ClC-3 deficiency protects preadipocytes against apoptosis induced by palmitate in vitro and in type 2 diabetes mice
ClC-3 deficiency protects preadipocytes against apoptosis induced by palmitate in vitro and in type 2 diabetes mice
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在体外和 2 型糖尿病小鼠中，ClC-3 缺乏可保护前脂肪细胞免受棕榈酸酯诱导的细胞凋亡。
DOI：
10.1007/s10495-014-1021-0
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发表时间：
2014-11-01
期刊：
影响因子：
7.2
通讯作者：
Wang, Guan-Lei
中科院分区：
文献类型：
--
作者：
Huang, Yun-Ying;Huang, Xiong-Qin;Wang, Guan-Lei
棕榈酸是一种常见的饱和游离脂肪酸（FFA），在缺乏脂肪形成刺激的情况下，棕榈酸可诱导前脂肪细胞凋亡，提示前脂肪细胞在脂肪形成不足的情况下，如2型糖尿病（T2 DM），可能易于发生凋亡。ClC-3编码Cl-通道或Cl-/H+反向转运蛋白，对于疾病条件下细胞增殖与凋亡的命运选择至关重要。然而，ClC-3是否与棕榈酸或T2 DM诱导的前脂肪细胞凋亡有关尚不清楚。棕榈酸，而不是油酸，诱导3 T3-L1前脂肪细胞凋亡和增加ClC-3蛋白表达和内质网（ER）应激。ClC-3特异性siRNA减弱棕榈酸诱导的细胞凋亡，并增加Grp 78、ATF 4、CHOP和JNK 1/2磷酸化的蛋白水平，而对增加的磷酸化PERK和磷酸化eIF 2 α蛋白表达没有影响。此外，高糖/脂、低剂量STZ诱导的高血糖、高脂血症（血清TG和FFA水平升高）和胰岛素抵抗的T2 DM小鼠模型的前脂肪细胞凋亡增强。C1 C-3基因敲除可显著减轻T2 DM小鼠前脂肪细胞凋亡及上述代谢紊乱。这些数据表明，ClC-3缺陷通过抑制ER应激来防止棕榈酸诱导的前脂肪细胞凋亡，并且还表明ClC-3可能在2型糖尿病期间调节细胞凋亡和糖脂代谢紊乱中起作用。
Palmitate, a common saturated free fatty acid (FFA), has been demonstrated to induce preadipocyte apoptosis in the absence of adipogenic stimuli, suggesting that preadipocytes may be prone to apoptosis under adipogenic insufficient conditions, like type 2 diabetes mellitus (T2DM). ClC-3, encoding Cl- channel or Cl-/H+ antiporter, is critical for cell fate choices of proliferation versus apoptosis under diseased conditions. However, it is unknown whether ClC-3 is related with preadipocyte apoptosis induced by palmitate or T2DM. Palmitate, but not oleate, induced apoptosis and increase in ClC-3 protein expression and endoplasmic reticulum (ER) stress in 3T3-L1 preadipocyte. ClC-3 specific siRNA attenuated palmitate-induced apoptosis and increased protein levels of Grp78, ATF4, CHOP and phosphorylation of JNK1/2, whereas had no effects on increased phospho-PERK and phospho-eIF2 alpha protein expression. Moreover, the enhanced apoptosis was shown in preadipocytes from high-sucrose/fat, low-dose STZ induced T2DM mouse model with hyperglycemia, hyperlipidemia (elevated serum TG and FFA levels) and insulin resistance. ClC-3 knockout significantly attenuated preadipocyte apoptosis and the above metabolic disorders in T2DM mice. These data demonstrated that ClC-3 deficiency prevent preadipocytes against palmitate-induced apoptosis via suppressing ER stress, and also suggested that ClC-3 may play a role in regulating cellular apoptosis and disorders of glucose and lipid metabolism during T2DM.