Apolipoprotein A-V associates with intrahepatic lipid droplets and influences triglyceride accumulation

Shu, Xiao Ou; Nelbach, Lisa; Ryan, Robert O.; Forte, Trudy M.

doi:10.1016/j.bbalip.2010.02.004

Cited by 54 publications

(67 citation statements)

References 22 publications

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“…Treatment of stably transfected McA-RH7777 hepatoma cells with oleate, which increased intracellular TG accumulation, caused a dramatic inhibition of apoA-V secretion and a reciprocal increase in intracellular apoA-V. Fluorescence confocal microscopy established that this was due to the association of apoA-V with the surface of cytosolic lipid droplets, as observed previously ( 23,24,32 ). Hence, it appears that hepatic TG synthesis or accumulation may drive a dynamic competition between apoA-V secretion and lipid droplet association.…”

Section: Discussionmentioning

confidence: 48%

“…Shu et al ( 32 ) observed that both the hepatic TG content and the apoA-V lipid droplet association were increased in human apoA-V transgenic mice, whereas inactivation of the mouse apoA-V gene had little effect. Although the impact on plasma TG was not examined in that study, Pamir et al ( 45 ) found that when human apoA-V transgenic mice were fed a high-fat and high-sucrose diet, fasting plasma TG levels fell instead of increasing, suggesting that apoA-V gene expression had inhibited diet-induced hepatic VLDL-TG secretion.…”

Section: Discussionmentioning

confidence: 99%

“…As apoA-V can associate with heparin sulfate proteoglycans ( 6,32 ), the limited recovery of apoA-V from medium fractions could result from binding of newly secreted apoA-V to the cell surface. To determine if newly secreted apoA-V associated with heparin-competable binding sites in McA-RH7777 cells, transfected cells were radiolabeled with [ 35 S]Met-Cys in the presence and absence of heparin, and the distribution of cell-associated and medium apoA-V was examined.…”

Section: Analysis Of Apoa-v Secretion Kinetics In Hepatic and Nonhepamentioning

confidence: 99%

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Biogenesis of apolipoprotein A-V and its impact on VLDL triglyceride secretion

Blade

Fabritius

et al. 2011

Journal of Lipid Research

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triglyceride (TG) metabolism ( 1 ). When it is overexpressed in transgenic mice, apoA-V reduces plasma TG levels by 65%, whereas inactivation of the apoA-V gene increases plasma TG by 4-fold ( 2 ). The preponderance of current literature suggests that apoA-V affects plasma TG turnover by stimulating LPL-mediated lipolysis of TG-rich lipoproteins, either directly or indirectly ( 3-7 ). ApoA-V has also been found to serve as a ligand for LDL receptor family members and other potential lipoprotein receptors and may thus contribute to the clearance of TG-rich lipoproteins and their remnants ( 8-11 ). However, recent studies have revealed that the effects of apoA-V on plasma TG concentration are complex and variable. In humans, several loss-of-function and null apoA-V alleles are associated with both reduced plasma apoA-V levels and elevated plasma TG ( 12, 13 ), yet other studies have found both positive and negative associations between plasma apoA-V and TG concentrations ( 7,14,15 ). Moreover, recent studies in mice have found a positive correlation between plasma apoA-V and TG concentrations ( 16,17 ).Despite its apparent impact on intravascular TG-rich lipoprotein lipolysis and clearance, a peculiar characteristic of apoA-V is that its plasma concentration is in the range of 100-200 µg/l, which is ‫ف‬ 10,000-fold lower than apoA-I and ‫ف‬ 1,000-fold lower than apoA-IV and corresponds to ‫ف‬ 1 molecule of apoA-V for every 1,000 VLDL particles ( 18,19 ). This presents a conundrum as to how an apolipoprotein circulating at such low levels could exert such a potent effect on plasma TG metabolism and concentration. Although it is certainly possible that apoA-V could function in plasma at extreme substoichiometric concentrations relative to that of TG-rich lipoproteins, it has also been suggested that apoA-V might function within the hepatocyte to directly modulate Apolipoprotein A-V (apoA-V), a member of the exchangeable apolipoprotein family synthesized predominantly in the liver, is a potent regulator of intravascular and This work was supported by National Institutes of Health Grants

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Apoa-v Secretion Kinetics In Hepatic and Nonhepamentioning

confidence: 99%

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Biogenesis of apolipoprotein A-V and its impact on VLDL triglyceride secretion

Blade

Fabritius

et al. 2011

Journal of Lipid Research

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“…Furthermore, this elevation was associated with elevated plasma and VLDL triglyceride concentrations. These observations suggest that moderate CKD could be associated with dysregulated apoA-V metabolism, which may have an impact on the metabolism of TRL ( 38,39 ). Future studies using VLDL triglyceride kinetics, coupled with cellular studies are warranted to better understand the role of apoA-V in vivo.…”

Section: Discussionmentioning

confidence: 99%

Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease

Ooi

Chan

Watts

et al. 2011

Journal of Lipid Research

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Supplementary key words kinetics • lipoprotein metabolism • triglyceridesCardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD) ( 1 ). While the precise mechanisms for increased CVD risk are unknown, both traditional and novel CVD risk factors have been implicated ( 1, 2 ). Dyslipidemia, a well-established risk factor for CVD in the general population, is highly prevalent in CKD ( 3, 4 ). The most frequent dyslipoproteinemic phenotype patterns are elevated plasma concentrations of triglycerides and increased numbers of atherogenic triglyceride-rich lipoprotein (TRL) particles, particularly VLDL and intermediate-density lipoprotein (IDL) ( 3, 4 ). The regulation of TRL metabolism in CKD, however, is poorly understood.Apolipoprotein C-III (apoC-III) is an 8.8 kDa glycoprotein synthesized by the liver and intestines ( 5 ). ApoC-III is highly associated with hypertriglyceridemia and is a powerful independent predictor of CVD risk in subjects without renal disease ( 5 ). In the circulation, apoC-III is associated with TRL and HDL exchanging rapidly between these lipoproteins ( 6 ). In vitro studies demonstrate that apoC-III Abstract Moderate chronic kidney disease (CKD) (defi ned by an estimated glomerular fi ltration rate of 30-60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age-and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, 2 H 3 ]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III ( P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 ± 0.15 vs. 0.74 ± 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was signifi cantly and negatively correlated with apoC-III FCR ( r = ؊ 0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR ( P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR ( P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modifi cation of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate

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“…Structural analysis showed that apoA-V is very hydrophobic and predominately lipid-bound (3,72), associating with plasma high-density lipoprotein, VLDL, and chylomicrons (47). What potentially made apoA-V elusive in its discovery was its low plasma concentration, a range of 114 -258 ng/ml in normolipemic individuals (26,47,59,64). The interesting question is how can an apolipoprotein of such low plasma concentration affect plasma TG so dramatically?…”

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confidence: 99%

Apolipoprotein A-V deficiency enhances chylomicron production in lymph fistula mice

Zhang¹,

Xu²,

Yang³

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Apolipoprotein A-V (apoA-V), a liver-synthesized apolipoprotein discovered in 2001, strongly modulates fasting plasma triglycerides (TG). Little is reported on the effect of apoA-V on postprandial plasma TG, an independent predictor for atherosclerosis. Overexpressing apoA-V in mice suppresses postprandial TG, but mechanisms focus on increased lipolysis or clearance of remnant particles. Unknown is whether apoA-V suppresses the absorption of dietary lipids by the gut. This study examines how apoA-V deficiency affects the steady-state absorption and lymphatic transport of dietary lipids in chow-fed mice. Using apoA-V knockout (KO, n ϭ 8) and wild-type (WT, n ϭ 8) lymph fistula mice, we analyzed the uptake and lymphatic transport of lipids during a continuous infusion of an emulsion containing [ 3 H]triolein and [14 C]cholesterol. ApoA-V KO mice showed a twofold increase in 3 H (P Ͻ 0.001) and a threefold increase in 14 C (P Ͻ 0.001) transport into the lymph compared with WT. The increased lymphatic transport was accompanied by a twofold reduction (P Ͻ 0.05) in mucosal 3 H, suggesting that apoA-V KO mice more rapidly secreted [3 H]TG out of the mucosa into the lymph. ApoA-V KO mice also produced chylomicrons more rapidly than WT (P Ͻ 0.05), as measured by the transit time of [ 14 C]oleic acid from the intestinal lumen to lymph. Interestingly, apoA-V KO mice produced a steadily increasing number of chylomicron particles over time, as measured by lymphatic apoB output. The data suggest that apoA-V suppresses the production of chylomicrons, playing a previously unknown role in lipid metabolism that may contribute to the postprandial hypertriglyceridemia associated with apoA-V deficiency. absorption; intestine AFTER DIETARY FAT INTAKE, the increase of plasma triglycerides (TG) is a normal metabolic consequence characterized by a transient accumulation of TG-rich lipoproteins comprised of intestinally derived chylomicrons and liver-derived very low density lipoprotein (VLDL). Hydrolysis of their TG cores releases free fatty acids to be taken up by muscle and adipose tissues, generating remnant particles that are efficiently removed from the circulation by the liver. Aberrations in lipoprotein metabolism result in elevated plasma TG and a prolonged accumulation of remnant particles that are atherogenic (16,76,24) and constitute a major risk factor for cardiovascular disease (51,43).Apolipoproteins play crucial roles in the regulation of lipoprotein metabolism by acting as structural proteins, as cofactors for enzymes involved in lipolysis, or as ligands for receptor-mediated clearance of lipoproteins (35). Apolipoprotein A-V (apoA-V) was discovered in 2001 to be expressed exclusively in the liver and located ϳ30 kb proximal to the APOAI/ CIII/AIV gene cluster (49, 69), a region well-known for regulating lipid metabolism (19). Early studies using genetically engineered mouse models revealed apoA-V to be a potent modulator of plasma TG. Knocking out apoA-V in mice resulted in a fourfold increase in plasma TG while overexp...

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Apolipoprotein A-V associates with intrahepatic lipid droplets and influences triglyceride accumulation

Cited by 54 publications

References 22 publications

Biogenesis of apolipoprotein A-V and its impact on VLDL triglyceride secretion

Biogenesis of apolipoprotein A-V and its impact on VLDL triglyceride secretion

Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease

Apolipoprotein A-V deficiency enhances chylomicron production in lymph fistula mice

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