Leptin Increases Lipoprotein Lipase Secretion by Macrophages: Involvement of Oxidative Stress and Protein Kinase C

Maingrette, Fritz; Renier, Geneviève

doi:10.2337/diabetes.52.8.2121

Cited by 107 publications

(86 citation statements)

References 51 publications

(41 reference statements)

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“…103 Excessive leptin concentrations are involved in angiogenesis, vascular calcification and thrombosis, and leptin has been postulated to be a cardiovascular risk factor in obese persons. 104 The potential roles of leptin in obesity-induced oxidative stress in obesity are illustrated in Figure 7. Obesity-induced oxidant stress HK Vincent and AG Taylor atherogenic precursor.…”

Section: Hyperleptinemiamentioning

confidence: 99%

“…105 Exposure of monocyte-derived macrophages to leptin elevates protein kinase C activity and macrophage lipoprotein lipase activity, which is proatherogenic. 104 Leptin indirectly stimulates production of inflammatory cytokines such as IL-6 and TNF-a, and these cytokines increase NADPH oxidase production. NADPH generates O 2 KÀ Leptin can also stimulate cholesterol accumulation in a murine macrophage cell line, especially in the presence of high glucose concentrations, 107 a mechanism that may promote lipid peroxidation.…”

Section: Hyperleptinemiamentioning

confidence: 99%

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Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans

2005

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Objective: Oxidative stress may be the unifying mechanism underlying the development of comorbidities in obesity. Evidence suggests that a clustering of sources of oxidative stress exists in obesity: hyperglycemia, hyperleptinemia, increased tissue lipid levels, inadequate antioxidant defenses, increased rates of free radical formation, enzymatic sources within the endothelium, and chronic inflammation. Method: This review provides a summary of the available evidence on systemic oxidative stress in humans and specific metabolic pathways by which obesity may elevate systemic oxidant stress. The authors suggest possible methods of reducing oxidative stress such as antioxidant supplementation, caloric restriction and/or physical activity and surgical intervention to combat free radicals and reduce adipose tissue. Results: Obesity is associated with oxidative stress and can be reduced with weight loss (regardless of exercise or surgery induced weight loss), caloric restriction or antioxidant rich diets. Conclusion: Oxidative stress levels are elevated in human obesity, and these levels are modifiable with various lifestyle modifications and surgical interventions.

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Section: Hyperleptinemiamentioning

confidence: 99%

Section: Hyperleptinemiamentioning

confidence: 99%

Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans

2005

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“…32 The known direct proatherogenic effects of CRP 33 may thus be partly regulated by leptin. Leptin interacts with lipid metabolism at several levels: by stimulating macrophages to secrete lipoprotein lipase in the vessel wall; 34 by increasing the accumulation of cholesterol esters in foam cells, especially during hyperglycaemia 6 and by lowering HDL through increased clearance consequent on the upregulation of the scavenger receptor. 35 In this study, we show that men treated with pravastatin have lower leptin levels.…”

Section: 23mentioning

confidence: 99%

Leptin, but not adiponectin, is a predictor of recurrent cardiovascular events in men: results from the LIPID study

et al. 2008

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Objective: To investigate the relationships between plasma leptin and adiponectin levels and recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes. Design, subjects and measurements: A nested case-control study examined circulating leptin and adiponectin levels in plasma obtained 4-6 years after entry into the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial. Plasma was assayed from 184 men who suffered recurrent events within 4.4 years after blood collection and 184 matched controls who remained free of further events. The association between cardiovascular events and the explanatory variables was examined by conditional logistic regression analysis. Results: Relative risk (RR) increased across increasing leptin quartiles; the highest quartile compared with the lowest quartile was related to the highest risk (P for trend ¼ 0.002); the increased risk remained after adjustment for risk factors (P ¼ 0.018) or for obesity (P ¼ 0.038), but in the final model (adjusted for randomized treatment, other drugs, LIPID risk score, age and body mass index), the risk was attenuated (RR ¼ 1.61, 95% CI: 0.72-3.57, P for trend ¼ 0.34). Adiponectin did not predict cardiovascular events. Subjects randomly allocated to pravastatin had 6% lower leptin levels (P ¼ 0.04) than those allocated to placebo. Conclusion: Plasma leptin was a significant and independent predictor of recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes.

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“…Expression of macrophage-derived LPL in the arterial wall is proatherogenic (13,14), probably via the enhancement of foam cell formation (15). We previously demonstrated that macrophage LPL is upregulated in patients with accelerated atherosclerosis, including type 2 diabetes (16)(17)(18), and have identified several macrophage LPL-stimulatory factors relevant to diabetes-related atherogenesis (19)(20)(21)(22)(23). Given the concomitant upregulation of CRP and macrophage LPL in human diabetes, we sought to investigate the regulation of macrophage LPL expression by CRP and the signaling pathways involved in this effect.…”

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confidence: 99%

C-reactive protein enhances macrophage lipoprotein lipase expression

Maingrette

Renier

2008

Journal of Lipid Research

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High serum levels of C-reactive protein (CRP), a strong predictor of cardiovascular events, are documented in patients with type 2 diabetes. Accumulating evidence suggests that CRP could directly promote arterial damage. To determine the role of CRP in diabetic atherosclerosis, we examined the effect of CRP on the expression of macrophage lipoprotein lipase (LPL), a proatherogenic molecule upregulated in type 2 diabetes. Treatment of human macrophages with native CRP increased, in a dose-and timedependent manner, LPL protein expression and secretion. Modified CRP reproduced these effects. Preincubation of human macrophages with antioxidants, protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) inhibitors prevented CRP-induced LPL expression. Exposure of human macrophages to CRP further increased intracellular reactive oxygen species generation, classic PKC isozymes expression, and extracellular signal-regulated protein kinase 1/2 phosphorylation. In CRP-treated J774 macrophages, increased macrophage LPL mRNA levels and enhanced binding of nuclear proteins to the activated protein-1 (AP-1)-enhancing element were observed. These effects were prevented by antioxidants, as well as by PKC, MAPK, and AP-1 inhibitors. These data show for the first time that CRP directly increases macrophage LPL expression and secretion. Given the predominant role of macrophage LPL in atherogenesis, LPL might represent a novel factor underlying the adverse effect of CRP on the diabetic vasculature.-Maingrette, F., L. Li, and G. Renier. C-reactive protein enhances macrophage lipoprotein lipase expression. J. Lipid Res. 2008Res. . 49: 1926Res. -1935 Since the hypothesis that inflammation might be an accomplice in the pathogenesis of atherosclerosis and type 2 diabetes was first proposed, many epidemiological and clinical studies have shown that circulating markers of inflammation predict the risk of future cardiovascular (CV) events and type 2 diabetes and that an ongoing acute phase response is present in patients with type 2 diabetes (1). In addition to being a CV risk marker (2, 3), C-reactive protein (CRP) could also make a direct contribution to the atherosclerotic process. Supporting this possibility, it has been shown that CRP is present in the plaque (4) and that exposure of cultured vascular cells to CRP leads to various proinflammatory and proatherogenic effects. Among the cell types found in the lesion, monocytes/macrophages have essential functions in all phases of atherosclerosis. Interaction of CRP with these cells induces an increase in the secretion of inflammatory mediators such as cytokines and chemokines (5, 6). Additional effects of CRP on monocytes/macrophages include induction of colony stimulating factor (CSF), matrix metalloproteinase (MMP), nitric oxide, and tumoricidal activity (7-10). Most importantly, CRP also appears to promote infiltration of monocytes into the vessel wall (11) and their subsequent development into foam cells (12).Lipoprotein lipase (LPL) is a key enzyme in the hydro...

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Leptin Increases Lipoprotein Lipase Secretion by Macrophages: Involvement of Oxidative Stress and Protein Kinase C

Cited by 107 publications

References 51 publications

Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans

Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans

Leptin, but not adiponectin, is a predictor of recurrent cardiovascular events in men: results from the LIPID study

C-reactive protein enhances macrophage lipoprotein lipase expression

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