Differential uptake of subfractions of triglyceride-rich lipoproteins by THP-1 macrophages

Palmer, A. Smythe; Nova, Esther; Anil, Eliz; Jackson, Kim G.; Bateman, Paul A.; Wolstencroft, Emma J.; Williams, Christine M.; Yaqoob, Parveen

doi:10.1016/j.atherosclerosis.2004.12.038

Cited by 32 publications

(30 citation statements)

References 42 publications

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“…Macrophages are known to secrete active lipoprotein lipase (35), and lipoprotein lipase activity has been shown to be upregulated by exposure to VLDL (8,30). Our data showing the absence of TG and FFA accumulation in macrophages treated with the lipoprotein lipase inhibitor Orlistat are in agreement with other reports (30,33,36) and implicate VLDL remnant and/or FFA uptake as the primary mechanisms by which VLDL induces macrophage foam cell formation.…”

Section: Discussionsupporting

confidence: 92%

“…Although modified lipoprotein uptake occurs via scavenger receptors, the most likely receptor for VLDL uptake is the low density lipoprotein receptor-related protein (LRP). Second, lipolysis of VLDL can lead to the uptake of VLDL remnants by receptor-mediated mechanisms (33). Third, FFA generated during the lipolysis of VLDL can also be brought into the cells via receptors or by passive diffusion (34).…”

Section: Discussionmentioning

confidence: 99%

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The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages

Saraswathi

Hasty

2006

Journal of Lipid Research

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Hypertriglyceridemia is an important risk factor for atherosclerosis, especially in obesity. Macrophages are one of the primary cell types involved in atherogenesis and are thought to contribute to lesion formation through both lipid accumulation and proinflammatory gene expression. In this study, we sought to determine the direct impact of triglyceride (TG)-rich VLDL-induced lipid accumulation on macrophage proinflammatory processes. Incubation of mouse peritoneal macrophages with 100 mg/ml VLDL for 6 h led to 2.8-and 3.7-fold increases in intracellular TGs and FFAs, respectively (P , 0.05). The inflammatory proteins tumor necrosis factor-a, interleukin-1b, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinase 3 (MMP3), and macrophage inflammatory protein1a (MIP-1a) were all upregulated by at least 2-fold (P , 0.05) in a dose-dependent manner in VLDL-treated macrophages. The increase in inflammatory gene expression coincided with the phosphorylation of the mitogen-activated protein kinase (MAPK) pathway members extracellular signal-regulated kinase (ERK) 1/2, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p38 MAPK and was ameliorated by U0126, an inhibitor of ERK1/2. Inhibition of extracellular TG hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by the amelioration of ERK1/2 phosphorylation and MIP-1a gene expression. These data indicate that VLDL hydrolysis, and the subsequent accumulation of intracellular FFAs and TGs, plays a substantive role in mediating the proinflammatory effects of VLDL. These data have important implications for the direct proatherogenic effects of VLDL on macrophage-driven atherosclerosis.-Saraswathi, V., and A. H. Hasty. Traditionally, LDLs have been thought to be the key plasma lipoproteins involved in atherosclerotic lesion development. However, with the dramatic increase in the prevalence of obesity around the world, associated lipoprotein abnormalities such as hypertriglyceridemia have been brought into focus. In fact, hypertriglyceridemia is now regarded as one of the main contributing factors to the development of atherosclerotic disease (1, 2), although the exact mechanisms by which triglycerides (TGs) function in atherogenesis are unknown. TGs in fasting plasma are carried in VLDLs, and these VLDLs have been found within human and experimental atherosclerotic lesions (3, 4), providing a rationale to study their direct effects on macrophage functions such as foam cell formation and inflammation. It is well established that VLDL causes the accumulation of TGs and FFAs in macrophages (5-9). This can occur through three different mechanisms: 1) uptake of intact VLDL particles; 2) uptake of VLDL remnants resulting from lipoprotein lipase-mediated lipolysis; and 3) uptake of FFAs produced by VLDL lipolysis, which can be taken into cells through both passive diffusion and receptor-mediated mechanisms. Despite these known pathways of mac...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages

Saraswathi

Hasty

2006

Journal of Lipid Research

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“…Chylomicron remnants and triglyceride-rich lipoproteins also produce lipid accumulation in macrophages (50). Uptake of larger lipid-rich VLDL particles is favored in macrophages, promoting lipid accumulation (51). Disruption of the VLDL receptor in macrophages reduces atherosclerosis in cholesterol-fed mice, while VLDL receptor expression in VLDL receptor-deficient recipient mice increases atherosclerosis (52).…”

Section: Triglyceride-rich Lipoproteins In Diabetesmentioning

confidence: 99%

Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies

2008

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Subjects with diabetes have increased cardiovascular disease risk compared to those without diabetes. Addressing residual cardiovascular disease risk in this disease, beyond blood pressure and LDL cholesterol control, remains important as the prevalence of diabetes increases worldwide. The accelerated atherosclerosis and cardiovascular disease in diabetes is likely multifactorial and there are numerous therapeutic approaches that can be considered. Results of mechanistic studies conducted in isolated cells, animals, or humans can provide important insights with potential to influence clinical management decisions and improve outcomes. In this review, we focus on three areas in which pathophysiologic considerations could be particularly informative in this regard; the roles of hyperglycemia, diabetic dyslipidemia (beyond LDL cholesterol level), and inflammation (including that in adipose tissue) for accelerating vascular injury and the rates of cardiovascular disease in Type 2 diabetes are outlined and evaluated.

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“…VLDL particles are larger (Palmer et al, 2005), having radii in the range 15-40nm, although this distribution is also highly skewed. We assume VLDL-2 particles are toward the lower end of this (15nm) and so cover 700nm 2 ; thus in addition to binding to a receptor, it will occlude others.…”

Section: A Parameter Valuesmentioning

confidence: 99%

A continuum receptor model of hepatic lipoprotein metabolism

Tindall¹,

Wattis

O’Malley

et al. 2009

Journal of Theoretical Biology

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Differential uptake of subfractions of triglyceride-rich lipoproteins by THP-1 macrophages

Cited by 32 publications

References 42 publications

The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages

The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages

Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies

A continuum receptor model of hepatic lipoprotein metabolism

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