title: ClC-3 deficiency protects preadipocytes against apoptosis induced by palmitate in vitro and in type 2 diabetes mice.
abstract: 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.
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2 Rd, Guangzhou, 510080, China.
authors.forename: Yun-Ying
authors.initials: YY
authors.lastname: Huang
authors.forename: Xiong-Qin
authors.initials: XQ
authors.lastname: Huang
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Zhao
authors.forename: Fang-Yun
authors.initials: FY
authors.lastname: Sun
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Chen
authors.forename: Jie-Yi
authors.initials: JY
authors.lastname: Du
authors.forename: Feng
authors.initials: F
authors.lastname: Yuan
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Xue-Lian
authors.initials: XL
authors.lastname: Huang
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Lv
authors.forename: Yong-Yuan
authors.initials: YY
authors.lastname: Guan
authors.forename: Jian-Wen
authors.initials: JW
authors.lastname: Chen
authors.forename: Guan-Lei
authors.initials: GL
authors.lastname: Wang
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D051379:Mice; D018345:Mice, Knockout; D019301:Oleic Acid / Q000494:pharmacology; D010168:Palmitates / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013234:Stem Cells; D013311:Streptozocin
chemical_list: D018118:Chloride Channels; C115376:ClC-3 channel; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D010168:Palmitates; D034741:RNA, Small Interfering; D019301:Oleic Acid; D013311:Streptozocin