title: 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.
abstract: 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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Huimin
authors.initials: H
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Liuyi
authors.initials: L
authors.lastname: Hao
authors.affiliation: 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.
authors.forename: Songtao
authors.initials: S
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Song
authors.initials: S
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Lin
authors.initials: L
authors.lastname: Lv
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Hongli
authors.initials: H
authors.lastname: Cui
authors.affiliation: 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.
authors.forename: Tianqi
authors.initials: T
authors.lastname: Zi
authors.affiliation: 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.
authors.forename: Xia
authors.initials: X
authors.lastname: Chu
authors.affiliation: 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.
authors.forename: Lixin
authors.initials: L
authors.lastname: Na
authors.affiliation: 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.|Research Institute of Food, Nutrition and Health, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, People's Republic of China. changhaosun2002@163.com.
authors.forename: Changhao
authors.initials: C
authors.lastname: Sun
mesh_terms: D000818:Animals; D002460:Cell Line; D006949:Hyperlipidemias / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010169:Palmitic Acids / Q000494:pharmacology; D051381:Rats; D013229:Stearic Acids / Q000494:pharmacology*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D035683:MicroRNAs; D010169:Palmitic Acids; D013229:Stearic Acids; D019892:eIF-2 Kinase; C551848:MIRN34a microRNA, mouse; C031183:stearic acid
keywords: Lipotoxicity; MicroRNA; Pancreatic beta cells; Stearic acid