Abstract 205: Impact of PLPP3 Gene Deficiency on Lipid Metabolism and Signaling

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Suchismita Halder
Keyword(s):  
Lipid Metabolism ◽  
Disease Risk ◽  
Biological Fluids ◽  
Association Studies ◽  
Cardiovascular Disease Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Genome Wide Association Studies ◽  
Low Density ◽  
Lipid Phosphate

Genome wide association studies identify heritable variants within the final intron of the PLPP3 gene that associate with coronary artery disease risk. The risk associated alleles of these variants alter activity of an enhancer sequence that acts in cis to upregulate expression of the gene in response to inflammatory and atherogenic stimuli (for example oxidized low density lipoprotein) and may have longer distance effects on expression of other genes. PLPP3 encodes lipid phosphate phosphatase 3 (LPP3) which is an integral membrane enzyme that dephosphorylates lipid phosphate esters. These substrates are bioactive signaling molecules at the cell surface including lysophosphatidic acid (LPA) and sphingosine 1 phosphate (S1P) and intracellular intermediates in pathways of lipid metabolism and signaling, for example ceramide 1 phosphate and phosphatidic acid. PLPP3 is essential for vascular development in mice. We have generated mice with inducible post-natal and tissue specific inactivation of this gene which are viable and exhibit accelerated atherosclerosis on a low density lipoprotein receptor knockout background after feeding atherogenic diets. Analysis using targeted and untargeted approaches using multistage and high resolution mass spectrometry reveal that LPP3 deficiency results in significant differences in levels of some LPP3 substrates and products in cells, tissues and biological fluids from these animals. These observations support the hypothesis that alterations in levels of these LPP3 substrates or their dephosphorylation products account for or contribute to the mechanisms by which alterations in LPP3 expression influence cardiovascular disease risk.

Triglyceride-Rich Lipoproteins as a Source of Proinflammatory Lipids in the Arterial Wall

2019 ◽  
Vol 26 (9) ◽  
pp. 1701-1710 ◽  
Author(s):  
Katariina Öörni ◽  
Satu Lehti ◽  
Peter Sjövall ◽  
Petri T. Kovanen
Keyword(s):  
Arterial Wall ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density Lipoproteins ◽  
Low Density ◽  
Lipoprotein Particles ◽  
Atherosclerotic Lesions ◽  
Remnant Lipoproteins

Apolipoprotein B –containing lipoproteins include triglyceride-rich lipoproteins (chylomicrons and their remnants, and very low-density lipoproteins and their remnants) and cholesterol-rich low-density lipoprotein particles. Of these, lipoproteins having sizes below 70-80 nm may enter the arterial wall, where they accumulate and induce the formation of atherosclerotic lesions. The processes that lead to accumulation of lipoprotein-derived lipids in the arterial wall have been largely studied with a focus on the low-density lipoprotein particles. However, recent observational and genetic studies have discovered that the triglyceriderich lipoproteins and their remnants are linked with cardiovascular disease risk. In this review, we describe the potential mechanisms by which the triglyceride-rich remnant lipoproteins can contribute to the development of atherosclerotic lesions, and highlight the differences in the atherogenicity between low-density lipoproteins and the remnant lipoproteins.

Exercise, Postprandial Triacylglyceridemia, and Cardiovascular Disease Risk

2004 ◽  
Vol 29 (6) ◽  
pp. 781-799 ◽  
Author(s):  
Terry E. Graham
Keyword(s):  
Cardiovascular Disease ◽  
Risk Factor ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Dietary Fats ◽  
Low Density ◽  
Key Words Atherosclerosis

An elevation of plasma triacylglycerides (TAG) is a well recognized cardiovascular risk factor. Less appreciated is that high and prolonged elevations in TAG in the postprandial (PP) phase is also a risk factor. Given that we spend approximately 18 hrs a day in the PP state, this is particularly critical. The elevation is due to both cylomicron and very low density lipoprotein TAG. It is thought that enhancing the concentrations of these lipoproprotein fractions increases the production of smaller, more dense low density lipoprotein and that this leads to increased cardiovascular disease risk. The PP TAG response is greater in men, in obese individuals, and in type 2 diabetics. It has been reported repeatedly that exercise the day before ingestion of a high fat meal is associated with a marked dampening of the PP TAG rise. The mechanisms for this are not clear and do not appear to be due to changes in the exercised muscle itself. There is some speculation that the production of plasma TAG may be decreased. The exercise benefits are lost within 3 days. The minimum exercise required has not been determined, but even 30 min of intermittent aerobic exercise or mild resistance exercise has a positive effect. This demonstrates a clear benefit from an active lifestyle and one that does not require intense exercise or months of training. Key words: atherosclerosis, type 2 diabetes, dietary fats, carbohydrates, VLDL, LDL, triglycerides, sex differences

scholarly journals Evaluating lipid-lowering drug targets for Parkinson disease prevention with Mendelian randomization

2020 ◽  
Author(s):  
Dylan M. Williams ◽  
Sara Bandres-Ciga ◽  
Karl Heilbron ◽  
David Hinds ◽  
Alastair J Noyce ◽  
...  
Keyword(s):  
Protective Effect ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Genome Wide Association Studies ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol

AbstractObjectiveTo examine whether long-term exposure to statins and other lipid-lowering drugs may affect PD risk – either beneficially or adversely – using Mendelian randomization (MR).MethodsMR analyses were based on variants in genes encoding the targets of several approved or emerging drug classes that reduce circulating low-density lipoprotein cholesterol (LDL-C) or triglycerides. Variants were weighted by their associations with differences in circulating LDL-C, triglycerides or apolipoprotein B (ApoB) using data from genome-wide association studies of lipids (N = 14,004 to 295,826). MR models indexing the effects of modulating each drug target on PD risk were then estimated from genetic associations with PD case-control status (N = 37,688 cases and 981,372 controls).ResultsEstimates for statin exposure were incompatible with drug use increasing PD risk, but were not precise enough to confirm a protective effect: odds ratio for PD per standard deviation (SD) reduction in low-density lipoprotein cholesterol = 0.83; 95% confidence interval (CI): 0.65, 1.07. Findings for other LDL-lowering targets were also close to the null. Among triglyceride-lowering targets, variants indexing Apolipoprotein-A5 / Apolipoprotein-C3 modulation suggested a protective effect (OR per SD lower triglycerides = 0.84; 95% CI = 0.80, 0.89), whereas others were null.InterpretationThis genetic evidence does not support findings from large observational studies which suggest that statin exposure could alter risk of PD. Our overall pattern of results suggest peripheral lipid transport may not influence PD etiology, but this does not necessarily exclude effects of statins or the modulation of apolipoproteins A5/C3 via other mechanisms.

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