scholarly journals Caveolae mediated endocytosis of VLDL particles in macrophages requires NPC1 and STARD3 for further lysosomal processing

2021 ◽  
Author(s):  
Lei Deng ◽  
Frank Vrieling ◽  
Rinke Stienstra ◽  
Guido Hooiveld ◽  
Anouk L. Feitsma ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Low Density Lipoproteins ◽  
Acid Lipase ◽  
Very Low Density Lipoproteins ◽  
Terminal Domain ◽  
Triglyceride Hydrolysis ◽  
Pathological Conditions ◽  
Lipoprotein Binding ◽  
Subsequent Storage ◽  
Macrophage Uptake

Macrophages accumulate triglycerides under certain pathological conditions such as atherosclerosis. Triglycerides are carried in the bloodstream as part of very low-density lipoproteins (VLDL) and chylomicrons. How macrophages take up and process VLDL-lipids is not very well known. Here, using VLDL-sized triglyceride-rich emulsion particles, we aimed to study the mechanism by which VLDL-triglycerides are taken up, processed, and stored in macrophages. Our results show that macrophage uptake of emulsion particles mimicking VLDL (VLDLm) is dependent on lipoproteins lipase (LPL) and requires the lipoprotein-binding C-terminal domain of LPL but not the catalytic N-terminal domain. Subsequent internalization of VLDLm-triglycerides by macrophages is carried out by caveolae-mediated endocytosis, followed by triglyceride hydrolysis catalyzed by lysosomal acid lipase. Transfer of lysosomal fatty acids to the ER for subsequent storage as triglycerides is mediated by Stard3, whereas NPC1 was found to promote the extracellular efflux of fatty acids from lysosomes. Our data provide novel insights into how macrophages process VLDL-derived triglycerides and suggest that macrophages have the remarkable capacity to excrete part of the internalized triglycerides as fatty acids.

scholarly journals Sirtuin 3 Restores Synthesis and Secretion of Very Low-Density Lipoproteins in Cow Hepatocytes Challenged with Nonesterified Fatty Acids In Vitro

2021 ◽  
Vol 8 (7) ◽  
pp. 121
Author(s):  
Dongmei Xing ◽  
Baogen Wang ◽  
Hong Lu ◽  
Tao Peng ◽  
Jianming Su ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Dairy Cows ◽  
Low Density Lipoproteins ◽  
Mrna Abundance ◽  
Low Density ◽  
Sirtuin 3 ◽  
Very Low Density Lipoproteins ◽  
Nonesterified Fatty Acids ◽  
Tag Accumulation

Fatty liver is closely associated with elevated concentrations of nonesterified fatty acids (NEFA) and a low level of very low-density lipoproteins (VLDL) in blood of dairy cows. High NEFA inhibit the VLDL synthesis and assembly, and cause hepatic triacylglycerol (TAG) deposition. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, antagonizes NEFA-induced TAG accumulation through modulating expressions of fatty acid synthesis and oxidation genes in cow hepatocytes. However, the role of SIRT3 in the VLDL synthesis and assembly was largely unknown. Here we aimed to test whether SIRT3 would recover the synthesis and assembly of VLDL in cow hepatocytes induced by high NEFA. Primary cow hepatocytes were isolated from 3 Holstein cows. Hepatocytes were infected with SIRT3 overexpression adenovirus (Ad-SIRT3), SIRT3-short interfering (si) RNA, or first infected with Ad-SIRT3 and then incubated with 1.0 mM NEFA (Ad-SIRT3 + NEFA). Expressions of key genes in VLDL synthesis and the VLDL contents in cell culture supernatants were measured. SIRT3 overexpression significantly increased the mRNA abundance of microsomal triglyceride transfer protein (MTP), apolipoprotein B100 (ApoB100) and ApoE (p < 0.01), and raised VLDL contents in the supernatants (p < 0.01). However, SIRT3 silencing displayed a reverse effect in comparison to SIRT3 overexpression. Compared with NEFA treatment alone, the Ad-SIRT3 + NEFA significantly upregulated the mRNA abundance of MTP, ApoB100 and ApoE (p < 0.01), and increased VLDL contents in the supernatants (p < 0.01). Our data demonstrated that SIRT3 restored the synthesis and assembly of VLDL in cow hepatocytes challenged with NEFA, providing an in vitro basis for further investigations testing its feasibility against hepatic TAG accumulation in dairy cows during the perinatal period.

scholarly journals Maternal loading with very low-density lipoproteins stimulates fetal surfactant synthesis

2002 ◽  
Vol 283 (2) ◽  
pp. L310-L318 ◽  
Author(s):  
Alan J. Ryan ◽  
Jheem D. Medh ◽  
Diann M. McCoy ◽  
Ronald G. Salome ◽  
Rama K. Mallampalli
Keyword(s):  
Fatty Acids ◽  
Knockout Mice ◽  
Low Density Lipoproteins ◽  
Alveolar Epithelial Cells ◽  
Type Ii Cells ◽  
Low Density ◽  
Type Ii ◽  
Very Low Density Lipoproteins ◽  
Pregnant Rat ◽  
Apolipoprotein E Knockout Mice

We examined whether administration of very low-density lipoproteins (VLDL) to pregnant rats increases surfactant phosphatidylcholine (PtdCho) content in fetal pre-type II alveolar epithelial cells. VLDL-triglycerides are hydrolyzed to fatty acids by lipoprotein lipase (LPL), an enzyme activated by heparin. Fatty acids released by LPL can incorporate into the PtdCho molecule or activate the key biosynthetic enzyme cytidylyltransferase (CCT). Dams were given BSA, heparin, VLDL, or VLDL with heparin intravenously. Radiolabeled VLDL given to the pregnant rat crossed the placenta and was distributed systemically in the fetus and incorporated into disaturated PtdCho (DSPtdCho) in pre-type II cells. Maternal administration of VLDL with heparin increased DSPtdCho content in cells by 45% compared with control ( P < 0.05). VLDL produced a dose-dependent, saturable, and selective increase in CCT activity. VLDL did not significantly alter immunoreactive CCT content but increased palmitic, stearic, and oleic acids in pre-type II cells. Furthermore, hypertriglyceridemic apolipoprotein E knockout mice contained significantly greater levels of DSPtdCho content in alveolar lavage and CCT activity compared with either LDL receptor knockout mice or wild-type controls that have normal serum triglycerides. Thus the nutritional or genetic modulation of serum VLDL-triglycerides provides specific fatty acids that stimulate PtdCho synthesis and CCT activity thereby increasing surfactant content.

scholarly journals Stimulation of triacylglycerol synthesis in rat adipocytes by plasma very-low-density lipoproteins

1978 ◽  
Vol 176 (1) ◽  
pp. 169-174 ◽  
Author(s):  
P Thomopoulos ◽  
M Berthelier ◽  
D Lagrange ◽  
M J Chapman ◽  
M H Laudat
Keyword(s):  
Fatty Acids ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density Lipoproteins ◽  
High Density Lipoproteins ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Very Low Density Lipoproteins ◽  
Rat Adipocytes ◽  
Triacylglycerol Synthesis

The effect of human plasma lipoproteins on lipogenesis from glucose has been studied in isolated rat adipocytes. The very-low-density lipoproteins increased lipogenesis specifically, whereas low-density lipoproteins and high-density lipoproteins were without effect. Such stimulation could be reproduced with partially delipidated very-low-density lipoproteins. Nod-esterified fatty acids and glycerol were also without effect. Pretreatment of the adipocytes with trypsin did not alter the effect of very-low-density lipoprotein. The presence of Ca2+ was required for the full activation of lipogenesis. The synthesis of acylglycerol fatty acids and of acylglycerol glycerol were equally increased. The effect of very-low-density lipoprotein was not additive to that of insulin. It is suggested that very-low-density lipoprotein may directly stimulate lipogenesis in fat-cells, particularly in states when the lipoproteins are present at high concentration in the circulation.

Insufficient accuracy and specificity of polyanion precipitation methods for quantifying low-density lipoproteins

1990 ◽  
Vol 36 (12) ◽  
pp. 2109-2113 ◽  
Author(s):  
R Siekmeier ◽  
W März ◽  
W Gross
Keyword(s):  
Fatty Acids ◽  
Dextran Sulfate ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density Lipoproteins ◽  
High Density Lipoproteins ◽  
Low Density ◽  
Very Low Density Lipoproteins ◽  
Nonesterified Fatty Acids ◽  
High Concentrations

Abstract Recently, polyanion precipitation assays for low-density lipoprotein (LDL)-cholesterol have been found to underestimate their analyte in normolipidemic samples (Siekmeier et al., Clin Chim Acta 1988;177:221-30). Therefore, accuracy, specificity, and interference by nonesterified fatty acids have been studied for three precipitants (obtained by heparin, dextran sulfate, or polyvinyl sulfate precipitation). At normal concentrations of LDL, precipitation is incomplete, whereas it is nearly quantitative at high concentrations of LDL. The polyvinyl sulfate reagent markedly responds to variations in the amount of non-LDL protein present in the precipitation mixture. In the dextran sulfate and the polyvinyl sulfate method, but not in the heparin method, the percentages of LDL precipitated notably increase as the concentration of the polyanion compound is decreased. In either assay, very-low-density lipoproteins, but not high-density lipoproteins, are significantly coprecipitated (dextran sulfate 28%, polyvinyl sulfate and heparin 66%) in a concentration-independent fashion. Increased concentrations of nonesterified fatty acids markedly interfere with the dextran sulfate and polyvinyl sulfate assay, but do not much affect results with the heparin reagent.

Atherogenic nature of triglycerides, postprandial lipidemia, and triglyceride-rich remnant lipoproteins

1995 ◽  
Vol 41 (1) ◽  
pp. 153-158 ◽  
Author(s):  
D B Zilversmit
Keyword(s):  
Animal Studies ◽  
Epidemiologic Studies ◽  
Low Density Lipoproteins ◽  
High Density Lipoproteins ◽  
Low Density ◽  
Lipid Transfer ◽  
Very Low Density Lipoproteins ◽  
Triglyceride Hydrolysis ◽  
Remnant Lipoproteins ◽  
Postprandial Triglyceride

Abstract In addition to low-density lipoproteins, plasma chylomicrons and very-low-density lipoproteins (VLDL) contribute to atherogenesis. When triglyceride-rich particles bind to arterial endothelium and to deendothelialized areas, locally present lipoprotein lipase initiates triglyceride hydrolysis and decreases the size of the adhering particles. Additional changes in composition are brought about by the exchange of lipids between chylomicron/VLDL remnants and the cholesteryl ester-rich low- and high-density lipoproteins. These exchanges are mediated by lipid transfer proteins in plasma. Animal studies with doubly labeled lipoproteins show that the size of lipoprotein particles determines their rate of entering the artery and contributes to the formation of lesions. This model supports epidemiologic studies that have identified plasma triglycerides as a risk factor for atherogenesis. The model for a causal role of pre- and postprandial triglyceride-rich lipoproteins in atherogenesis suggests that measuring them may improve the assessment of cardiovascular risk factors.

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