Lipotoxicity reduces β cell survival through islet stellate cell activation regulated by lipid metabolism-related molecules

TY - JOUR

T1 - Lipotoxicity reduces β cell survival through islet stellate cell activation regulated by lipid metabolism-related molecules

AU - Zhou, Yunting

AU - Li, Wei

AU - Zhou, Junming

AU - Chen, Juan

AU - Wang, Xiaohang

AU - Cai, Min

AU - Li, Fengfei

AU - Xu, Wei

AU - Carlsson, Per Ola

AU - Sun, Zilin

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

KW - Islet stellate cell

KW - Lipid metabolism

KW - Lipotoxicity

KW - SREBP-1c

KW - β cell

UR - http://www.scopus.com/inward/record.url?scp=85064326431&partnerID=8YFLogxK

U2 - 10.1016/j.yexcr.2019.04.012

DO - 10.1016/j.yexcr.2019.04.012

M3 - Article

C2 - 30998947

AN - SCOPUS:85064326431

SN - 0014-4827

VL - 380

SP - 1

EP - 8

JO - Experimental Cell Research

JF - Experimental Cell Research

IS - 1

ER -