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Diabetologia. 2016 Jun;59(6):1247-57. doi: 10.1007/s00125-016-3900-0. Epub 2016 Mar 11.

Elevated circulating stearic acid leads to a major lipotoxic effect on mouse pancreatic beta cells in hyperlipidaemia via a miR-34a-5p-mediated PERK/p53-dependent pathway.

Lu H1, Hao L1, Li S1, Lin S1, Lv L1, Chen Y1, Cui H1, Zi T1, Chu X1, Na L2, Sun C3,4.

Author information

1
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.
2
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. nalixin2003@163.com.
3
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. changhaosun2002@163.com.
4
Research Institute of Food, Nutrition and Health, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, People's Republic of China. changhaosun2002@163.com.

Abstract

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.

METHODS:

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.

RESULTS:

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.

KEYWORDS:

Lipotoxicity; MicroRNA; Pancreatic beta cells; Stearic acid

PMID:
26969487
DOI:
10.1007/s00125-016-3900-0
[Indexed for MEDLINE]

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