Linoleic Acid-Enriched Phospholipids Act through Peroxisome Proliferator-Activated Receptors α To Stimulate Hepatic Apolipoprotein A-I Secretion

Pandey, Nihar R.; Renwick, Joanna; Misquith, Ayesha; Sokoll, Ken; Sparks, Daniel L.

doi:10.1021/bi702148f

Cited by 33 publications

(45 citation statements)

References 62 publications

(93 reference statements)

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“…A previous work has shown that cellular metabolism and extracellular nucleotide signaling are similar in primary human hepatocytes and human hepatic cell lines [29,30]. We now show that hepatic cells rapidly release nucleotides after a change in media, and we have made the completely novel finding that hepatocarcinoma cells release ADP.…”

Section: Introductionsupporting

confidence: 55%

P2X receptors regulate adenosine diphosphate release from hepatic cells

Chatterjee

Sparks

2014

Purinergic Signalling

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Extracellular nucleotides act as paracrine regulators of cellular signaling and metabolic pathways. Adenosine polyphosphate (adenosine triphosphate (ATP) and adenosine diphosphate (ADP)) release and metabolism by human hepatic carcinoma cells was therefore evaluated. Hepatic cells maintain static nanomolar concentrations of extracellular ATP and ADP levels until stress or nutrient deprivation stimulates a rapid burst of nucleotide release. Reducing the levels of media serum or glucose has no effect on ATP levels, but stimulates ADP release by up to 10-fold. Extracellular ADP is then metabolized or degraded and media ADP levels fall to basal levels within 2-4 h. Nucleotide release from hepatic cells is stimulated by the Ca 2+ ionophore, ionomycin, and by the P2 receptor agonist, 2′3′-O-(4-benzoyl-benzoyl)-adenosine 5′-triphosphate (BzATP). Ionomycin (10 μM) has a minimal effect on ATP release, but doubles media ADP levels at 5 min. In contrast, BzATP (10-100 μM) increases both ATP and ADP levels by over 100-fold at 5 min. Ion channel purinergic receptor P2X7 and P2X4 gene silencing with small interference RNA (siRNA) and treatment with the P2X inhibitor, A438079 (100 μM), decrease ADP release from hepatic cells, but have no effect on ATP. P2X inhibitors and siRNA have no effect on BzATP-stimulated nucleotide release. ADP release from human hepatic carcinoma cells is therefore regulated by P2X receptors and intracellular Ca 2+ levels. Extracellular ADP levels increase as a consequence of a cellular stress response resulting from serum or glucose deprivation.

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Section: Introductionsupporting

confidence: 55%

P2X receptors regulate adenosine diphosphate release from hepatic cells

Chatterjee

Sparks

2014

Purinergic Signalling

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“…31 Both MAP kinase and PPAR have been shown to affect hepatic apoA-I secretion. 32,33 The analysis of HDL subpopulations by 2-dimensional gel electrophoresis suggests that niacin promotes the maturation of HDL into large particles, such as ␣1 and ␣2 and their corresponding pre␣ particles. The mechanism that mediates this effect is not known, but a reduction in CETP activity, caused by the lowering in TG and TRL particle concentrations, may play a role.…”

Section: Discussionmentioning

confidence: 99%

Extended-Release Niacin Alters the Metabolism of Plasma Apolipoprotein (Apo) A-I and ApoB-Containing Lipoproteins

Lamon‐Fava

Diffenderfer²,

Barrett³

et al. 2008

ATVB

137

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Objectives-Extended-release niacin effectively lowers plasma TG levels and raises plasma high-density lipoprotein (HDL) cholesterol levels, but the mechanisms responsible for these effects are unclear. Methods and Results-We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to placebo, on the kinetics of apolipoprotein (apo) A-I and apoA-II in HDL, apoB-100 in TG-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), and apoB-48 in TRL in 5 men with combined hyperlipidemia. Niacin significantly increased HDL cholesterol and apoA-I concentrations, associated with a significant increase in apoA-I production rate (PR) and no change in fractional catabolic rate (FCR). Plasma TRL apoB-100 levels were significantly lowered by niacin, accompanied by a trend toward an increase in FCR and no change in PR. Niacin treatment significantly increased TRL apoB-48 FCR but had no effect on apoB-48 PR. No effects of niacin on concentrations or kinetic parameters of IDL and LDL apoB-100 and HDL apoA-II were noted. The addition of lovastatin to niacin promoted a lowering in LDL apoB-100 attributable to increased LDL apoB-100 FCR. Conclusion-Niacin treatment was associated with significant increases in HDL apoA-I concentrations and production, as well as enhanced clearance of TRL apoB-100 and apoB-48. Key Words: apolipoprotein Ⅲ high-density lipoprotein Ⅲ kinetics Ⅲ lipid-lowering medications Ⅲ triglyceride T he cholesterol-lowering effect of the vitamin nicotinic acid, or niacin, was first reported by Altschul et al 1 more than 50 years ago. Since then, treatment with pharmacological doses of niacin has been found to significantly lower the risk of coronary heart disease (CHD). 2,3 Several trials have also tested the effect of niacin in combination with other lipid-lowering medications on CHD risk, overall showing a beneficial effect. 4 -6 Niacin primarily decreases plasma triglyceride (TG) levels and very low-density lipoprotein (VLDL) cholesterol (C) levels and increases plasma highdensity lipoprotein (HDL)-C levels. 2,7 It has been hypothesized that the reduction in TG and VLDL-C is mediated by the niacin-associated inhibition of free-fatty acid (FFA) release from the adipose tissue, which may lead to reduced substrate availability for TG synthesis and secretion in hepatic cells. 8 However, a study conducted in 1 hypertriglyceridemic subject showed faster clearance of autologous 125 Ilabeled VLDL after niacin treatment. 9 Niacin is one of the most potent HDL-C-raising agents currently available. Two previous studies have attempted to elucidate the effect of niacin on HDL metabolism in young normocholesterolemic subjects. 10,11 The first study was conducted in 2 subjects and found an increase in HDL-C levels associated with a slower HDL catabolism with niacin. 10 The second study, in 5 young healthy subjects, found a significant increase in plasma HDL-C and apolipoprotein (apo) A-I levels with niacin withou...

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“…43 Phospholipid treatment does not appear to affect HL transcription, because PLs have no effect on steady-state mRNA levels. 43 Instead, PLs stimulate PPAR␣ expression 44 and inhibit membrane nucleotide signaling events on the cell surface to block retroendocytic degradative pathways. 45 The data suggest that PLs block membrane recycling pathways that promote the reuptake and degradation of cell surface proteins such as HL (Figure 2).…”

Section: Regulation Of Hl Secretion From the Livermentioning

confidence: 99%

Hepatic Lipase, High Density Lipoproteins, and Hypertriglyceridemia

Chatterjee

Sparks

2011

The American Journal of Pathology

Self Cite

107

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Hepatic lipase (HL) is a lipolytic enzyme that contributes to the regulation of plasma triglyceride (TG) levels. Elevated TG levels may increase the risk of developing coronary heart disease, and studies suggest that mutations in the HL gene may be associated with elevated TG levels and increased risk of coronary heart disease. Hepatic lipase facilitates the clearance of TG from the very low density lipoprotein (VLDL) pool, and this function is governed by the composition and quality of high density lipoprotein (HDL) particles. In humans, HL is a liver resident enzyme regulated by factors that release it from the liver and activate it in the bloodstream. HDL regulates the release of HL from the liver and HDL structure controls HL transport and activation in the circulation. Alterations in HDL-apolipoprotein composition can perturb HL function by inhibiting the release and activation of the enzyme. HDL structure may therefore affect plasma TG levels and coronary heart disease risk. Triglycerides and Heart DiseaseElevated plasma triglyceride (TG) levels have been viewed as a risk factor for coronary heart disease (CHD) for more than a decade.1,2 Plasma TG levels are regulated by both synthesis and degradation of both very low density lipoprotein (VLDL) and chylomicron particles. The clearance of TG-rich lipoproteins from the circulation is controlled by the actions of lipoprotein lipase (LPL) and hepatic lipase (HL) and by the interlipoprotein exchange of TG by cholesteryl ester transfer protein. Lipoprotein lipase is the predominant TG lipase and is responsible for hydrolyzing TG in chylomicrons and VLDL, whereas HL is both a phospholipase and a TG lipase and plays an important role in HDL metabolism and in the conversion of VLDL to LDL.3 Single nucleotide polymorphisms (SNPs) in the HL gene (LIPC) have been shown to associate with plasma lipid concentrations and increased CHD risk. 4,5 Hepatic lipase deficiency is a result of relatively rare LIPC mutations that give rise to a loss in circulating HL activity (due to impaired secretion or inactive enzyme) and cause an increase in TG-rich HDL and VLDL remnants and increased CHD risk.

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Linoleic Acid-Enriched Phospholipids Act through Peroxisome Proliferator-Activated Receptors α To Stimulate Hepatic Apolipoprotein A-I Secretion

Cited by 33 publications

References 62 publications

P2X receptors regulate adenosine diphosphate release from hepatic cells

P2X receptors regulate adenosine diphosphate release from hepatic cells

Extended-Release Niacin Alters the Metabolism of Plasma Apolipoprotein (Apo) A-I and ApoB-Containing Lipoproteins

Hepatic Lipase, High Density Lipoproteins, and Hypertriglyceridemia

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