scholarly journals Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-11 ◽  
Author(s):  
Sander Kersten
Keyword(s):  
Lipoprotein Metabolism ◽  
Physiological Role ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Molecular Target ◽  
Plasma Triglyceride ◽  
Dietary Fatty Acids ◽  
Plasma Lipoproteins ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptors

Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that mediates the effect of dietary fatty acids and certain drugs on plasma lipoproteins are the peroxisome proliferator activated receptors (PPARs). Three PPAR isotypes can be distinguished, all of which have a major role in regulating lipoprotein metabolism. PPARαis the molecular target for the fibrate class of drugs. Activation of PPARαin mice and humans markedly reduces hepatic triglyceride production and promotes plasma triglyceride clearance, leading to a clinically significant reduction in plasma triglyceride levels. In addition, plasma high-density lipoprotein (HDL)-cholesterol levels are increased upon PPARαactivation in humans. PPARγis the molecular target for the thiazolidinedione class of drugs. Activation of PPARγin mice and human is generally associated with a modest increase in plasma HDL-cholesterol and a decrease in plasma triglycerides. The latter effect is caused by an increase in lipoprotein lipase-dependent plasma triglyceride clearance. Analogous to PPARα, activation of PPARβ/δleads to increased plasma HDL-cholesterol and decreased plasma triglyceride levels. In this paper, a fresh perspective on the relation between PPARs and lipoprotein metabolism is presented. The emphasis is on the physiological role of PPARs and the mechanisms underlying the effect of synthetic PPAR agonists on plasma lipoprotein levels.

scholarly journals Mechanism of Action of a Peroxisome Proliferator-Activated Receptor (PPAR)-δ Agonist on Lipoprotein Metabolism in Dyslipidemic Subjects with Central Obesity

2011 ◽  
Vol 96 (10) ◽  
pp. E1568-E1576 ◽  
Author(s):  
Esther M. M. Ooi ◽  
Gerald F. Watts ◽  
Dennis L. Sprecher ◽  
Dick C. Chan ◽  
P. Hugh R. Barrett
Keyword(s):  
High Density Lipoprotein ◽  
Central Obesity ◽  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Peroxisome Proliferator ◽  
Low Density ◽  
Peroxisome Proliferator Activated Receptor ◽  
Plasma Triglycerides

Abstract Context: Dyslipidemia increases the risk of cardiovascular disease in obesity. Peroxisome proliferator-activated receptor (PPAR)-δ agonists decrease plasma triglycerides and increase high-density lipoprotein (HDL)-cholesterol in humans. Objective: The aim of the study was to examine the effect of GW501516, a PPAR-δ agonist, on lipoprotein metabolism. Design, Setting, and Intervention: We conducted a randomized, double-blind, crossover trial of 6-wk intervention periods with placebo or GW501516 (2.5 mg/d), with 2-wk placebo washout between treatment periods. Participants: We recruited 13 dyslipidemic men with central obesity from the general community. Main Outcome Measures: We measured the kinetics of very low-density lipoprotein (VLDL)-, intermediate-density lipoprotein-, and low-density lipoprotein (LDL)-apolipoprotein (apo) B-100, plasma apoC-III, and high-density lipoprotein (HDL) particles (LpA-I and LpA-I:A-II). Results: GW501516 decreased plasma triglycerides, fatty acid, apoB-100, and apoB-48 concentrations. GW501516 decreased the concentrations of VLDL-apoB by increasing its fractional catabolism and of apoC-III by decreasing its production rate (P < 0.05). GW501516 reduced VLDL-to-LDL conversion and LDL-apoB production. GW501516 increased HDL-cholesterol, apoA-II, and LpA-I:A-II concentrations by increasing apoA-II and LpA-I:A-II production (P < 0.05). GW501516 decreased cholesteryl ester transfer protein activity, and this was paralleled by falls in the triglyceride content of VLDL, LDL, and HDL and the cholesterol content of VLDL and LDL. Conclusions: GW501516 increased the hepatic removal of VLDL particles, which might have resulted from decreased apoC-III concentration. GW501516 increased apoA-II production, resulting in an increased concentration of LpA-I:A-II particles. This study elucidates the mechanism of action of this PPAR-δ agonist on lipoprotein metabolism and supports its potential use in treating dyslipidemia in obesity.

scholarly journals Threshold Effects of Circulating Angiopoietin-Like 3 Levels on Plasma Lipoproteins

2017 ◽  
Vol 102 (9) ◽  
pp. 3340-3348 ◽  
Author(s):  
Sergio Fazio ◽  
Jessica Minnier ◽  
Michael D Shapiro ◽  
Sotirios Tsimikas ◽  
Patrizia Tarugi ◽  
...  
Keyword(s):  
Particle Concentration ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Plasma Lipoproteins ◽  
Critical Threshold ◽  
Low Density ◽  
Loss Of Function

Abstract Context Angiopoietin-like 3 (ANGPTL3) deficiency in plasma due to loss-of-function gene mutations results in familial combined hypobetalipoproteinemia type 2 (FHBL2) in homozygotes. However, the lipid phenotype in heterozygotes is much milder and does not appear to relate directly to ANGPTL3 levels. Furthermore, the low-density lipoprotein (LDL) phenotype in carriers of ANGPTL3 mutations is unexplained. Objective To determine whether reduction below a critical threshold in plasma ANGPTL3 levels is a determinant of lipoprotein metabolism in FHBL2, and to determine whether proprotein convertase subtilisin kexin type 9 (PCSK9) is involved in determining low LDL levels in this condition. Design We studied subjects from 19 families with ANGPTL3 mutations and subjects with familial combined hypobetalipoproteinemia type 1 (FHBL1) due to truncated apolipoprotein B (apoB) species. Results First, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and HDL and LDL particle concentration correlated with plasma ANGPTL3 levels but only when the latter was <25% of normal (<60 ng/dL). Second, the very low-density lipoprotein particle concentration correlated strongly with plasma ANGPTL3 when the latter was <58% of normal. Third, both FHBL1 and FHBL2 subjects showed low levels of mature and LDL-bound PCSK9 and higher levels of its furin-cleaved form. Finally, LDL-bound PCSK9 is protected from cleavage by furin and binds to the LDL receptor more strongly than apoB-free PCSK9. Conclusions Our results suggest that the hypolipidemic effects of ANGPTL3 mutations in FHBL2 are dependent on a threshold of plasma ANGPTL3 levels, with differential effects on various lipoprotein particles. The increased inactivation of PCSK9 by furin in FHBL1 and FHBL2 is likely to cause increased LDL clearance and suggests novel therapeutic avenues.

Abstract 76: MicroRNA-144 Regulates Hepatic ABCA1 and Plasma HDL Following Activation of the Nuclear Receptor FXR

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Thomas Vallim ◽  
Elizabeth Tarling ◽  
Tammy Kim ◽  
Mete Civelek ◽  
Angel Baldan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Nuclear Receptor ◽  
Molecular Mechanisms ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Farnesoid X Receptor ◽  
Abca1 Protein

Rationale The bile acid receptor Farnesoid-X-Receptor (FXR) regulates many aspects of lipid metabolism by various complex and not fully understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. Objective To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. Methods and Results ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma High Density Lipoprotein (HDL)-cholesterol levels. Here we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lower hepatic ABCA1 and plasma HDL levels. We identified two complementary sequences to miR-144 in the 3’ untranslated region (UTR) of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I (ApoA-I) protein, whilst overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL- cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL- cholesterol. In addition, we utilized tissue-specific FXR deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal FXR. Finally, we identified functional FXR response elements (FXREs) upstream of the miR-144 locus, consistent with direct FXR regulation. Conclusion In conclusion, we have identified a pathway involving FXR, miR-144 and ABCA1 that together regulate plasma HDL cholesterol. This pathway may be therapeutically targeted in the future in order to increase HDL levels.

scholarly journals Loss of hepatic PPARα promotes inflammation and serum hyperlipidemia in diet-induced obesity

2019 ◽  
Vol 317 (5) ◽  
pp. R733-R745 ◽  
Author(s):  
David E. Stec ◽  
Darren M. Gordon ◽  
Jennifer A. Hipp ◽  
Stephen Hong ◽  
Zachary L. Mitchell ◽  
...  
Keyword(s):  
Fat Mass ◽  
Lean Mass ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Significant Shift ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Triglyceride Accumulation ◽  
M1 Macrophage ◽  
Significant Difference

Agonists for PPARα are used clinically to reduce triglycerides and improve high-density lipoprotein (HDL) cholesterol levels in patients with hyperlipidemia. Whether the mechanism of PPARα activation to lower serum lipids occurs in the liver or other tissues is unknown. To determine the function of hepatic PPARα on lipid profiles in diet-induced obese mice, we placed hepatocyte-specific peroxisome proliferator-activated receptor-α (PPARα) knockout ( PparaHepKO) and wild-type ( Pparafl/fl) mice on high-fat diet (HFD) or normal fat diet (NFD) for 12 wk. There was no significant difference in weight gain, percent body fat mass, or percent body lean mass between the groups of mice in response to HFD or NFD. Interestingly, the PparaHepKO mice on HFD had worsened hepatic inflammation and a significant shift in the proinflammatory M1 macrophage population. These changes were associated with higher hepatic fat mass and decreased hepatic lean mass in the PparαHepKO on HFD but not in NFD as measured by Oil Red O and noninvasive EchoMRI analysis (31.1 ± 2.8 vs. 20.2 ± 1.5, 66.6 ± 2.5 vs. 76.4 ± 1.5%, P < 0.05). We did find that this was related to significantly reduced peroxisomal gene function and lower plasma β-hydroxybutyrate in the PparaHepKO on HFD, indicative of reduced metabolism of fats in the liver. Together, these provoked higher plasma triglyceride and apolipoprotein B100 levels in the PparaHepKO mice compared with Pparafl/fl on HFD. These data indicate that hepatic PPARα functions to control inflammation and liver triglyceride accumulation that prevent hyperlipidemia.

Associations between Sex Hormones, Thyroid Hormones and Lipoproteins

1981 ◽  
Vol 61 (5) ◽  
pp. 649-651 ◽  
Author(s):  
R. F. Heller ◽  
N. E. Miller ◽  
B. Lewis ◽  
A. Vermeulen ◽  
Angela Fairney ◽  
...  
Keyword(s):  
Alcohol Intake ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Serum Testosterone ◽  
Plasma Triglyceride ◽  
Coronary Heart Disease Prevention ◽  
Thyrotropic Hormone ◽  
Positive Correlations

1. A study of 150 middle-aged male industrial employees has shown significant positive correlations between plasma levels of high-density-lipoprotein (HDL) cholesterol and both serum testosterone and alcohol intake, and significant negative correlations between HDL cholesterol and both serum thyroxine and obesity. These associations persist when examined by multiple linear regression, indicating their independence. 2. Significant positive correlations are also shown between plasma triglyceride levels and both obesity and serum thyrotropic hormone (TSH) levels. 3. There are no evident relationships between serum oestrone or oestradiol and either HDL cholesterol or triglyceride levels, nor between any of the hormones and either total or low-density-lipoprotein (LDL) cholesterol. 4. Because of the potential importance in relation to coronary heart disease prevention, further studies are needed to try and understand the mechanisms of the associations between HDL cholesterol and obesity, alcohol intake and thyroid and sex hormone levels.

scholarly journals Effects of macrophage-specific adiponectin expression on lipid metabolism in vivo

2011 ◽  
Vol 301 (1) ◽  
pp. E180-E186 ◽  
Author(s):  
Nanlan Luo ◽  
Xiangdong Wang ◽  
B. Hong Chung ◽  
Mi-Hye Lee ◽  
Richard L. Klein ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Liver Tissue ◽  
Ldl Receptor ◽  
Lipoprotein Metabolism ◽  
Hdl Cholesterol ◽  
Epidemiological Studies ◽  
Plasma Lipoproteins ◽  
Altered Expression ◽  
Mouse Macrophages

Epidemiological studies have associated low circulating levels of the adipokine adiponectin with multiple metabolic disorders, including metabolic syndrome, obesity, insulin resistance, type II diabetes, and cardiovascular disease. Recently, we reported that adiponectin selectively overexpressed in mouse macrophages can improve insulin sensitivity and protect against inflammation and atherosclerosis. To further investigate the role of adiponectin and macrophages on lipid and lipometabolism in vivo, we engineered the expression of adiponectin in mouse macrophages (Ad-TG mice) and examined effects on plasma lipoproteins and on the expression levels of genes involved in lipoprotein metabolism in tissues. Compared with the wild-type (WT) mice, Ad-TG mice exhibited significantly lower levels of plasma total cholesterol (−21%, P < 0.05) due to significantly decreased LDL (−34%, P < 0.05) and VLDL (−32%, P < 0.05) cholesterol concentrations together with a significant increase in HDL cholesterol (+41%, P < 0.05). Further studies investigating potential mechanisms responsible for the change in lipoprotein cholesterol profile revealed that adiponectin-producing macrophages altered expression of key genes in liver tissue, including apoA1, apoB, apoE, the LDL receptor, ( P < 0.05), and ATP-binding cassette G1 ( P < 0.01). In addition, Ad-TG mice also exhibited higher total and high-molecular-weight adipnection levels in plasma and increased expression of the anti-inflammatory cytokine IL-10 as well as a decrease in the proinflammatory cytokine IL-6 in adipose tissue. These results indicate that macrophages engineered to produce adiponectin can influence in vivo gene expression in adipose tissue in a manner that reduces inflammation and macrophage infiltration and in liver tissue in a manner that alters the circulating lipoprotein profile, resulting in a decrease in VLDL and LDL and an increase in HDL cholesterol. The data support further study addressing the use of genetically manipulated macrophages as a novel therapeutic approach for treatment of cardiometabolic disease.

Libyan family with hypercholesterolemia and increased high-density lipoprotein cholesterol in plasma

1994 ◽  
Vol 40 (12) ◽  
pp. 2313-2316 ◽  
Author(s):  
D S Sheriff ◽  
M el Fakhri ◽  
K Ghwarsha
Keyword(s):  
High Density Lipoprotein ◽  
Cholesteryl Ester ◽  
Cholesterol Metabolism ◽  
Hepatic Lipase ◽  
Plasma Concentrations ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
High Density ◽  
Lipoprotein Cholesterol ◽  
Plasma Lipoproteins

Abstract Genetic deficiencies of cholesteryl ester transport protein (CETP) and hepatic lipase activities have been associated with hyperalpha-lipoproteinemias. Here we present a family of 11 members, of which 9, including the father, mother, 5 sons, and 2 daughters, show a marked increase in high-density lipoprotein (HDL) cholesterol alone with low plasma concentrations of triglycerides. Analyses of lecithin:cholesterol acyltransferase (LCAT) activity, cholesteryl ester transfer between HDL fractions, hepatic lipase (HL) activity, and lipoprotein lipase (LPL) activity in these cases showed that a decrease in the heparin-releasable HL activity was the possible cause of the marked increase of HDL2 fractions observed in nine of them. Such a defect in HL activity could significantly affect HDL metabolism in particular and lipoprotein metabolism in general. Evidently, a marked increase in serum total cholesterol due to abnormal metabolism of HDL cholesterol, separate from known causes of altered low-density lipoprotein cholesterol metabolism, e.g., a clearance or a receptor defect, is not uncommon. The coordinated action of HL, LCAT, LPL, and CETP may be essential for normal metabolism of plasma lipoproteins.

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