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Salman Azhar - One of the best experts on this subject based on the ideXlab platform.
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effect of creosote bush derived ndga on expression of genes involved in lipid metabolism in liver of high fructose fed rats relevance to ndga amelioration of Hypertriglyceridemia and hepatic steatosis
PLOS ONE, 2015Co-Authors: Haiyan Zhang, Wenjun Shen, Madhurima Singh, Xiaoming Hou, Alex Bittner, Stefanie Bittner, Yuan Cortez, Juveria Tabassum, Fredric B Kraemer, Salman AzharAbstract:Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote bush, has been shown to have profound effects on the core components of the metabolic syndrome (MetS), lowering blood glucose, free fatty acids (FFA) and triglyceride (TG) levels in several models of dyslipidemia, as well as improving body weight (obesity), insulin resistance, diabetes and hypertension, and ameliorating hepatic steatosis. In the present study, a high-fructose diet (HFrD) fed rat model of Hypertriglyceridemia was employed to further delineate the underlying mechanism by which NDGA exerts its anti-hypertriglyceridemic action. In the HFrD treatment group, NDGA administration by oral gavage decreased plasma levels of TG, glucose, FFA, and insulin, increased hepatic mitochondrial fatty acid oxidation and attenuated hepatic TG accumulation. qRT-PCR measurements indicated that NDGA treatment increased the mRNA expression of key fatty acid transport (L-FABP, CD36), and fatty acid oxidation (ACOX1, CPT-2, and PPARα transcription factor) genes and decreased the gene expression of enzymes involved in lipogenesis (FASN, ACC1, SCD1, L-PK and ChREBP and SREBP-1c transcription factors). Western blot analysis indicated that NDGA administration upregulated hepatic insulin signaling (P-Akt), AMPK activity (P-AMPK), MLYCD, and PPARα protein levels, but decreased SCD1, ACC1 and ACC2 protein content and also inactivated ACC1 activity (increased P-ACC1). These findings suggest that NDGA ameliorates Hypertriglyceridemia and hepatic steatosis primarily by interfering with lipogenesis and promoting increased channeling of fatty acids towards their oxidation.
Alan T. Remaley - One of the best experts on this subject based on the ideXlab platform.
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apolipoprotein ciii and angiopoietin like protein 8 are elevated in lipodystrophy and decrease after metreleptin
Journal of the Endocrine Society, 2021Co-Authors: Marissa Lightbourne, Anna Wolska, Alan T. Remaley, Sungyoung Auh, Robert D Shamburek, Brent S Abel, Kristina I Rother, Mary Walter, Yevgeniya Kushchayeva, Ranganath MuniyappaAbstract:Context Lipodystrophy syndromes cause Hypertriglyceridemia that improves with leptin treatment using metreleptin. Mechanisms causing Hypertriglyceridemia and improvements after metreleptin are incompletely understood. Objective Determine relationship of circulating lipoprotein lipase (LPL) modulators with Hypertriglyceridemia in healthy controls and in patients with lipodystrophy before and after metreleptin. Methods Cross-sectional comparison of patients with lipodystrophy (generalized lipodystrophy n = 3; partial lipodystrophy n = 11) vs age/sex-matched healthy controls (n = 28), and longitudinal analyses in patients before and after 2 weeks and 6 months of metreleptin. The study was carried out at the National Institutes of Health, Bethesda, Maryland. Outcomes were LPL stimulators apolipoprotein (apo) C-II and apoA-V and inhibitors apoC-III and angiopoietin-like proteins (ANGPTLs) 3, 4, and 8; ex vivo activation of LPL by plasma. Results Patients with lipodystrophy were hypertriglyceridemic and had higher levels of all LPL stimulators and inhibitors vs controls except for ANGPTL4, with >300-fold higher ANGPTL8, 4-fold higher apoC-III, 3.5-fold higher apoC-II, 1.9-fold higher apoA-V, 1.6-fold higher ANGPTL3 (P < .05 for all). At baseline, all LPL modulators except ANGPLT4 positively correlated with triglycerides. Metreleptin decreased apoC-II and apoC-III after 2 weeks and 6 months, and decreased ANGPTL8 after 6 months (P < 0.05 for all). Plasma from patients with lipodystrophy caused higher ex vivo LPL activation vs hypertriglyceridemic control plasma (P < .0001), which did not change after metreleptin. Conclusion Elevations in LPL inhibitors apoC-III and ANGPTL8 may contribute to Hypertriglyceridemia in lipodystrophy, and may mediate reductions in circulating and hepatic triglycerides after metreleptin. These therefore are strong candidates for therapies to lower triglycerides in these patients.
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apolipoprotein c ii mimetic peptide is an efficient activator of lipoprotein lipase in human plasma as studied by a calorimetric approach
Biochemical and Biophysical Research Communications, 2019Co-Authors: Mart Reimund, Anna Wolska, Alan T. Remaley, Denis Sviridov, Sierra Wilson, Robert Risti, Aivar LookeneAbstract:Abstract Elevated plasma triglyceride (TG) levels are associated with higher risk of atherosclerotic cardiovascular disease. One way to reduce plasma TG is to increase the activity of lipoprotein lipase (LPL), the rate limiting enzyme in plasma TG metabolism. An apolipoprotein (apo) C-II mimetic peptide (18A–CII–a) has been recently developed that stimulated LPL activity in vitro and decreased plasma TG concentration in animal models for Hypertriglyceridemia. Since this peptide can serve as a new therapeutic approach for treatment of Hypertriglyceridemia, we investigated how 18A–CII–a peptide influences LPL activity in human plasma. We used recently described isothermal titration calorimetry based approach to assess the peptide, which enables the analysis in nearly undiluted human plasma. The 18A–CII–a peptide was 3.5-fold more efficient in stimulating LPL activity than full-length apoC-II in plasma sample from normolipidemic individual. Furthermore, 18A–CII–a also increased LPL activity in hypertriglyceridemic plasma samples. Unlike apoC-II, high concentrations of the 18A–CII–a peptide did not inhibit LPL activity. The increase in LPL activity after addition of 18A–CII–a or apoC-II to plasma was due to the increase of the amount of available substrate for LPL. Measurements with isolated lipoproteins revealed that the relative activation effects of 18A–CII–a and apoC-II on LPL activity were greater in smaller size lipoprotein fractions, such as remnant lipoproteins, low-density lipoproteins and high-density lipoproteins. In summary, this report describes a novel mechanism of action for stimulation of LPL activity by apoC-II mimetic peptides.
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a novel apolipoprotein c ii mimetic peptide that activates lipoprotein lipase and decreases serum triglycerides in apolipoprotein e knockout mice
Journal of Pharmacology and Experimental Therapeutics, 2015Co-Authors: Toshihiro Sakurai, Lita A Freeman, Denis Sviridov, Akiko Sakuraiikuta, Lusana Ahsan, Alan T. RemaleyAbstract:Apolipoprotein A-I (apoA-I) mimetic peptides are currently being developed as possible new agents for the treatment of cardiovascular disease based on their ability to promote cholesterol efflux and their other beneficial antiatherogenic properties. Many of these peptides, however, have been reported to cause transient Hypertriglyceridemia due to inhibition of lipolysis by lipoprotein lipase (LPL). We describe a novel bihelical amphipathic peptide (C-II-a) that contains an amphipathic helix (18A) for binding to lipoproteins and stimulating cholesterol efflux as well as a motif based on the last helix of apolipoprotein C-II (apoC-II) that activates lipolysis by LPL. The C-II-a peptide promoted cholesterol efflux from ATP-binding cassette transporter ABCA1-transfected BHK cells similar to apoA-I mimetic peptides. Furthermore, it was shown in vitro to be comparable to the full-length apoC-II protein in activating lipolysis by LPL. When added to serum from a patient with apoC-II deficiency, it restored normal levels of LPL-induced lipolysis and also enhanced lipolysis in serum from patients with type IV and V Hypertriglyceridemia. Intravenous injection of C-II-a (30 mg/kg) in apolipoprotein E–knockout mice resulted in a significant reduction of plasma cholesterol and triglycerides of 38 ± 6% and 85 ± 7%, respectively, at 4 hours. When coinjected with the 5A peptide (60 mg/kg), the C-II-a (30 mg/kg) peptide was found to completely block the hypertriglyceridemic effect of the 5A peptide in C57Bl/6 mice. In summary, C-II-a is a novel peptide based on apoC-II, which promotes cholesterol efflux and lipolysis and may therefore be useful for the treatment of apoC-II deficiency and other forms of Hypertriglyceridemia.
Fernando Civeira - One of the best experts on this subject based on the ideXlab platform.
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common genetic variants contribute to primary Hypertriglyceridemia without differences between familial combined hyperlipidemia and isolated Hypertriglyceridemia
Circulation-cardiovascular Genetics, 2014Co-Authors: Isabel De Castrooros, Ana Cenarro, Miguel Pocovi, M T Tejedor, Lucia Bailarueda, R Mateogallego, Itziar Lamiquizmoneo, Fernando CiveiraAbstract:Background— The majority of Hypertriglyceridemias are diagnosed as familial combined hyperlipidemia (FCHL) and primary isolated Hypertriglyceridemias. The contribution of common genetic variants in primary Hypertriglyceridemias and the genetic difference between FCHL and isolated Hypertriglyceridemias have not been thoroughly examined. Methods and Results— This study involved 580 patients with Hypertriglyceridemias and 403 controls. Of the 37 single nucleotide polymorphisms examined, 12 located in 10 genes showed allelic and genotype frequency differences between Hypertriglyceridemias and controls. The minor alleles of APOE , APOA5 , GALNTN2 , and GCKR variants were positively correlated with plasma triglycerides, whereas minor alleles of ADIPOR2 , ANGPTL3 , LPL , and TRIB1 polymorphisms were inversely associated. Body mass index, glucose, sex, rs328 and rs7007797 in LPL , rs662799 and rs3135506 in APOA5 , and rs1260326 in GCKR explained 36% of the variability in plasma triglycerides, 7.3% of which was attributable to the genetic variables. LPL , GCKR , and APOA5 polymorphisms fit dominant, recessive, and additive inheritance models, respectively. Variants more frequently identified in isolated Hypertriglyceridemias were rs7412 in APOE and rs1800795 in IL6 ; rs2808607 in CYP7A1 and rs3812316 and rs17145738 in MLXIPL were more frequent in FCHL. The other 32 single nucleotide polymorphisms presented similar frequencies between isolated Hypertriglyceridemias and FCHL. Conclusions— Common genetic variants found in LPL , APOA5 , and GCKR are associated with triglycerides levels in patients with primary Hypertriglyceridemias. FCHL and isolated Hypertriglyceridemias are probably trace to an accumulation of genetic variants predisposing to familial and sporadic Hypertriglyceridemias or to Hypertriglyceridemias and hypercholesterolemia in case of FCHL.
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Iron deposits and dietary patterns in familial combined hyperlipidemia and familial Hypertriglyceridemia
Journal of Physiology and Biochemistry, 2010Co-Authors: Rocio Mateo-gallego, Maria Solanas-barca, Iva Marques-lopes, Elena Burillo, Ana Cenarro, Fernando CiveiraAbstract:Iron deposits are associated with lipid phenotype in familial Hypertriglyceridemias, mainly familial combined hyperlipidemia (FCH) and familial Hypertriglyceridemia (FHTG). In turn, diet plays an important role in Hypertriglyceridemias although it is not known if dietary patterns are associated with iron concentration in these disorders. The objective was to determine the relationship between diet and iron deposits, measured through serum ferritin concentration, in patients with FCH and FHTG. The study was composed of 140 patients, 107 with FCH and 33 with FHTG. Subjects completed a validated 137-item food frequency questionnaire. Dividing subjects by ferritin tertiles adjusted by sex, there were no significant differences in dietary patterns except in dairy products consumption which was lower in the highest ferritin tertile. Subjects were also divided by triglycerides tertiles adjusted by sex. Those subjects in the highest tertile had lower HDL cholesterol and higher ferritin concentrations. Regarding to dietary parameters, there were significant differences in marine omega three fatty acids and vegetables presenting higher and lower consumption, respectively, those patients in the highest tertile of triglycerides. Moreover, there was not a significant correlation between dietary iron intake and any parameter, both biochemical and dietary, including ferritin concentrations. In conclusion, in patients with primary Hypertriglyceridemia, triglycerides are associated with ferritin concentrations but dietary patterns are not related to iron deposits. Our results highly support the concept that the genetic mechanisms driven to Hypertriglyceridemia also favor iron overload.
Francis Sluse - One of the best experts on this subject based on the ideXlab platform.
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liver proteomic response to Hypertriglyceridemia in human apolipoprotein c iii transgenic mice at cellular and mitochondrial compartment levels
Lipids in Health and Disease, 2014Co-Authors: Gregory Ehx, Helena C F Oliveira, Stephanie Gerin, Gregory Mathy, Fabrice Franck, Anibal E Vercesi, Francis SluseAbstract:Hypertriglyceridemia (HTG) is defined as a triglyceride (TG) plasma level exceeding 150 mg/dl and is tightly associated with atherosclerosis, metabolic syndrome, obesity, diabetes and acute pancreatitis. The present study was undertaken to investigate the mitochondrial, sub-mitochondrial and cellular proteomic impact of Hypertriglyceridemia in the hepatocytes of hypertriglyceridemic transgenic mice (overexpressing the human apolipoproteinC-III). Quantitative proteomics (2D-DIGE) analysis was carried out on both “low-expressor” (LE) and “high-expressor” (HE) mice, respectively exhibiting moderate and severe HTG, to characterize the effect of the TG plasma level on the proteomic response. The mitoproteome analysis has revealed a large-scale phenomenon in transgenic mice, i.e. a general down-regulation of matricial proteins and up-regulation of inner membrane proteins. These data also demonstrate that the magnitude of proteomic changes strongly depends on the TG plasma level. Our different analyses indicate that, in HE mice, the capacity of several metabolic pathways is altered to promote the availability of acetyl-CoA, glycerol-3-phosphate, ATP and NADPH for TG de novo biosynthesis. The up-regulation of several cytosolic ROS detoxifying enzymes has also been observed, suggesting that the cytoplasm of HTG mice is subjected to oxidative stress. Moreover, our results suggest that iron over-accumulation takes place in the cytosol of HE mice hepatocytes and may contribute to enhance oxidative stress and to promote cellular proliferation. These results indicate that the metabolic response to HTG in human apolipoprotein C-III overexpressing mice may support a high TG production rate and that the cytosol of hepatocytes is subjected to an important oxidative stress, probably as a result of FFA over-accumulation, iron overload and enhanced activity of some ROS-producing catabolic enzymes.
Haiyan Zhang - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE Effect of Creosote Bush-Derived NDGA on Expression of Genes Involved in Lipid Metabolism in Liver of High-Fructose Fed Rats: Relevance to NDGA Amelioration of
2016Co-Authors: Hepatic Steatosis, Haiyan Zhang, Wenjun Shen, Madhurima Singh, Xiaoming Hou, Alex Bittner, Stefanie Bittner, Yuan CortezAbstract:Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote bush, has been shown to have profound effects on the core components of the metabolic syndrome (MetS), lower-ing blood glucose, free fatty acids (FFA) and triglyceride (TG) levels in several models of dyslipidemia, as well as improving body weight (obesity), insulin resistance, diabetes and hypertension, and ameliorating hepatic steatosis. In the present study, a high-fructose diet (HFrD) fed rat model of Hypertriglyceridemia was employed to further delineate the underly-ing mechanism by which NDGA exerts its anti-hypertriglyceridemic action. In the HFrD treatment group, NDGA administration by oral gavage decreased plasma levels of TG, glu-cose, FFA, and insulin, increased hepatic mitochondrial fatty acid oxidation and attenuated hepatic TG accumulation. qRT-PCR measurements indicated that NDGA treatment increased the mRNA expression of key fatty acid transport (L-FABP, CD36), and fatty acid oxidation (ACOX1, CPT-2, and PPARα transcription factor) genes and decreased the gene expression of enzymes involved in lipogenesis (FASN, ACC1, SCD1, L-PK and ChREBP and SREBP-1c transcription factors). Western blot analysis indicated that NDGA adminis
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effect of creosote bush derived ndga on expression of genes involved in lipid metabolism in liver of high fructose fed rats relevance to ndga amelioration of Hypertriglyceridemia and hepatic steatosis
PLOS ONE, 2015Co-Authors: Haiyan Zhang, Wenjun Shen, Madhurima Singh, Xiaoming Hou, Alex Bittner, Stefanie Bittner, Yuan Cortez, Juveria Tabassum, Fredric B Kraemer, Salman AzharAbstract:Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote bush, has been shown to have profound effects on the core components of the metabolic syndrome (MetS), lowering blood glucose, free fatty acids (FFA) and triglyceride (TG) levels in several models of dyslipidemia, as well as improving body weight (obesity), insulin resistance, diabetes and hypertension, and ameliorating hepatic steatosis. In the present study, a high-fructose diet (HFrD) fed rat model of Hypertriglyceridemia was employed to further delineate the underlying mechanism by which NDGA exerts its anti-hypertriglyceridemic action. In the HFrD treatment group, NDGA administration by oral gavage decreased plasma levels of TG, glucose, FFA, and insulin, increased hepatic mitochondrial fatty acid oxidation and attenuated hepatic TG accumulation. qRT-PCR measurements indicated that NDGA treatment increased the mRNA expression of key fatty acid transport (L-FABP, CD36), and fatty acid oxidation (ACOX1, CPT-2, and PPARα transcription factor) genes and decreased the gene expression of enzymes involved in lipogenesis (FASN, ACC1, SCD1, L-PK and ChREBP and SREBP-1c transcription factors). Western blot analysis indicated that NDGA administration upregulated hepatic insulin signaling (P-Akt), AMPK activity (P-AMPK), MLYCD, and PPARα protein levels, but decreased SCD1, ACC1 and ACC2 protein content and also inactivated ACC1 activity (increased P-ACC1). These findings suggest that NDGA ameliorates Hypertriglyceridemia and hepatic steatosis primarily by interfering with lipogenesis and promoting increased channeling of fatty acids towards their oxidation.