Changes in plasma free fatty acid concentrations in rheumatoid arthritis patients during fasting and their effects upon T-lymphocyte proliferation

Fraser, David A.; Thöen, J.; Rustan, Arild C.; Førre, Ø; Kjeldsen‐Kragh, Jens

doi:10.1093/rheumatology/38.10.948

Cited by 42 publications

(39 citation statements)

References 16 publications

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“…In fact, inhibition of insulin signal transduction was observed at concentrations of 75 nM and above with the maximal inhibition observed at 750 M. The concentrations, which activate signal transduction, are slightly below what has been observed in circulating plasma (400 -600 M, total FFA and 100 -200 M, palmitate) but are well within the range for the concentrations observed in muscle tissue, where muscle palmitoyl-CoA has been observed in the range of 1 nM in type 2 diabetics (33)(34)(35). These concentrations appear to fit well within range of the concentrations observed in vivo, suggesting that these observations are relevant to the study of high fat diet-and obesity-related insulin resistance and inflammation (33,35).…”

Section: Discussionmentioning

confidence: 46%

Toll-like Receptor-2 Is Essential for the Development of Palmitate-induced Insulin Resistance in Myotubes

Senn

2006

Journal of Biological Chemistry

233

191

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Fatty acids can activate proinflammatory pathways leading to the development of insulin resistance, but the mechanism is undiscovered. Toll like receptor 2 (TLR2) recognizes lipids, activates proinflammatory pathways, and is genetically associated with inflammatory diseases. This study aimed to examine the role of TLR2 in palmitate-induced insulin resistance in C2C12 myotubes. Treatment with palmitate rapidly induced the association of myeloid differentiation factor 88 (MyD88) with the TLR2 receptor, activated the stress-linked kinases p38, JNK, and protein kinase C, induced degradation of IB␣, and increased NF-B DNA binding. The activation of these pathways by palmitate was sensitive and temporally regulated and occurred within the upper physiologic range of saturated fatty acid concentrations in vivo, suggesting a receptor-mediated event and not simple lipotoxicity. When compared with an equimolar concentration of palmitate, fibroblast-stimulating lipopeptide-1, a known TLR2 ligand, was a slightly more potent activator of signal transduction and interleukin (IL)-6 production. Palmitate inhibited insulin signal transduction in C2C12 cells beginning 1-2 h after exposure and reached a maximum at 12-16 h. An antagonist TLR2 antibody, mAb 2.5, led to a 50 -60% decrease in palmitate-induced IL-6 production and partially restored insulin signal transduction, whereas an isotype-matched control antibody had no effect. RNA interference-mediated inhibition of TLR2 and MyD88 expression in C2C12 muscle cells resulted in a near complete inhibition of palmitate-induced insulin resistance and IL-6 production. This study provides strong evidence that TLR2 mediates the initial events of fatty acid-induced insulin resistance in muscle.

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Section: Discussionmentioning

confidence: 46%

Toll-like Receptor-2 Is Essential for the Development of Palmitate-induced Insulin Resistance in Myotubes

Senn

2006

Journal of Biological Chemistry

233

191

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“…Findings from serum metabonomics partially ascertained the previous report that FFAs would increase in RA individuals [20,21]. A report indicated that fasting-associated increases in total plasma FFAs promoted lymphocyte proliferation in vitro and might not facilitate to alleviate inflammation [22]. Generally speaking, lysophosphatidylcholines involve in inflammation and inflammation is a key pathological event in RA.…”

Section: Effect Of Ynb On the Down-stream Metabolism Of Aa In Osteoblmentioning

confidence: 55%

Therapeutic effect of Yunnan Baiyao on rheumatoid arthritis was partially due to regulating arachidonic acid metabolism in osteoblasts

He¹,

Ren²,

Wang³

et al. 2012

Journal of Pharmaceutical and Biomedical Analysis

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“…The concentrations of palmitic acid used here are within the reported pathophysiologic range. 16,17 Exposure to Palmitic Acid Results in Intracellular Lipid Accumulation in Hepatocytes. Human hepatoma cells (HepG2) were cultured with different concentrations of palmitic acid for varying intervals.…”

Section: Resultsmentioning

confidence: 99%

Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes

et al. 2007

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Obesity and the metabolic syndrome are closely correlated with hepatic steatosis. Simple hepatic steatosis in nonalcoholic fatty liver disease can progress to nonalcoholic steatohepatitis (NASH), which can be a precursor to more serious liver diseases, such as cirrhosis and hepatocellular carcinoma. The pathogenic mechanisms underlying progression of steatosis to NASH remain unclear; however, inflammation, proinflammatory cytokines, and oxidative stress have been postulated to play key roles. We previously reported that patients with NASH have elevated serum levels of proinflammatory cytokines, such as interleukin-8 (IL-8), which are likely to contribute to hepatic injury. This study specifically examines the effect of hepatic steatosis on IL-8 production. We induced lipid accumulation in hepatocytes (HepG2, rat primary hepatocytes, and human primary hepatocytes) by exposing them to pathophysiologically relevant concentrations of palmitic acid to simulate the excessive influx of fatty acids into hepatocytes. Significant fat accumulation was documented morphologically by Oil Red O staining in cells exposed to palmitic acid, and it was accompanied by an increase in intracellular triglyceride levels. Importantly S everal studies suggest that elevated levels of circulating free fatty acids (FFAs) contribute to the complications of obesity and the metabolic syndrome by promoting excess fat deposition in nonadipose tissues not suited for fat storage, such as the liver. 1 A strong correlation exists between obesity and fatty liver (hepatic steatosis); indeed, nonalcoholic fatty liver disease is considered to be the hepatic manifestation of the metabolic syndrome. 2 Liver steatosis is often considered a benign condition, but it can progress to nonalcoholic steatohepatitis (NASH), which may be a precursor to more severe liver diseases such as cirrhosis and hepatocellular carcinoma. 3 NASH is a common liver disease in the United States, and its prevalence is on the rise worldwide. NASH is characterized by microvesicular and macrovesicular steatosis, inflammation with mixed cellularity including neutrophils, hepatocyte degeneration and injury, and sometimes fibrosis. 3 The pathogenesis of NASH and the mechanisms of progression of hepatic steatosis to NASH remain unclear. 4 Current understanding supports the "multiple-hit model" for the development of NASH, wherein hepatic steatosis represents the "first hit," whereas the "second" or "subsequent" hits must induce liver damage and promote inflammation with neutrophil infiltration. The nature of the subsequent hits is hypothesized to include direct lipid toxicity, mitochondrial dys-

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Changes in plasma free fatty acid concentrations in rheumatoid arthritis patients during fasting and their effects upon T-lymphocyte proliferation

Abstract: Fasting-associated increases in total plasma FFA concentrations do not inhibit, but rather enhance, in vitro lymphocyte proliferation. An inhibitory effect could only be achieved by manipulating the balance between the unsaturated and saturated fatty acids.

Cited by 42 publications

References 16 publications

Toll-like Receptor-2 Is Essential for the Development of Palmitate-induced Insulin Resistance in Myotubes

Toll-like Receptor-2 Is Essential for the Development of Palmitate-induced Insulin Resistance in Myotubes

Therapeutic effect of Yunnan Baiyao on rheumatoid arthritis was partially due to regulating arachidonic acid metabolism in osteoblasts

Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes

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