脂毒性通过脂质代谢相关分子调控胰岛星状细胞激活减少β细胞存活。
Lipotoxicity reduces β cell survival through islet stellate cell activation regulated by lipid metabolism-related molecules.
机构信息
Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China.
Department of Outpatient, Army Engineering University, Jingling Hospital, Nanjing University, Nanjing, China.
出版信息
Exp Cell Res. 2019 Jul 1;380(1):1-8. doi: 10.1016/j.yexcr.2019.04.012. Epub 2019 Apr 15.
BACKGROUND
Islet stellate cells (ISCs) activation is mainly associated with islet fibrosis, which contributes to the progression of type 2 diabetes. However, the molecular mechanism underlying this process is not fully understood.
METHODS
In order to investigate this process the current study examined ectopic fat accumulation in rats with high-fat diet (HFD) induced obesity. Levels of lipotoxicity-induced ISC activation and islet function were assessed via intraperitoneal glucose and insulin tolerance tests, and immunohistochemistry. The expression of lipid metabolism- and ISC activation-related markers was evaluated in cultured ISCs treated with palmitic acid (PA) using quantitative PCR and western blotting. We also overexpressed sterol regulatory element-binding protein (SREBP)-1c in ISCs by lentiviral transduction, and assessed the effects on insulin release in co-cultures with isolated rat islets.
RESULTS
HFD increased body weight and ectopic fat accumulation in pancreatic islets. Lipotoxicity caused progressive glucose intolerance and insulin resistance, upregulated α-smooth muscle actin, and stimulated the secretion of extracellular matrix. Lipotoxicity reduced the expression of lipid metabolism-related molecules in ISCs treated with PA, especially SREBP-1c. Overexpression of SREBP-1c in ISCs improved islet viability and insulin secretion in co-cultures.
CONCLUCIONS
These results indicate that lipotoxicity-induced ISC activation alters islet function via regulation of lipid metabolism, suggesting that therapeutic strategies targeting activated ISC may be an effective treatment for prevention of ISC activation-associated islet dysfunction.
背景
胰岛星状细胞（ISCs）的激活主要与胰岛纤维化有关，这有助于 2 型糖尿病的进展。然而，这一过程的分子机制尚不完全清楚。
方法
为了研究这一过程，本研究检查了高脂肪饮食（HFD）诱导肥胖大鼠的异位脂肪积累。通过腹腔内葡萄糖和胰岛素耐量试验以及免疫组织化学评估脂毒性诱导的 ISC 激活和胰岛功能。使用定量 PCR 和 Western blot 评估用棕榈酸（PA）处理的培养 ISCs 中脂质代谢和 ISC 激活相关标志物的表达。我们还通过慢病毒转导过表达 ISC 中的固醇调节元件结合蛋白 1c（SREBP-1c），并评估其与分离的大鼠胰岛共培养物中胰岛素释放的影响。
结果
HFD 增加了体重和胰腺胰岛的异位脂肪积累。脂毒性导致进行性葡萄糖不耐受和胰岛素抵抗，上调α-平滑肌肌动蛋白，并刺激细胞外基质的分泌。脂毒性降低了用 PA 处理的 ISCs 中与脂质代谢相关的分子的表达，特别是 SREBP-1c。ISCs 中 SREBP-1c 的过表达改善了共培养物中的胰岛活力和胰岛素分泌。
结论
这些结果表明，脂毒性诱导的 ISC 激活通过调节脂质代谢改变胰岛功能，提示靶向激活的 ISC 的治疗策略可能是预防 ISC 激活相关胰岛功能障碍的有效治疗方法。
Zotero 插件