Serum triglycerides and risk of cardiovascular disease

Boullart, A. C. Inge; Graaf, Jacqueline de; Stalenhoef, Anton F. H.

doi:10.1016/j.bbalip.2011.10.002

Cited by 133 publications

(103 citation statements)

References 110 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similar to other patients with genetic causes of hypertriglyceridemia, they are usually managed by treatment with low-fat diets (Wilson et al, 2003). High-carbohydrate foods should also probably be avoided to limit the hepatic conversion of excess carbohydrates into endogenous triglycerides (van de Woestijne et al, 2011;Boullart et al, 2012). Previously, we showed that the C-II-a peptide restored lipolysis when added along with LPL to plasma from a patient with apoC-II deficiency , suggesting that it could be a possible therapy for this disorder.…”

Section: Discussionmentioning

confidence: 99%

Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide

Sakurai¹,

Sakurai²,

Vaisman³

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Apolipoprotein C-II (apoC-II) is a cofactor for lipoprotein lipase, a plasma enzyme that hydrolyzes triglycerides (TGs). ApoC-II deficiency in humans results in hypertriglyceridemia. We used zinc finger nucleases to create Apoc2 mutant mice to investigate the use of C-II-a, a short apoC-II mimetic peptide, as a therapy for apoC-II deficiency. Mutant mice produced a form of apoC-II with an uncleaved signal peptide that preferentially binds high-density lipoproteins (HDLs) due to a 3-amino acid deletion at the signal peptide cleavage site. Homozygous Apoc2 mutant mice had increased plasma TG (757.5 6 281.2 mg/dl) and low HDL cholesterol (31.4 6 14.7 mg/dl) compared with wild-type mice (TG, 55.9 6 13.3 mg/dl; HDL cholesterol, 55.9 6 14.3 mg/dl). TGs were found in light (density , 1.063 g/ml) lipoproteins in the size range of verylow-density lipoprotein and chylomicron remnants (40-200 nm). Intravenous injection of C-II-a (0.2, 1, and 5 mmol/kg) reduced plasma TG in a dose-dependent manner, with a maximum decrease of 90% occurring 30 minutes after the high dose. Plasma TG did not return to baseline until 48 hours later. Similar results were found with subcutaneous or intramuscular injections. Plasma half-life of C-II-a is 1.33 6 0.72 hours, indicating that C-II-a only acutely activates lipolysis, and the sustained TG reduction is due to the relatively slow rate of new TG-rich lipoprotein synthesis. In summary, we describe a novel mouse model of apoC-II deficiency and show that an apoC-II mimetic peptide can reverse the hypertriglyceridemia in these mice, and thus could be a potential new therapy for apoC-II deficiency.

show abstract

Section: Discussionmentioning

confidence: 99%

Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide

Sakurai¹,

Sakurai²,

Vaisman³

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…(6) Triglycerides can be degraded by most cells, neither can cholesterol. The cholesterol content of TRL is one of causes of atherosclerosis and CVD.…”

Section: Serum Triglycerides As Risk Factor For Cardiovascular Diseasementioning

confidence: 99%

“…This abnormality is homozygotic type for the binding defective apo-E E2 isoform. (4,6) In secondary HTG, there is some metabolic conditions that are frequently associated with high triglyceridemia levels. Obesity with poorly controlled type 2 diabetes is the most common of metabolic stressor.…”

Section: Hypertriglyceridemiamentioning

confidence: 99%

“…Some medications may increase plasma triglyceride levels, such as estrogens, glucocorticoids, some beta-blockers, tacrolimus, cyclosporine and thiazide diuretics. (6,7) Pathophysiology of Hypertriglyceridemia HTG can be induced by 1) disturbance of hepatic VLDL production and intestinal chylomicron production; 2) abnormalities of LPL-mediated lipolysis; or 3) dysfunctional remnant clearance. In intestinal chylomicron synthesis, dietary lipids are taken up in the enterocytes, incorporated into chylomicron particles that are secreted into the lymphatic system, whereas hepatic VLDL synthesis involved a series of intracellular process enabling the formation of lipid-enriched apo-B100 particles that can be excreted.…”

Section: Hypertriglyceridemiamentioning

confidence: 99%

See 1 more Smart Citation

The Association between Cardiovascular Risk and Elevated Triglycerides

Sargowo

Handayani

2017

Indones Biomed J

View full text Add to dashboard Cite

BACKGROUND: The association between elevated triglycerides and cardiovascular risk has been extensively studied. The elevated level of triglycerides occurs through abnormalities in hepatic very low-density lipoprotein (VLDL) production and intestinal chylomicron synthesis, dysfunctional lipoprotein lipase (LPL)-mediated lipolysis or impaired remnant clearance.CONTENT: Hypertriglyceridemia (HTG) commonly leads to a reduction in high-density lipoprotein (HDL) and increase in atherogenic small dense low-density lipoprotein (LDL) cholesterol, called the atherogenic dyslipidemia (AD). Triglycerides may also stimulate atherogenesis by mechanisms, such excessive release of free fatty acids, and production of pro-inflammatory cytokines, fibrinogen, coagulation factors and impairment of fibrinolysis. Genetic studies strongly support hypertriglyceridemia (HTG) and high concentration of triglyceride-rich lipoprotein (TRL) as causal risk factors for cardiovascular disease. Therefore, lipid management is crucial in reducing cardiovascular risk. Combination of lipid lowering drug therapy may be needed to achieve both LDL and non-HDL cholesterols treatment goal for cardiovascular disease prevention in patients with elevated triglyceride levels, particularly those with triglyceride ≥500 mg/dL.SUMMARY: LDL and non-HDL cholesterol can be a promising target therapy in HTG. Additional clinical outcomes data are needed to provide a more evidence-based rationale for clinical lipid management of hypertriglyceridemic patients.KEYWORDS: hypertriglyceridemia, non-HDL cholesterol, dyslipidemia, CV risk

show abstract

“…The effect on triglyceride levels is thought to be mediated through farnesol and/or a farnesol metabolite (Hiyoshi et al, 2003), as farnesol treatment also decreased triglyceride biosynthesis and reduced hepatic steatosis, in part through PPARa activation (Duncan and Archer, 2008;Goto et al, 2011a). Elevated triglycerides are a known risk factor for CVD and are commonly associated with metabolic dyslipidemia (Eckel et al, 2005;Boullart et al, 2012). Although the SSI lapaquistat (TAK-475) showed promising effects on serum lipid profiles in primates , its development was terminated during phase III clinical trials because of safety concerns and the lack of commercial viability at lower doses (Stein et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes

Rondini

Duniec-Dmuchowski

Cukovic

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Squalene synthase inhibitors (SSIs), such as squalestatin 1 (SQ1), reduce cholesterol biosynthesis but cause the accumulation of isoprenoids derived from farnesyl pyrophosphate (FPP), which can modulate the activity of nuclear receptors, including the constitutive androstane receptor (CAR), farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs). In comparison, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (e.g., pravastatin) inhibit production of both cholesterol and nonsterol isoprenoids. To characterize the effects of isoprenoids on hepatocellular physiology, microarrays were used to compare orthologous gene expression from primary cultured mouse and rat hepatocytes that were treated with either SQ1 or pravastatin. Compared with controls, 47 orthologs were affected by both inhibitors, 90 were affected only by SQ1, and 51 were unique to pravastatin treatment (P , 0.05, $1.5-fold change). When the effects of SQ1 and pravastatin were compared directly, 162 orthologs were found to be differentially coregulated between the two treatments. Genes involved in cholesterol and unsaturated fatty acid biosynthesis were up-regulated by both inhibitors, consistent with cholesterol depletion; however, the extent of induction was greater in rat than in mouse hepatocytes. SQ1 induced several orthologs associated with microsomal, peroxisomal, and mitochondrial fatty acid oxidation and repressed orthologs involved in cell cycle regulation. By comparison, pravastatin repressed the expression of orthologs involved in retinol and xenobiotic metabolism. Several of the metabolic genes altered by isoprenoids were inducible by a PPARa agonist, whereas cytochrome P450 isoform 2B was inducible by activators of CAR. Our findings indicate that SSIs uniquely influence cellular lipid metabolism and cell cycle regulation, probably due to FPP catabolism through the farnesol pathway.

show abstract

Serum triglycerides and risk of cardiovascular disease

Cited by 133 publications

References 110 publications

Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide

Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide

The Association between Cardiovascular Risk and Elevated Triglycerides

Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes

Contact Info

Product

Resources

About