ClC-3 chloride channel/antiporter defect contributes to inflammatory bowel disease in humans and mice

Huang, Linyan; He, Qing-Yu; Liang, Shi-Dong; Su, Ying-Xue; Xiong, Li-Xiong; Wu, Qianqian; Wu, Qin-Yan; Tao, Jin‐Hui; Wang, Jianping; Tang, Yong-Bo; Lv, Xiao‐Fei; Liu, Jie; Guan, Yong‐Yuan; Pang, Rui‐Ping; Zhou, Jia‐Guo

doi:10.1136/gutjnl-2013-305168

Cited by 43 publications

(34 citation statements)

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“…These results provide the first and compelling evidence that ClC-3 is critically linked to preadipocyte apoptosis induced by saturated FFA in vitro and in T2DM. ClC-3 has been suggested to be essential for apoptosis in a variety of cell types, such as vascular smooth muscle cells [19,34], endothelial progenitor cells [21], tumor and carcinoma cells [38,39] and bronchial and intestinal epithelial cells [20,40,41], and thus may play roles in the disease processes of hypertensive vascular remodeling [19], inflammatory responses [20] and tumor cell death [38]. Our presented data demonstrated that ClC-3 protein expression and cellular apoptosis in preadipocytes could be significantly increased in response to saturated FFAs (palmitate), but not unsaturated FFAs.…”

Section: Discussionmentioning

confidence: 99%

“…ClC-3 has been suggested to be responsible for the volume-regulated outwardly rectifying Cl -currents, thus it may be critical for some basic cellular functions, including neutrophil infiltration [14], vascular smooth muscle ROS generation and inflammatory responses [15][16][17], b cell insulin secretion [18] and cellular proliferation and apoptosis [19][20][21][22]. By using ClC-3 knockout mice, our recent study have shown that ClC-3 deficiency can prevent the angiotensin II-induced apoptosis in endothelial progenitor cells [21] but promote DSS-induced apoptosis of intestinal epithelial cells [20], highlighting the importance of disruption of ClC-3 in apoptosis cell damage under diseased conditions. ClC-3 is also abundantly expressed in preadipocytes [23] where its function is unknown.…”

Section: Introductionmentioning

confidence: 99%

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ClC-3 deficiency protects preadipocytes against apoptosis induced by palmitate in vitro and in type 2 diabetes mice

Huang

Zhao

et al. 2014

Apoptosis

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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-eIF2α 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ClC-3 deficiency protects preadipocytes against apoptosis induced by palmitate in vitro and in type 2 diabetes mice

Huang

Zhao

et al. 2014

Apoptosis

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“…Apoptotic IEC death has been implicated as a major homeostatic and pathogenic mechanism of IBD,2 3 and RKIP deficiency inhibits DSS/TNBS-induced IEC apoptosis. The FITC-dextran permeability experiment suggests that RKIP deficiency is helpful in maintaining the integrity of colonic epithelial barrier, which leads to the resistance of RKIP-KO mice to experimental colitis.…”

Section: Discussionmentioning

confidence: 99%

Raf kinase inhibitor protein mediates intestinal epithelial cell apoptosis and promotes IBDs in humans and mice

Lin

et al. 2016

Gut

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“…The immunoprecipitation assay was performed, as previously described. 24 Briefly, the supernatants were incubated with endophilin A2 (Santa Cruz, CA, USA), ClC-3 (Alomone Labs), or GFP antibodies (Santa Cruz) overnight at 4°C, then incubated with Protein A/G beads (Santa Cruz) for 4 h. Beads were washed three times with lysis buffer and the proteins were separated by Western Blotting.…”

Section: Immunoprecipitation and Western Blot Analysismentioning

confidence: 99%

Endophilin A2 Influences Volume-Regulated Chloride Current by Mediating ClC-3 Trafficking in Vascular Smooth Muscle Cells

Liu

et al. 2016

Circ J

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Background: Previous research has demonstrated that ClC-3 is responsible for volume-regulated Cl -current (ICl.vol) in vascular smooth muscle cells (VSMCs). However, it is still not clear whether and how ClC-3 is transported to cell membranes, resulting in alteration of ICl.vol. Methods and Results:Volume-regulated chloride current (ICl.vol) was recorded by whole-cell patch clamp recording, and Western blotting and co-immunoprecipitation were performed to examine protein expression and protein-protein interaction. Live cell imaging was used to observe ClC-3 transporting. The results showed that an overexpression of endophilin A2 could increase ICl.vol, while endophilin A2 knockdown decreased ICl.vol. In addition, the SH3 domain of endophilin A2 mediated its interaction with ClC-3 and promotes ClC-3 transportation from the cytoplasm to cell membranes. The regulation of ClC-3 channel activity was also verified in basilar arterial smooth muscle cells (BASMCs) isolated from endophilin A2 transgenic mice. Moreover, endophilin A2 increase VSMCs proliferation induced by endothelin-1 or hypo-osmolarity. Conclusions:The present study identified endophilin A2 as a ClC-3 channel partner, which serves as a new ClC-3 trafficking insight in regulating ICl.vol in VSMCs. This study provides a new mechanism by which endophilin A2 regulates ClC-3 channel activity, and sheds light on how ClC-3 is transported to cell membranes to play its critical role as a chloride channel in VSMCs function, which may be involved in cardiovascular diseases. mechanism, coupling intracellular ClC-3 to cell membrane ICl. vol for VSMC functions.

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ClC-3 chloride channel/antiporter defect contributes to inflammatory bowel disease in humans and mice

Abstract: A defect in ClC-3 may contribute to the pathogenesis of IBD by promoting intestinal epithelial cell apoptosis and Paneth cell loss, suggesting that modulation of ClC-3 expression might be a new strategy for the treatment of IBD.

Cited by 43 publications

References 45 publications

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

Raf kinase inhibitor protein mediates intestinal epithelial cell apoptosis and promotes IBDs in humans and mice

Endophilin A2 Influences Volume-Regulated Chloride Current by Mediating ClC-3 Trafficking in Vascular Smooth Muscle Cells

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