scholarly journals Augmentation of Ca2+-Induced Microsomal Triglyceride Transfer Protein Activity by Glucose Supply Enhances Hypertriglyceridemia in Vivo

2006 ◽  
Vol 29 (5) ◽  
pp. 889-895 ◽  
Author(s):  
Hyun-Jeong Cho ◽  
Hyo-Chan Kang ◽  
Young-Cheol Ju ◽  
Hyun-Sub Lee ◽  
Hyeong-Soo Kim ◽  
...  
Keyword(s):  
Microsomal Triglyceride Transfer Protein ◽  
Protein Activity ◽  
Transfer Protein ◽  
Glucose Supply

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.

Decreased microsomal triglyceride transfer protein activity contributes to initiation of alcoholic liver steatosis in rats

2002 ◽  
Vol 36 (2) ◽  
pp. 157-162 ◽  
Author(s):  
Taizo Sugimoto ◽  
Shizuya Yamashita ◽  
Masato Ishigami ◽  
Naohiko Sakai ◽  
Ken-ichi Hirano ◽  
...  
Keyword(s):  
Liver Steatosis ◽  
Microsomal Triglyceride Transfer Protein ◽  
Protein Activity ◽  
Transfer Protein

scholarly journals Microsomal triglyceride transfer protein activity remains unchanged in rat livers under conditions of altered very-low-density lipoprotein secretion

1995 ◽  
Vol 310 (1) ◽  
pp. 11-14 ◽  
Author(s):  
D J Brett ◽  
R J Pease ◽  
J Scott ◽  
G F Gibbons
Keyword(s):  
Cultured Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Microsomal Triglyceride Transfer Protein ◽  
Autosomal Recessive Disorder ◽  
Diabetic Rat ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Protein Activity ◽  
Transfer Protein

Microsomal triglyceride transfer protein (MTP) is a heterodimeric protein consisting of a unique 97 kDa subunit and protein disulphide isomerase, that mediates the transfer of lipid between membranes and nascent lipoproteins. Mutations in the gene encoding the 97 kDa subunit of the protein cause the rare autosomal recessive disorder abetalipoproteinaemia. Recent findings in cultured cells indicate that the 5′ promoter region contains an insulin-responsive element, suggesting that the gene is responsive to insulin regulation. In this study we examined two cases where very-low-density lipoprotein (VLDL) secretion is markedly reduced: the streptozotocin-diabetic rat and 10-day-old suckling rats. In both cases MTP activity was unaltered compared with that in control animals. Equal levels of MTP were also apparent in the livers of all groups of animals, as measured by immunoblotting with an anti-MTP antiserum. These findings indicate that factors other than MTP activity are responsible for the reduction in hepatic VLDL triglyceride secretion observed in the suckling and diabetic animals.

scholarly journals 17β-Estradiol-Induced Conformational Changes of Human Microsomal Triglyceride Transfer Protein: A Computational Molecular Modelling Study

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1566
Author(s):  
Yongxiao Yang ◽  
Peng Li ◽  
Pan Wang ◽  
Baoting Zhu
Keyword(s):  
Molecular Dynamics ◽  
Lipid Metabolism ◽  
Conformational Changes ◽  
Liver Lipid ◽  
Microsomal Triglyceride Transfer Protein ◽  
Blood Levels ◽  
Transfer Protein ◽  
17Β Estradiol ◽  
Dynamics Analyses

Human microsomal triglyceride transfer protein (hMTP) plays an essential role in the assembly of apoB-containing lipoproteins, and has become an important drug target for the treatment of several disease states, such as abetalipoproteinemia, fat malabsorption and familial hypercholesterolemia. hMTP is a heterodimer composed of a larger hMTPα subunit and a smaller hMTPβ subunit (namely, protein disulfide isomerase, hPDI). hPDI can interact with 17β-estradiol (E2), an endogenous female sex hormone. It has been reported that E2 can significantly reduce the blood levels of low-density lipoprotein, cholesterol and triglyceride, and modulate liver lipid metabolism in vivo. However, some of the estrogen’s actions on lipid metabolism are not associated with estrogen receptors (ER), and the exact mechanism underlying estrogen’s ER-independent lipid-modulating action is still not clear at present. In this study, the potential influence of E2 on the stability of the hMTP complex is investigated by jointly using multiple molecular dynamics analyses based on available experimental structures. The molecular dynamics analyses indicate that the hMTP complex in the presence of E2 has reduced interface contacts and surface areas. A steered molecular dynamics analysis shows that the forces required to separate the two subunits (namely, hPDI and hMTPα subunit) of the hMTP complex in the absence of E2 are significantly higher than the forces required to separate the complex in which its hPDI is already bound with E2. E2 makes the interface between hMTPα and hPDI subunits more flexible and less stable. The results of this study suggest that E2-induced conformational changes of the hMTP complex might be a novel mechanism partly accounting for the ER-independent lipid-modulating effect of E2.

scholarly journals Intestinal Lipoprotein Overproduction, a Newly Recognized Component of Insulin Resistance, Is Ameliorated by the Insulin Sensitizer Rosiglitazone: Studies in the Fructose-Fed Syrian Golden Hamster

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 247-255 ◽  
Author(s):  
Gary F. Lewis ◽  
Kristine Uffelman ◽  
Mark Naples ◽  
Linda Szeto ◽  
Mehran Haidari ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Microsomal Triglyceride Transfer Protein ◽  
Fold Increase ◽  
Hamster Model ◽  
Insulin Sensitizer ◽  
Insulin Resistant ◽  
Protein Mass ◽  
Transfer Protein ◽  
Triglyceride Rich Lipoprotein

We investigated whether intestinal lipoprotein overproduction in a fructose-fed, insulin-resistant hamster model is prevented with insulin sensitization. Syrian Golden hamsters were fed either chow, 60% fructose for 5 wk, chow for 5 wk with the insulin sensitizer rosiglitazone added for the last 3 wk, or 60% fructose plus rosiglitazone. In vivo Triton studies showed a 2- to 3-fold increase in the large (Svedberg unit &gt; 400) and smaller (Sf 100–400) triglyceride-rich lipoprotein particle apolipoprotein B48 (apoB48) but not triglyceride secretion with fructose feeding in the fasted state (P &lt; 0.01) and partial normalization with rosiglitazone in fructose-fed hamsters. Ex vivo pulse-chase labeling of enterocytes confirmed the oversecretion of apoB48 lipoproteins with fructose feeding. Intestinal lipoprotein oversecretion was associated with increased expression of microsomal triglyceride transfer protein expression. With rosiglitazone treatment of fructose-fed hamsters, there was approximately 50% reduction in apoB48 secretion from primary cultured enterocytes and amelioration of the elevated microsomal triglyceride transfer protein mass and activity in fructose-fed hamsters. In contrast, in the postprandial state, the major differences between nutritional and drug intervention protocols were evident in triglyceride-rich lipoprotein triglyceride and not apoB48 secretion rates. The data suggest that intestinal lipoprotein overproduction can be ameliorated with the insulin sensitizer rosiglitazone.

scholarly journals Adaptation of enterocytic Caco-2 cells to glucose modulates triacylglycerol-rich lipoprotein secretion through triacylglycerol targeting into the endoplasmic reticulum lumen

2006 ◽  
Vol 395 (2) ◽  
pp. 393-403 ◽  
Author(s):  
Thomas Pauquai ◽  
Julien Bouchoux ◽  
Danielle Chateau ◽  
Romain Vidal ◽  
Monique Rousset ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Subcellular Fractionation ◽  
Dietary Lipids ◽  
Protein Activity ◽  
Transfer Protein ◽  
Endoplasmic Reticulum Lumen ◽  
Mean Size ◽  
Low Glucose ◽  
Lipoprotein Assembly ◽  
Glucose Supply

Enterocytes are responsible for the absorption of dietary lipids, which involves TRL [TG (triacylglycerol)-rich lipoprotein] assembly and secretion. In the present study, we analysed the effect on TRL secretion of Caco-2 enterocyte adaptation to a differential glucose supply. We showed that TG secretion in cells adapted to a low glucose supply for 2 weeks after confluence was double that of control cells maintained in high-glucose-containing medium, whereas the level of TG synthesis remained similar in both conditions. This increased secretion resulted mainly from an enlargement of the mean size of the secreted TRL. The increased TG availability for TRL assembly and secretion was not due to an increase in the MTP (microsomal TG transfer protein) activity that is required for lipid droplet biogenesis in the ER (endoplasmic reticulum) lumen, or to the channelling of absorbed fatty acids towards the monoacylglycerol pathway for TG synthesis. Interestingly, by electron microscopy and subcellular fractionation studies, we observed, in the low glucose condition, an increase in the TG content available for lipoprotein assembly in the ER lumen, with the cytosolic/microsomal TG levels being verapamil-sensitive. Overall, we demonstrate that Caco-2 enterocytes modulate TRL secretion through TG partitioning between the cytosol and the ER lumen according to the glucose supply. Our model will help in identifying the proteins involved in the control of the balance between TRL assembly and cytosolic lipid storage. This mechanism may be a way for enterocytes to regulate TRL secretion after a meal, and thus impact on our understanding of post-prandial hypertriglyceridaemia.

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