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

• 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 a-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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

Islet stellate cell

Lipotoxicity

beta cell

Lipid metabolism

SREBP-1c

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