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    Low expression of IL-18 and IL-18 receptor in human skeletal muscle is associated with systemic and intramuscular lipid metabolism:Role of HIV lipodystrophy

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    Interleukin (IL)-18 is involved in regulation of lipid and glucose metabolism. Mice lacking whole-body IL-18 signalling are prone to develop weight gain and insulin resistance, a phenotype which is associated with impaired fat oxidation and ectopic skeletal muscle lipid deposition. IL-18 mRNA is expressed in human skeletal muscle but a role for IL-18 in muscle has not been identified. Patients with HIV-infection and lipodystrophy (LD) are characterized by lipid and glucose disturbances and increased levels of circulating IL-18. We hypothesized that skeletal muscle IL-18 and IL-18 receptor (R) expression would be altered in patients with HIV-lipodystrophy.Twenty-three HIV-infected patients with LD and 15 age-matched healthy controls were included in a cross-sectional study. Biopsies from the vastus lateralis muscle were obtained and IL-18 and IL-18R mRNA expression were measured by real-time PCR and sphingolipids (ceramides, sphingosine, sphingosine-1-Phosphate, sphinganine) were measured by HPLC. Insulin resistance was assessed by HOMA and the insulin response during an OGTT.Patients with HIV-LD had a 60% and 54% lower level of muscular IL-18 and IL-18R mRNA expression, respectively, compared to age-matched healthy controls. Patients with HIV-LD had a trend towards increased levels of ceramide (18.3±4.7 versus 14.8±3.0,p = 0.06) and sphingosine (0.41±0.13 versus 0.32±0.07, and lower level of sphinganine (p = 0.06). Low levels of muscle IL-18 mRNA correlated to high levels of ceramides (r = -0.31, p = 0.038) and sphingosine-1P (r = -0.29, p = 0.046) in skeletal muscle, whereas such a correlation was not found in healthy controls. Low expression of IL-18 mRNA in skeletal muscle correlated to elevated concentration of circulating triglycerides (Rp = -0.73, p<0.0001). Neither muscle expression of IL-18 mRNA or ceramide correlated to parameters of insulin resistance.IL-18 (mRNA) in skeletal muscle appears to be involved in the regulation of intramuscular lipid metabolism and hypertriglyceridemia

    Patients with HIV-lipodystrophy have reduced levels of IL-18 mRNA and IL-18 receptor mRNA in skeletal muscle.

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    <p>(A) mRNA expression of IL-18 in skeletal muscle. In the healthy control group 2 subjects had very high levels of IL-18 mRNA levels. Even if those two subjects were deleted the difference between healthy controls and patients with HIV-Lipodystrophy were still high significant p = 0.003). (B) mRNA expression of IL-18 receptor in skeletal muscle. The levels of IL-18 mRNA and IL-18 receptor mRNA were calculated with GAPDH as a housekeeping gene. In the dot plots data for each subjects are given and the line represent means and SD. * P<0.05 and ***P<0.001 for healthy vs HIV-lipodystrophy patients.</p

    The correlation relationship between muscle IL-18 mRNA and muscle sphingolipid content, circulating triglycerides and HDL-cholesterol in patients with HIV-lipodystrophy (to the right) and in healthy controls (to the left).

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    <p>IL-18 mRNA in muscle is negatively correlated to ceramide (A) and sphingosine-1P (C) content in muscle in patients with HIV-Lipodystrophy, but not in healthy controls (B, D, F). Il-18 mRNA in muscle is negatively correlated to triglycerides in patients with HIV-Lipodystrophy and in healthy controls (G), and positively correlated to HDL-Cholesterol in patients with HIV-lipodystrophy. Regressions lines, correlations coefficient and significance levels are given for healthy controls and patients with HIV-Lipodystrophy separately.</p
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