Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts
Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts
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DOI：
10.1016/j.bbadis.2013.07.021
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发表时间：
2013-12-01
影响因子：
6.2
通讯作者：
de Lonlay, Pascale
中科院分区：
文献类型：
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作者：
Michot, Caroline;Mamoune, Asmaa;de Lonlay, Pascale
Lipin-1缺乏症与人类大量横纹肌溶解症发作有关，由发热性疾病引起。尽管众所周知lipin-1在脂质生物合成和转录调节中的作用，但导致横纹肌溶解的致病机制仍然未知。在这里，我们发现，从lipin-1缺乏患者的原代成肌细胞表现出显着的LPIN 1表达和磷脂酸磷酸酶1活性的下降，和一个显着的积累脂滴（LD）。LPIN 1靶基因[过氧化物酶体增殖物激活受体δ和α]的表达水平（过氧化物酶体增殖物激活受体δ，过氧化物酶体增殖物激活受体α），过氧化物酶体增殖物激活受体γ共激活因子1-α（PGC-1 alpha）、酰基辅酶A脱氢酶，非常长（ACADVL）、卡米丁棕榈酰转移酶IB和2（CPT 1B和CPT 2）]没有受到影响，而脂蛋白-2蛋白水平，一个密切相关的家庭成员，增加。患者肌管的微阵列分析确定了19个下调和51个上调基因，表明lipin-1缺乏的多效性效应。特别注意的是上调ACACB（乙酰辅酶A羧化酶β），脂肪酸合成/氧化平衡的关键酶。我们证明，ACACB的过度表达与患者成肌细胞中游离脂肪酸的积累有关，而丙二酰-卡米丁（作为丙二酰-CoA的测量）和CPT 1活性在基础条件下处于正常范围，与患者报告的正常日常活动相对应。值得注意的是，患者成肌细胞中的ACACB失效减少了LD的数量和大小，而对照组中的LPIN 1失效诱导了LD的积累。此外，促炎治疗肿瘤坏死因子α +白细胞介素-1 β（TNF 1 α + IL-1 β），旨在模拟发热性疾病，导致丙二酰-卡米丁水平增加，CPT 1活性降低，LD积累增加，地塞米松和TNF α逆转的现象。或IL-1 β抑制剂。我们的数据表明，横纹肌溶解症的发病机制在lipin-1缺乏的患者相结合的易感性组成性损害的脂质代谢和其恶化的促炎细胞因子。(C)2013年由Elsevier B. V.出版
Lipin-1 deficiency is associated with massive rhabdomyolysis episodes in humans, precipitated by febrile illnesses. Despite well-known roles of lipin-1 in lipid biosynthesis and transcriptional regulation, the pathogenic mechanisms leading to rhabdomyolysis remain unknown. Here we show that primary myoblasts from lipin-1-deficient patients exhibit a dramatic decrease in LPIN1 expression and phosphatidic acid phosphatase 1 activity, and a significant accumulation of lipid droplets (LD). The expression levels of LPIN1-target genes [peroxisome proliferator-activated receptors delta and alpha (PPAR delta, PPAR alpha), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), acyl-coenzyme A dehydrogenase, very long (ACADVL), camitine palmitoyltransferase IB and 2 (CPT1B and CPT2)] were not affected while lipin-2 protein level, a closely related member of the family, was increased. Microarray analysis of patients' myotubes identified 19 down-regulated and 51 up-regulated genes, indicating pleiotropic effects of lipin-1 deficiency. Special attention was paid to the up-regulated ACACB (acetyl-CoA carboxylase beta), a key enzyme in the fatty acid synthesis/oxidation balance. We demonstrated that overexpression of ACACB was associated with free fatty acid accumulation in patients' myoblasts whereas malonyl-camitine (as a measure of malonyl-CoA) and CPT1 activity were in the normal range in basal conditions accordingly to the normal daily activity reported by the patients. Remarkably ACACB invalidation in patients' myoblasts decreased LD number and size while LPIN1 invalidation in controls induced LD accumulation. Further, pro-inflammatory treatments tumor necrosis factor alpha + Interleukin-1beta(TNF1 alpha + IL-1 beta) designed to mimic febrile illness, resulted in increased malonyl-camitine levels, reduced CPT1 activity and enhanced LD accumulation, a phenomenon reversed by dexamethasone and TNF alpha. or IL-1 beta inhibitors. Our data suggest that the pathogenic mechanism of rhabdomyolysis in lipin-1-deficient patients combines the predisposing constitutive impairment of lipid metabolism and its exacerbation by pro-inflammatory cytokines. (C) 2013 Published by Elsevier B.V.