miR-375 enhances palmitate-induced lipoapoptosis in insulin-secreting NIT-1 cells by repressing myotrophin (V1) protein expression.
Lipoapoptosis of pancreatic beta cells caused by elevated circulating free fatty acids (FFAs) has now been recognized to be a pivotal factor contributing to beta cellular dysfunction and beta-mass lose in type 2 diabetes. Although recent studies suggested an important role for the ceramide pathway in the late destructive phase of lipid overload in the pancreatic beta cells, the overall underlying mechanisms leading to lipoapoptosis, however, remained poorly understood. mir-375 was recently characterized to be a pancreatic islet-specific miRNA implicated in the regulation of insulin secretion and beta-mass turnover. In the present study we further examined its effect on palmitate-induced lipoapoptosis in NIT-1 cells, a NOD-derived beta-cell line. It was found that NIT-1 cells with ectopic mir-375 expression were much more susceptible to palmitate-induced lipoapoptosis. In contrast, knockdown of endogenous pri-mir-375 expression by a modified antisense oligo, 2'-O-me-375, almost completely protected NIT-1 cells from palmitate-induced lipoapoptosis. We further demonstrated that mir-375 could target V1 mRNA and repress its translation. Consistent with this assumption, NIT-1 cells transfected with 2'-O-me-375 showed significant higher levels of V1 protein after palmitate induction. Together, our data suggest that mir-375 could be a potential therapeutic target for prevention and intervention of beta-cell dysfunction and beta-mass lose in type 2 diabetes.
Li
Yan
Y
Department of Endocrinology, The Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. liyan19642002@yahoo.cn
Xu
Xuejuan
X
Liang
Ying
Y
Liu
Shanying
S
Xiao
Huisheng
H
Li
Feng
F
Cheng
Hua
H
Fu
Zuzhi
Z
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010168:Palmitates / Q000009:adverse effects*
D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; C540349:Mirn375 microRNA, mouse; D016376:Oligonucleotides, Antisense; D010168:Palmitates; C065700:myotrophin
Lipoapoptosis; NIT-1 cells; mir-375; type 2 diabetes; β-cell dysfunction; β-mass