人类骨骼肌中白细胞介素-18和白细胞介素-18受体的低表达与全身及肌肉内脂质代谢相关——人类免疫缺陷病毒脂肪代谢障碍的作用
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.
作者信息
Lindegaard Birgitte, Hvid Thine, Wolsk Mygind Helene, Mortensen Ole Hartvig, Grøndal Thomas, Abildgaard Julie, Gerstoft Jan, Pedersen Bente Klarlund, Baranowski Marcin
机构信息
The Centre of Inflammation and Metabolism and The Centre of Physical Activity Research, Rigshospital, Copenhagen, Denmark.
The Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
出版信息
PLoS One. 2018 Jan 17;13(1):e0186755. doi: 10.1371/journal.pone.0186755. eCollection 2018.
INTRODUCTION
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.
DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSION
IL-18 (mRNA) in skeletal muscle appears to be involved in the regulation of intramuscular lipid metabolism and hypertriglyceridemia.
引言
白细胞介素（IL）-18参与脂质和葡萄糖代谢的调节。缺乏全身IL-18信号传导的小鼠容易出现体重增加和胰岛素抵抗，这种表型与脂肪氧化受损和异位骨骼肌脂质沉积有关。IL-18 mRNA在人类骨骼肌中表达，但IL-18在肌肉中的作用尚未明确。感染人类免疫缺陷病毒（HIV）并患有脂肪代谢障碍（LD）的患者具有脂质和葡萄糖紊乱以及循环IL-18水平升高的特征。我们推测HIV脂肪代谢障碍患者骨骼肌中IL-18和IL-18受体（R）的表达会发生改变。
设计与方法
一项横断面研究纳入了23例感染HIV且患有LD的患者以及15名年龄匹配的健康对照。获取股外侧肌活检样本，通过实时聚合酶链反应（PCR）测量IL-18和IL-18R mRNA表达，并通过高效液相色谱法（HPLC）测量鞘脂（神经酰胺、鞘氨醇、鞘氨醇-1-磷酸、二氢鞘氨醇）。通过稳态模型评估法（HOMA）和口服葡萄糖耐量试验（OGTT）期间的胰岛素反应评估胰岛素抵抗。
结果
与年龄匹配的健康对照相比，HIV-LD患者的肌肉IL-18和IL-18R mRNA表达水平分别降低了60%和54%。HIV-LD患者的神经酰胺水平有升高趋势（18.3±4.7对14.8±3.0，p = 0.06）和鞘氨醇水平升高（0.41±0.13对0.32±0.07），而二氢鞘氨醇水平较低（p = 0.06）。骨骼肌中低水平的肌肉IL-18 mRNA与高水平的神经酰胺（r = -0.31，p = 0.038）和鞘氨醇-1磷酸（r = -0.29，p = 0.046）相关，而在健康对照中未发现这种相关性。骨骼肌中IL-18 mRNA的低表达与循环甘油三酯浓度升高相关（Rp = -0.73，p<0.0001）。IL-18 mRNA或神经酰胺的肌肉表达均与胰岛素抵抗参数无关。
结论
骨骼肌中的IL-18（mRNA）似乎参与肌肉内脂质代谢和高甘油三酯血症的调节。
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