein Activity ◽  
Cholesterol Efflux Capacity ◽  
Transfer Protein

Introduction: A potential approach to reduce CV risk is to increase HDL-C levels. This could be achieved by reducing cholesteryl ester transfer protein (CETP) activity. Dalcetrapib, which modulates CETP activity by changing its conformation and raises HDL-C without inhibiting CETP-induced pre-β-HDL formation in humans, was shown to decrease progression of atherosclerosis in rabbits. Hypothesis: Investigate the modifications of HDL particle size distribution and cholesterol efflux capacity of serum produced by dalcetrapib in normocholesterolemic rabbits. Methods: New Zealand white rabbits were treated with dalcetrapib (300 mg/kg as food admix) or placebo for 14 days. We evaluated CETP conformation and mass by ELISAs (including antibodies sensitive to conformational change), CETP activity by fluorescent lipid transfer, lipid profile and apoA-I distribution in HDL subclasses by 2D-non denaturing gradient gels (2D-NDGGE). Cholesterol efflux capacity of rabbit sera was determined after loading cells with 3 H-free cholesterol, using HepG2 hepatocytes to measure SR-BI-dependent efflux and by inducing ABCA1 or ABCG1 expression in BHK cells. Results: Dalcetrapib modified the conformation of rabbit CETP in vitro and in vivo and, after 14 days, this was associated with increased CETP mass (+50%, p<0.001) and reduced CETP activity (-86%, p<0.001). Total cholesterol was increased with dalcetrapib (+178%, p<0.001), due to a higher HDL-C level. In contrast, dalcetrapib reduced LDL-C and triglycerides by 41% (p<0.01) and 48% (p<0.001). Serum analysis by 2D-NDGGE showed that total rabbit apoA-I was increased 1.7- fold in animals treated with dalcetrapib. This was associated with an increase in large HDL but also in small α-migrating HDL with pre-β-HDL size. Cholesterol efflux assays showed that ABCA1-, ABCG1- and SR-BI-dependent efflux were all increased in dalcetrapib-treated rabbits (+24%, p=0.038; +21%, p=0.021; +44%, p<0.001). Conclusion: Modulation of CETP activity and conformation by dalcetrapib increases HDL-C and apoA-I levels and affects apoA-I distribution in HDL subclasses. These changes are associated with increased cholesterol efflux capacity, suggesting that HDL functionality is preserved in dalcetrapib-treated chow-fed rabbits.

scholarly journals Human CETP lacks lipopolysaccharide transfer activity, but worsens inflammation and sepsis outcomes in mice

2020 ◽  
pp. jlr.RA120000704
Author(s):  
Aloïs Dusuel ◽  
Valérie Deckert ◽  
Jean-Paul PAIS DE BARROS ◽  
Kevin Van Dongen ◽  
Hélène Choubley ◽  
...  
Keyword(s):  
Cecal Ligation ◽  
Plasma Lipid ◽  
Plasma Lipoproteins ◽  
Protective Effects ◽  
Lipid Transfer ◽  
Transfer Property ◽  
Transfer Activity ◽  
Lps Binding

Bacterial lipopolysaccharides (LPSs or endotoxins) can bind most proteins of the lipid transfer/LPS-binding protein (LT/LBP) family in host organisms. The LPS-bound LT/LBP proteins then trigger either an LPS-induced proinflammatory cascade or LPS binding to lipoproteins that are involved in endotoxin inactivation and detoxification. Cholesteryl ester transfer protein (CETP) is an LT/LBP member, but its impact on LPS metabolism and sepsis outcome is unclear. Here, we performed fluorescent LPS transfer assays to assess the ability of CETP to bind and transfer LPS. The effects of intravenous (iv) infusion of purified LPS or polymicrobial infection (cecal ligation and puncture [CLP]) were compared in transgenic mice expressing human CETP and wild-type mice naturally having no CETP activity. CETP displayed no LPS transfer activity in vitro, but it tended to reduce biliary excretion of LPS in vivo. The CETP expression in mice was associated with significantly lower basal plasma lipid levels and with higher mortality rates in both models of endotoxemia and sepsis. Furthermore, CETPTg plasma modified cytokine production of macrophages in vitro. In conclusion, despite having no direct LPS binding and transfer property, human CETP worsens sepsis outcomes in mice by altering the protective effects of plasma lipoproteins against endotoxemia, inflammation, and infection.

scholarly journals Response of ApoA-IV in pigs to long-term increased dietary oil intake and to the degree of unsaturation of the fatty acids

2004 ◽  
Vol 92 (5) ◽  
pp. 763-769 ◽  
Author(s):  
María A. Navarro ◽  
Sergio Acín ◽  
Ricardo Carnicer ◽  
Mario A. Guzmán-García ◽  
José M. Arbonés-Mainar ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Sunflower Oil ◽  
Control Diet ◽  
Dietary Lipids ◽  
Degree Of Saturation ◽  
Plasma Lipoproteins ◽  
Mrna Levels ◽  
Hepatic Expression

ApoA-IV is a protein constituent of HDL particles; the gene coding for it is a member of the ApoA-I–ApoC-III–ApoA-IV cluster. To investigate the effects of the quantity and the degree of saturation of dietary lipid on the long-term response of this Apo, and on the hypothetical coordinated regulation of the cluster in vivo, pigs were fed isoenergetic, cholesterol-free, low-lipid or lipid-enriched diets (containing either extra olive oil (rich in MUFA) or sunflower oil (rich in n−6 PUFA)) for 42 d. In animals fed on the control diet, ApoA-IV was mainly associated with plasma lipoproteins. An increase in plasma ApoA-IV concentration, mainly in the lipoprotein-free fraction, was induced by the lipid-enriched diets, independent of the degree of saturation of the fatty acids involved. The latter diets also led to increases in hepatic ApoA-I, ApoA-IV and ApoC-III mRNA levels, more so with the sunflower oil-rich diet. The present results show that porcine plasma ApoA-IV levels and their association with lipoproteins are very sensitive to increases in dietary lipids, independent of the degree of fatty acid saturation. Furthermore, hepatic expression of RNA appears to be coordinated along with that of the other members of the gene cluster.

Interfacial and lipid transfer properties of human phospholipid transfer protein

2007 ◽  
Vol 149 ◽  
pp. S88-S89
Author(s):  
Niko Setälä ◽  
Jari Metso ◽  
Susanne Wiedmer ◽  
Gebrenegus Yohannes ◽  
Paavo Kinnunen ◽  
...  
Keyword(s):  
Phospholipid Transfer Protein ◽  
Lipid Transfer ◽  
Transfer Protein ◽  
Phospholipid Transfer ◽  
Transfer Properties

Interfacial and Lipid Transfer Properties of Human Phospholipid Transfer Protein:  Implications for the Transfer Mechanism of Phospholipids†

Biochemistry ◽  
2007 ◽  
Vol 46 (5) ◽  
pp. 1312-1319 ◽  
Author(s):  
Niko L. Setälä ◽  
Juha M. Holopainen ◽  
Jari Metso ◽  
Susanne K. Wiedmer ◽  
Gebrenegus Yohannes ◽  
...  
Keyword(s):  
Transfer Mechanism ◽  
Phospholipid Transfer Protein ◽  
Lipid Transfer ◽  
Transfer Protein ◽  
Phospholipid Transfer ◽  
Transfer Properties

In vivo and in vitro techniques in the diagnosis of lipid transfer protein sensitization

2013 ◽  
Vol 111 (6) ◽  
pp. 571-573 ◽  
Author(s):  
Felicia Berroa ◽  
Gabriel Gastaminza ◽  
Noemí Saiz ◽  
Julián Azofra ◽  
Pedro M. Gamboa ◽  
...  
Keyword(s):  
Lipid Transfer Protein ◽  
Lipid Transfer ◽  
In Vitro Techniques ◽  
Transfer Protein ◽  
Protein Sensitization

Abstract 192: Characterization of Microsomal Triglyceride Transfer Protein Missense Mutations Found in Abetalipoproteinemia and Hybobetalipoproteinemia Subjects

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Meghan T Walsh ◽  
Enza Di Leo ◽  
Patrizia Tarugi ◽  
M. Mahmood Hussain
Keyword(s):  
Plasma Lipid ◽  
Microsomal Triglyceride Transfer Protein ◽  
The Other ◽  
Plasma Lipoproteins ◽  
Missense Mutations ◽  
Lipid Transfer ◽  
Novel Proteins ◽  
Transfer Protein ◽  
Apob Secretion ◽  
Familial Hypobetalipoproteinemia

We describe two new hypolipidemic patients with very low plasma triglyceride and apolipoprotein B (apoB) levels and lipid malabsorption with plasma lipid profiles similar to abetalipoproteinemia (ABL) patients. In these patients, we identified two previously uncharacterized missense mutations in the microsomal triglyceride transfer protein (MTP) gene, R46G and D361Y, and studied their effects on function. We also characterized three missense mutations (H297Q, D384A, and G661A) reported earlier in a familial hypobetalipoproteinemia patient. R46G had no effect on MTP expression or function and supported apoB secretion. Similarly, H297Q, D384A, and G661A mutants supported apoB secretion similarly to WT MTP. Contrary to these four missense mutations, D361Y was unable to support apoB secretion. Functional analysis revealed that this mutant was unable to bind protein disulfide isomerase (PDI) or transfer lipids. The negative charge at residue 361 was critical for MTP function as D361E was able to support apoB secretion and transfer lipids. D361Y most likely disrupts the tightly packed middle α-helical region of MTP, mitigates PDI binding, abolishes lipid transfer activity, and causes ABL. On the other hand, the hypolipidemia in the other two patients was not due to MTP dysfunction. Thus, in this study of five missense mutations spread throughout MTP’s three structural domains found in three hypolipidemic patients, we found that four of the mutations did not affect MTP function. Thus, there probably exist novel mutations in other genes that cause severe hypolipidemia and their recognition may identify novel proteins involved in the synthesis and/or catabolism of plasma lipoproteins.

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