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Bart Staels - One of the best experts on this subject based on the ideXlab platform.
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hepatoprotective effects of the dual peroxisome proliferator activated receptor alpha delta agonist gft505 in rodent models of nonalcoholic fatty liver disease nonalcoholic steatohepatitis
Hepatology, 2013Co-Authors: Bart Staels, Morgane Baron, Anne Rubenstrunk, Bernard Noel, Geraldine Rigou, Philippe Delataille, Lesley J Millatt, Anthony Lucas, Anne Tailleux, Dean W HumAbstract:Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]-fed human Apolipoprotein E2 [hApoE2] transgenic mice, methionine- and choline-deficient diet-fed db/db mice, and CCl4-induced fibrosis in rats). GFT505 demonstrated liver-protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR-α-independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock-in/PPAR-α knockout mice. In these mice, GFT505 also prevented WD-induced liver steatosis and inflammation, indicating a contribution of PPAR-α-independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase. Conclusion: The dual PPAR-α/δ agonist, GFT505, is a promising liver-targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR-α-dependent and -independent mechanisms. (Hepatology 2013; 58:1941–1952)
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hepatoprotective effects of the dual peroxisome proliferator activated receptor alpha delta agonist gft505 in rodent models of nonalcoholic fatty liver disease nonalcoholic steatohepatitis
Hepatology, 2013Co-Authors: Bart Staels, Morgane Baron, Anne Rubenstrunk, Bernard Noel, Geraldine Rigou, Philippe Delataille, Lesley J Millatt, Anthony Lucas, Anne Tailleux, V RatziuAbstract:Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]-fed human Apolipoprotein E2 [hApoE2] transgenic mice, methionine- and choline-deficient diet-fed db/db mice, and CCl4-induced fibrosis in rats). GFT505 demonstrated liver-protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR-α-independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock-in/PPAR-α knockout mice. In these mice, GFT505 also prevented WD-induced liver steatosis and inflammation, indicating a contribution of PPAR-α-independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase. Conclusion: The dual PPAR-α/δ agonist, GFT505, is a promising liver-targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR-α-dependent and -independent mechanisms. (Hepatology 2013; 58:1941–1952)
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dietary cholesterol rather than liver steatosis leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis
Hepatology, 2008Co-Authors: Kristiaan Wouters, Patrick J Van Gorp, Veerle Bieghs, Marion J J Gijbels, Hans Duimel, Dieter Lutjohann, Anja Kerksiek, Roger Van Kruchten, Nobuyo Maeda, Bart StaelsAbstract:Nonalcoholic steatohepatitis (NASH) involves liver lipid accumulation (steatosis) combined with hepatic inflammation. The transition towards hepatic inflammation represents a key step in pathogenesis, because it will set the stage for further liver damage, culminating in hepatic fibrosis, cirrhosis, and liver cancer. The actual risk factors that drive hepatic inflammation during the progression to NASH remain largely unknown. The role of steatosis and dietary cholesterol in the etiology of diet-induced NASH was investigated using hyperlipidemic mouse models fed a Western diet. Livers of male and female hyperlipidemic (low-density lipoprotein receptor–deficient [ldlr−/−] and Apolipoprotein E2 knock-in [APOE2ki]) mouse models were compared with livers of normolipidemic wild-type (WT) C57BL/6J mice after short-term feeding with a high-fat diet with cholesterol (HFC) and without cholesterol. Whereas WT mice displayed only steatosis after a short-term HFC diet, female ldlr−/− and APOE2ki mice showed steatosis with severe inflammation characterized by infiltration of macrophages and increased nuclear factor κB (NF-κB) signaling. Remarkably, male ldlr−/− and APOE2ki mice developed severe hepatic inflammation in the absence of steatosis after 7 days on an HFC diet compared with WT animals. An HFC diet induced bloated, “foamy” Kupffer cells in male and female ldlr−/− and APOE2ki mice. Hepatic inflammation was found to be linked to increased plasma very low-density lipoprotein (VLDL) cholesterol levels. Omitting cholesterol from the HFC diet lowered plasma VLDL cholesterol and prevented the development of inflammation and hepatic foam cells. Conclusion: These findings indicate that dietary cholesterol, possibly in the form of modified plasma lipoproteins, is an important risk factor for the progression to hepatic inflammation in diet-induced NASH. (HEPATOLOGY 2008;48:474–486.)
Morgane Baron - One of the best experts on this subject based on the ideXlab platform.
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hepatoprotective effects of the dual peroxisome proliferator activated receptor alpha delta agonist gft505 in rodent models of nonalcoholic fatty liver disease nonalcoholic steatohepatitis
Hepatology, 2013Co-Authors: Bart Staels, Morgane Baron, Anne Rubenstrunk, Bernard Noel, Geraldine Rigou, Philippe Delataille, Lesley J Millatt, Anthony Lucas, Anne Tailleux, Dean W HumAbstract:Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]-fed human Apolipoprotein E2 [hApoE2] transgenic mice, methionine- and choline-deficient diet-fed db/db mice, and CCl4-induced fibrosis in rats). GFT505 demonstrated liver-protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR-α-independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock-in/PPAR-α knockout mice. In these mice, GFT505 also prevented WD-induced liver steatosis and inflammation, indicating a contribution of PPAR-α-independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase. Conclusion: The dual PPAR-α/δ agonist, GFT505, is a promising liver-targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR-α-dependent and -independent mechanisms. (Hepatology 2013; 58:1941–1952)
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hepatoprotective effects of the dual peroxisome proliferator activated receptor alpha delta agonist gft505 in rodent models of nonalcoholic fatty liver disease nonalcoholic steatohepatitis
Hepatology, 2013Co-Authors: Bart Staels, Morgane Baron, Anne Rubenstrunk, Bernard Noel, Geraldine Rigou, Philippe Delataille, Lesley J Millatt, Anthony Lucas, Anne Tailleux, V RatziuAbstract:Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]-fed human Apolipoprotein E2 [hApoE2] transgenic mice, methionine- and choline-deficient diet-fed db/db mice, and CCl4-induced fibrosis in rats). GFT505 demonstrated liver-protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR-α-independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock-in/PPAR-α knockout mice. In these mice, GFT505 also prevented WD-induced liver steatosis and inflammation, indicating a contribution of PPAR-α-independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase. Conclusion: The dual PPAR-α/δ agonist, GFT505, is a promising liver-targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR-α-dependent and -independent mechanisms. (Hepatology 2013; 58:1941–1952)
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peroxisome proliferator activated receptor alpha gene level differently affects lipid metabolism and inflammation in Apolipoprotein E2 knock in mice
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Fanny Lalloyer, Kristiaan Wouters, Morgane Baron, Sandrine Caron, Emmanuelle Vallez, Jonathan VanhoutteAbstract:Objective— Peroxisome proliferator–activated receptor-α (PPARα) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPARα is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPARα agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPARα therein has not been assessed. The human Apolipoprotein E2 knock-in (apoE2-KI) mouse is a model of mixed dyslipidemia, atherosclerosis, and nonalcoholic steatohepatitis (NASH). The aim of this study was to analyze, using homo- and heterozygous PPARα-deficient mice, the consequences of quantitative variations of PPARα gene levels and their response to the synthetic PPARα agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice. Methods and Results— Wild-type (+/+), heterozygous (+/−), and homozygous (−/−) PPARα-deficient mice in the apoE2-KI background were generated and subjected to a Western diet supplemented with fenofibrate or not supplemented. Western diet–fed PPARα−/− apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPARα+/+ and PPARα+/− apoE2-KI mice, indicating a role of PPARα in liver protection. Moreover, PPARα expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPARα+/+ and PPARα+/− apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPARα gene were required. Surprisingly, atherosclerosis development was not significantly different among PPARα+/+, PPARα+/−, and PPARα−/− apoE2-KI mice. However, PPARα gene level determined both the antiatherosclerotic and vascular antiinflammatory responses to fenofibrate in a dose-dependent manner. Conclusion— These results demonstrate a necessary but quantitatively different role of PPARα in the modulation of liver metabolism, inflammation, and atherogenesis.
Jonathan Vanhoutte - One of the best experts on this subject based on the ideXlab platform.
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the novel selective pparα modulator spparmα pemafibrate improves dyslipidemia enhances reverse cholesterol transport and decreases inflammation and atherosclerosis
Atherosclerosis, 2016Co-Authors: Nathalie Hennuyer, Sophie Lestavel, Veronique Touche, Emmanuelle Vallez, Jonathan Vanhoutte, Isabelle Duplan, Charlotte Paquet, Eloise Woitrain, Sophie Colin, Philippe LefebvreAbstract:Abstract Background Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of Apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of functional high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated transcription factor, controls lipid metabolism, cellular cholesterol trafficking in macrophages and influences inflammation. Objective To study whether pharmacological activation of PPARα with a novel highly potent and selective PPARα modulator, pemafibrate, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in vitro and in vivo using human Apolipoprotein E2 Knock-In (apoE2KI) and human apoA-I transgenic (hapoA-I tg) mice. Approach and results Pemafibrate treatment decreases apoB secretion in chylomicrons by polarized Caco-2/TC7 intestinal epithelium cells and reduces triglyceride levels in apoE2KI mice. Pemafibrate treatment of hapoA-I tg mice increases plasma HDL cholesterol, apoA-I and stimulates RCT to feces. In primary human macrophages, pemafibrate promotes macrophage cholesterol efflux to HDL and exerts anti-inflammatory activities. Pemafibrate also reduces markers of inflammation and macrophages in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apoE2KI mice. Conclusions These results demonstrate that the novel selective PPARα modulator pemafibrate exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties.
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abstract 19434 the novel pparalpha selective agonist k 877 improves dyslipidemia enhances reverse cholesterol transport and decreases inflammation and atherosclerosis
Circulation, 2013Co-Authors: Nathalie Hennuyer, Sophie Lestavel, Veronique Touche, Jonathan Vanhoutte, Isabelle Duplan, Charlotte Paquet, Giulia Chinetti, Toshiaki Takizawa, Yukiyoshi Yamazaki, Sohei TanabeAbstract:Background: Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of Apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing HDL functionality and reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated transcription factor, controls plasma lipid metabolism, macrophage cholesterol handling as well as the inflammatory response. Objective: To study whether pharmacological activation of PPARalpha with the highly potent PPARalpha ligand, K-877, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in human apoA-I transgenic mice and in the human Apolipoprotein E2 knock-in mouse (apo E2KI) model of mixed dyslipidemia and atherosclerosis. Methods and results: I...
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peroxisome proliferator activated receptor alpha gene level differently affects lipid metabolism and inflammation in Apolipoprotein E2 knock in mice
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Fanny Lalloyer, Kristiaan Wouters, Morgane Baron, Sandrine Caron, Emmanuelle Vallez, Jonathan VanhoutteAbstract:Objective— Peroxisome proliferator–activated receptor-α (PPARα) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPARα is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPARα agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPARα therein has not been assessed. The human Apolipoprotein E2 knock-in (apoE2-KI) mouse is a model of mixed dyslipidemia, atherosclerosis, and nonalcoholic steatohepatitis (NASH). The aim of this study was to analyze, using homo- and heterozygous PPARα-deficient mice, the consequences of quantitative variations of PPARα gene levels and their response to the synthetic PPARα agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice. Methods and Results— Wild-type (+/+), heterozygous (+/−), and homozygous (−/−) PPARα-deficient mice in the apoE2-KI background were generated and subjected to a Western diet supplemented with fenofibrate or not supplemented. Western diet–fed PPARα−/− apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPARα+/+ and PPARα+/− apoE2-KI mice, indicating a role of PPARα in liver protection. Moreover, PPARα expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPARα+/+ and PPARα+/− apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPARα gene were required. Surprisingly, atherosclerosis development was not significantly different among PPARα+/+, PPARα+/−, and PPARα−/− apoE2-KI mice. However, PPARα gene level determined both the antiatherosclerotic and vascular antiinflammatory responses to fenofibrate in a dose-dependent manner. Conclusion— These results demonstrate a necessary but quantitatively different role of PPARα in the modulation of liver metabolism, inflammation, and atherogenesis.
Louis M. Havekes - One of the best experts on this subject based on the ideXlab platform.
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Expression of Type III Hyperlipoproteinemia in Apolipoprotein E2 (Arg1583Cys) Homozygotes Is Associated With Hyperinsulinemia
2015Co-Authors: F. De ,beer, Louis M. Havekes, Anton F H Stalenhoef, Nicoline Hoogerbrugge, John J P Kastelein, Jan Gevers A Leuven, Cornelia M Van Duijn, Augustinus H. M. SmeltAbstract:Abstract—Type III hyperlipoproteinemia (HLP) is mainly found in homozygous carriers of Apolipoprotein E2 (apoE2, Arg1583Cys). Only a small percentage (5%) of these apoE2 homozygotes develops hyperlipidemia, indicating that additional environmental and genetic factors contribute to the expression of type III HLP. In the present study, first, the prevalence of type III HLP among apoE2 homozygotes was estimated in a Dutch population sample of 8888 participants. Second, 68 normocholesterolemic and 162 hypercholesterolemic apoE2 homozygotes (type III HLP patients) were collected to investigate additional factors influencing type III HLP expression. In the Dutch population sample, apoE2 homozygosity occurred with a frequency of 0.6 % (57 of 8888 individuals). Among the 57 E2/2 subjects, 10 type III HLP patients were identified (prevalence 18%). Comparison of normocholesterolemic E2/2 subjects and type III HLP patients showed that the latter had a significantly increased body mass index (25.64.0 versus 26.93.8 kg/m2, respectively; P0.03) and prevalence of hyperinsulinemia (26 % versus 63%, respectively; P0.001). Multiple linear regression analysis demonstrated that most of the variability in type III HLP expression can be explained by fasting insulin levels (partial correlation coefficient 0.50, P0.001). In contrast to men, apoE2 homozygous women aged 50 years had significantly higher plasma lipid levels than their counterparts aged 50 years. These data demonstrate that the expression of type III HLP in E2/2 subjects is elicited to a large extent by hyperinsulinemia. In addition, in female apoE2 homozygotes, the expression increases with age; this increase is most likely due to the loss of estroge
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molecular mechanisms of type iii hyperlipoproteinemia the contribution of the carboxy terminal domain of apoe can account for the dyslipidemia that is associated with the E2 E2 phenotype
Biochemistry, 2003Co-Authors: Kyriakos E Kypreos, Louis M. Havekes, Ko Willems Van Dijk, Vassilis I ZannisAbstract:Apolipoprotein E2, which has an R158 for C substitution, has reduced affinity for the LDL receptor and is associated with type III hyperlipoproteinemia in humans. Consistent with these observations, we have found that following adenovirus-mediated gene transfer, full-length apoE2 aggravates the hypercholesterolemia and induces hypertriglyceridemia in E-deficient mice and induces combined hyperlipidemia in C57BL/6 mice. Unexpectedly, the truncated apoE2-202 form that has an R158 for C substitution when expressed at levels similar to those of the full-length apoE2 normalized the cholesterol levels of E-deficient mice without induction of hypertriglyceridemia. The apoE2 truncation increased the affinity of POPC-apoE particles for the LDL receptor, and the full-length apoE2 had a dominant effect in VLDL triglyceride secretion. Hyperlipidemia in normal C57BL/6 mice was prevented by coinfection with equal doses of each, the apoE2 and the apoE2-202-expressing adenoviruses, indicating that truncated apoE forms have a dominant effect in remnant clearance. Hypertriglyceridemia was completely corrected by coinfection of mice with an adenovirus-expressing wild-type lipoprotein lipase, whereas an inactive lipoprotein lipase had a smaller effect. The findings suggest that the apoE2-induced dyslipidemia is not merely the result of substitution of R158 for C but results from increased secretion of a triglyceride-enriched VLDL that cannot undergo lipolysis, inhibition of LpL activity, and impaired clearance of chylomicron remnants. Infection of E(-)(/)(-)xLDLr(-)(/)(-) double-deficient mice with apoE2-202 did not affect the plasma cholesterol levels, and also did not induce hypertriglyceridemia. In contrast, apoE2 exacerbated the hypercholesterolemia and induced hypertriglyceridemia, suggesting that the LDL receptor is the predominant receptor in remnant clearance.
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expression of type iii hyperlipoproteinemia in Apolipoprotein E2 arg158 cys homozygotes is associated with hyperinsulinemia
Arteriosclerosis Thrombosis and Vascular Biology, 2002Co-Authors: F. De ,beer, Louis M. Havekes, Anton F H Stalenhoef, Nicoline Hoogerbrugge, John J P Kastelein, Jan Gevers A Leuven, Cornelia M Van Duijn, A H M SmeltAbstract:Type III hyperlipoproteinemia (HLP) is mainly found in homozygous carriers of Apolipoprotein E2 (apoE2, Arg158→Cys). Only a small percentage (<5%) of these apoE2 homozygotes develops hyperlipidemia, indicating that additional environmental and genetic factors contribute to the expression of type III HLP. In the present study, first, the prevalence of type III HLP among apoE2 homozygotes was estimated in a Dutch population sample of 8888 participants. Second, 68 normocholesterolemic and 162 hypercholesterolemic apoE2 homozygotes (type III HLP patients) were collected to investigate additional factors influencing type III HLP expression. In the Dutch population sample, apoE2 homozygosity occurred with a frequency of 0.6% (57 of 8888 individuals). Among the 57 E2/2 subjects, 10 type III HLP patients were identified (prevalence 18%). Comparison of normocholesterolemic E2/2 subjects and type III HLP patients showed that the latter had a significantly increased body mass index (25.6±4.0 versus 26.9±3.8 kg/m2, respectively; P=0.03) and prevalence of hyperinsulinemia (26% versus 63%, respectively; P<0.001). Multiple linear regression analysis demonstrated that most of the variability in type III HLP expression can be explained by fasting insulin levels (partial correlation coefficient ≈0.50, P<0.001). In contrast to men, apoE2 homozygous women aged ≥50 years had significantly higher plasma lipid levels than their counterparts aged <50 years. These data demonstrate that the expression of type III HLP in E2/2 subjects is elicited to a large extent by hyperinsulinemia. In addition, in female apoE2 homozygotes, the expression increases with age; this increase is most likely due to the loss of estrogen production. Chemicals/CAS: Apolipoprotein E2; Apolipoproteins E; Estrogens
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Severe Hyperlipidemia in Apolipoprotein E2 Homozygotes Due to a Combined Effect of Hyperinsulinemia and an SstI Polymorphism
Arteriosclerosis thrombosis and vascular biology, 1999Co-Authors: Eric J.g. Sijbrands, Augustinus H. M. Smelt, Mariëtte J.v. Hoffer, A.e. Meinders, Louis M. Havekes, Rune R. Frants, P. De KnijffAbstract:More than 90% of patients with type III hyperlipoproteinemia are homozygous carriers of the Apolipoprotein (apo) E*2 allele. The great majority of these apoE2(Arg158→Cys) homozygotes in the general population, however, are normolipidemic. Apparently, expression of the hyperlipidemic state requires additional genetic and/or environmental factors, suggesting a multifactorial etiology. To elucidate these additional risk factors, we analyzed normolipidemic and hyperlipidemic apoE2 homozygotes. Hyperinsulinemia was observed in 27 of 49 apoE2 homozygotes and associated with elevated lipid levels: hyperinsulinemic apoE2 homozygotes had type III hyperlipoproteinemia 6 times more often than apoE2 homozygotes with normal insulin levels (odds ratio 6.2, P=0.02). We screened the normolipidemic and hyperlipidemic apoE2 homozygotes for common variants in candidate genes involved in lipolysis-the APOA1-C3-A4 gene cluster, lipoprotein lipase, and hepatic lipase-and analyzed for associations with the expression of hyperlipidemia. In the hyperinsulinemic group, the 7 carriers of the SstI polymorphism (S2) in the APOC3 gene displayed severely elevated VLDL cholesterol (P(insulin by SstI)
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reversal of hypercholesterolemia in Apolipoprotein E2 and Apolipoprotein e3 leiden transgenic mice by adenovirus mediated gene transfer of the vldl receptor
Arteriosclerosis Thrombosis and Vascular Biology, 1998Co-Authors: K W Van Dijk, Louis M. Havekes, B J M Van Vlijmen, A Van Der Zee, B Van T Hof, H Van Der Boom, Kunihisa Kobayashi, Lawrence Chan, M H HofkerAbstract:We have investigated the interaction of Apolipoprotein E2(Arg158- Cys) (apoE2) and Apolipoprotein E3Leiden (apoE3-Leiden) with the very low density lipoprotein (VLDL) receptor in vivo and in vitro to define the possible role of this receptor in lipoprotein metabolism and atherosclerosis. The in vivo binding specificity of the VLDL receptor for apoE2 and apoE3- Leiden was investigated by adenovirus-mediated gene transfer of the VLDL receptor in apoE2 and apoE3-Leiden transgenic mice lacking endogenous mouse apoE (Apoe-/-). Ectopic overexpression of the VLDL receptor gene in the liver resulted in a >50% decrease of plasma cholesterol levels in both apoE2 and apoE3-Leiden transgenic mice compared with liver expression of the β- galactosidase gene. This reduction in plasma cholesterol was mainly due to a reduction in the VLDL level. Overexpression of the VLDL receptor did not affect the hepatic VLDL triglyceride production, indicating that the hypocholesterolemic effect is due to an increased level of plasma clearance mediated by the VLDL receptor. In vitro binding analysis showed that both apoE2 and apoE3-Leiden VLDL compete efficiently with rabbit β-VLDL for binding to the VLDL receptor expressed on LDL receptor-deficient Chinese hamster ovary cells. We conclude from these data that both apoE2 and apoE3- Leiden function as proper ligands for the VLDL receptor in vitro and in vivo. This finding substantiates a possible role for the VLDL receptor in atherosclerosis in hyperlipidemic subjects homozygous for apoE2 or carrying apoE3-Leiden and indicates that the VLDL receptor expressed on the liver has therapeutic potential as an alternative route for clearance of binding- defective lipoproteins.
Nathalie Hennuyer - One of the best experts on this subject based on the ideXlab platform.
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the novel selective pparα modulator spparmα pemafibrate improves dyslipidemia enhances reverse cholesterol transport and decreases inflammation and atherosclerosis
Atherosclerosis, 2016Co-Authors: Nathalie Hennuyer, Sophie Lestavel, Veronique Touche, Emmanuelle Vallez, Jonathan Vanhoutte, Isabelle Duplan, Charlotte Paquet, Eloise Woitrain, Sophie Colin, Philippe LefebvreAbstract:Abstract Background Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of Apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of functional high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated transcription factor, controls lipid metabolism, cellular cholesterol trafficking in macrophages and influences inflammation. Objective To study whether pharmacological activation of PPARα with a novel highly potent and selective PPARα modulator, pemafibrate, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in vitro and in vivo using human Apolipoprotein E2 Knock-In (apoE2KI) and human apoA-I transgenic (hapoA-I tg) mice. Approach and results Pemafibrate treatment decreases apoB secretion in chylomicrons by polarized Caco-2/TC7 intestinal epithelium cells and reduces triglyceride levels in apoE2KI mice. Pemafibrate treatment of hapoA-I tg mice increases plasma HDL cholesterol, apoA-I and stimulates RCT to feces. In primary human macrophages, pemafibrate promotes macrophage cholesterol efflux to HDL and exerts anti-inflammatory activities. Pemafibrate also reduces markers of inflammation and macrophages in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apoE2KI mice. Conclusions These results demonstrate that the novel selective PPARα modulator pemafibrate exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties.
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abstract 19434 the novel pparalpha selective agonist k 877 improves dyslipidemia enhances reverse cholesterol transport and decreases inflammation and atherosclerosis
Circulation, 2013Co-Authors: Nathalie Hennuyer, Sophie Lestavel, Veronique Touche, Jonathan Vanhoutte, Isabelle Duplan, Charlotte Paquet, Giulia Chinetti, Toshiaki Takizawa, Yukiyoshi Yamazaki, Sohei TanabeAbstract:Background: Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of Apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing HDL functionality and reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated transcription factor, controls plasma lipid metabolism, macrophage cholesterol handling as well as the inflammatory response. Objective: To study whether pharmacological activation of PPARalpha with the highly potent PPARalpha ligand, K-877, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in human apoA-I transgenic mice and in the human Apolipoprotein E2 knock-in mouse (apo E2KI) model of mixed dyslipidemia and atherosclerosis. Methods and results: I...