Carnitine palmitoyltransferase 1A prevents fatty acid-induced adipocyte dysfunction through suppression of c-Jun N-terminal kinase
Carnitine palmitoyltransferase 1A prevents fatty acid-induced adipocyte dysfunction through suppression of c-Jun N-terminal kinase
复制标题
肉碱棕榈酰转移酶 1A 通过抑制 c-Jun N 末端激酶来预防脂肪酸诱导的脂肪细胞功能障碍
DOI：
10.1042/bj20101680
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发表时间：
2011-05-01
影响因子：
4.1
通讯作者：
Wu, Donghai
中科院分区：
文献类型：
--
作者：
Gao, Xuefei;Li, Kuai;Wu, Donghai
脂肪细胞是储存脂肪的主要细胞类型。CPT 1（肉毒碱棕榈酰转移酶-1）是脂肪酸β-氧化的限速酶，但CPT 1在脂肪细胞中的生理作用仍不清楚。在本研究中，我们专注于CPT 1A在脂肪细胞正常功能中的特定作用。建立了稳定表达hCPT 1A（human CPT 1A）cDNA、小鼠CPT 1A shRNA（short-hairpin RNA）和GFP（绿色荧光蛋白）的3种3 T3-L1脂肪细胞系，并对其生物学功能进行了表征。CPT 1活性的改变，无论是异位过表达或药理学抑制使用依托莫西，不影响脂肪细胞分化。然而，当脂肪细胞用脂肪酸攻击时，与对照细胞相比，hCPT IA的过表达显著降低了细胞内NEFA（非酯化脂肪酸）的含量。这些变化伴随着脂肪酸摄取的增加和脂肪酸释放的减少。有趣的是，CPT 1A可以防止脂肪酸诱导的胰岛素抵抗和脂肪细胞中促炎性脂肪因子如TNF-α（肿瘤坏死因子-α）和IL-6（白细胞介素-6）的表达。进一步的研究表明，JNK（c-Jun N末端激酶）的活性在CPT 1A过表达时被显著抑制，而CPT 1的敲除或药物抑制引起JNK活性的显著增强。JNK SP 600125的特异性抑制剂在很大程度上消除了由shRNA和依托莫西介导的CPT 1活性降低引起的变化。此外，C2 C12肌细胞与脂肪酸预处理的脂肪细胞共培养显示胰岛素敏感性改变。总之，我们的研究结果已经确定了脂肪细胞中CPT 1A通过抑制JNK来减轻脂肪酸诱发的胰岛素抵抗和炎症的有利作用。
The adipocyte is the principal cell type for fat storage. CPT1 (carnitine palmitoyltransferase-1) is the rate-limiting enzyme for fatty acid beta-oxidation, but the physiological role of CPT1 in adipocytes remains unclear. In the present study, we focused on the specific role of CPT1A in the normal functioning of adipocytes. Three 3T3-L1 adipocyte cell lines stably expressing hCPT1A (human CPT1A) cDNA, mouse CPT1A shRNA (short-hairpin RNA) or GFP (green fluorescent protein) were generated and the biological functions of these cell lines were characterized. Alteration in CPT1 activity, either by ectopic overexpression or pharmacological inhibition using etomoxir, did not affect adipocyte differentiation. However, overexpression of hCPT I A significantly reduced the content of intracellular NEFAs (non-esterified fatty acids) compared with the control cells when adipocytes were challenged with fatty acids. The changes were accompanied by an increase in fatty acid uptake and a decrease in fatty acid release. Interestingly, CPT1A protected against fatty acid-induced insulin resistance and expression of pro-inflammatory adipokines such as TNF-alpha (tumour necrosis factor-alpha) and IL-6 (interleukin-6) in adipocytes. Further studies demonstrated that JNK (c-Jun N terminal kinase) activity Was substantially suppressed upon CPT1A overexpression, whereas knockdown or pharmacological inhibition of CPT1 caused a significant enhancement of JNK activity. The specific inhibitor of JNK SP600125 largely abolished the changes caused by the shRNA- and etomoxir-mediated decrease in CPT1 activity. Moreover, C2C12 myocytes co-cultured with adipocytes pre-treated with fatty acids displayed altered insulin sensitivity. Taken together, our findings have identified a favourable role for CPT1A in adipocytes to attenuate fatty acid-evoked insulin resistance and inflammation via suppression of JNK.