Lu Huimin, Hao Liuyi, Li Songtao, Lin Song, Lv Lin, Chen Yang, Cui Hongli, Zi Tianqi, Chu Xia, Na Lixin, Sun Changhao
Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, People's Republic of China.
Research Institute of Food, Nutrition and Health, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, People's Republic of China.
Diabetologia. 2016 Jun;59(6):1247-57. doi: 10.1007/s00125-016-3900-0. Epub 2016 Mar 11.
AIMS/HYPOTHESIS: Serum stearic acid (C18:0) is elevated in individuals with hyperlipidaemia and type 2 diabetes. However, the lipotoxicity induced by increased stearic acid in beta cells has not been well described. This study aimed to examine the adverse effects of stearic acid on beta cells and the potential mechanisms through which these are mediated.
Three groups of C57BL/6 mice were fed a normal diet or a high-stearic-acid/high-palmitic-acid diet for 24 weeks, respectively. The microRNA (miR) profiles of islets were determined by microarray screening. Islet injury was detected with co-staining using the TUNEL assay and insulin labelling. A lentiviral vector expressing anti-miRNA-34a-5p oligonucleotide (AMO-34a-5p) was injected into mice via an intraductal pancreatic route.
In both mouse islets and cultured rat insulinoma INS-1 cells, stearic acid exhibited a stronger lipotoxic role than other fatty acids, owing to repression of B cell CLL/lymphoma 2 (BCL-2) and BCL-2-like 2 (BCL-W) by stearic acid stimulation of miR-34a-5p. The stearic-acid-induced lipotoxicity and reduction in insulin secretion were alleviated by AMO-34a-5p. Further investigations in INS-1 cells revealed that p53 was involved in stearic-acid-induced elevation of miR-34a-5p, owing in part to activation of protein kinase-like endoplasmic reticulum kinase (PERK). Conversely, silencing PERK alleviated stearic-acid-induced p53, miR-34a-5p and lipotoxicity.
CONCLUSIONS/INTERPRETATION: These findings provide new insight for understanding the molecular mechanisms underlying not only the deleterious impact of stearic-acid-induced lipotoxicity but also apoptosis in beta cells and progression to type 2 diabetes.
目的/假设：高脂血症和2型糖尿病患者的血清硬脂酸（C18:0）水平升高。然而，硬脂酸增加对β细胞诱导的脂毒性尚未得到充分描述。本研究旨在探讨硬脂酸对β细胞的不良影响及其潜在的介导机制。
将三组C57BL/6小鼠分别喂食正常饮食或高硬脂酸/高棕榈酸饮食24周。通过微阵列筛选确定胰岛的微小RNA（miR）谱。使用TUNEL测定法和胰岛素标记进行共染色检测胰岛损伤。通过胰管内途径将表达抗miRNA-34a-5p寡核苷酸（AMO-34a-5p）的慢病毒载体注入小鼠体内。
在小鼠胰岛和培养的大鼠胰岛素瘤INS-1细胞中，硬脂酸比其他脂肪酸表现出更强的脂毒性作用，这是由于硬脂酸刺激miR-34a-5p抑制了B细胞淋巴瘤/白血病-2（BCL-2）和BCL-2样蛋白2（BCL-W）。AMO-34a-5p减轻了硬脂酸诱导的脂毒性和胰岛素分泌减少。对INS-1细胞的进一步研究表明，p53参与了硬脂酸诱导的miR-34a-5p升高，部分原因是蛋白激酶样内质网激酶（PERK）的激活。相反，沉默PERK减轻了硬脂酸诱导的p53、miR-34a-5p和脂毒性。
结论/解读：这些发现为理解硬脂酸诱导的脂毒性的有害影响、β细胞凋亡以及2型糖尿病进展的分子机制提供了新的见解。
