Annexin A1 exacerbates islet stellate cell activation by regulating triglyceride catabolism via the PPARα/ACOX1/CYP4a pathway.

BACKGROUND: Activation of islet stellate cells (ISCs) contributes to islet fibrosis and diabetes progression through excessive extracellular matrix secretion and lipid loss. Annexin A1 (ANXA1) has been reported to modulate lipid metabolism in other tissues, but its role in ISCs remains unclear. METHODS: ISCs were isolated from 9-and 28-week-old db/m and db/db mice. Lipid content analysis, qRT‒PCR, and Western blotting were used to assess lipid metabolism-related molecules. ANXA1 expression was analyzed by immunohistochemistry and Western blotting. Recombinant ANXA1 was co-cultured with db/db ISCs to evaluate lipid synthesis and lipolysis. The interaction between ANXA1 and peroxisome proliferator-activated receptor alpha (PPARα) was examined by immunoprecipitation. RESULTS: Activation of ISCs markedly reduced intracellular triglycerides, with decreased Diacylglycerol Acyltransferase 1/2 (DGAT1/2) and increased adipose triglyceride lipase (ATGL) and hormone-sensitive triglyceride lipase (HSL) expression. ANXA1 was detected in islets, MIN6 cells, and their culture supernatants. Recombinant ANXA1 treatment lowered triglyceride levels and upregulated PPARα and its downstream genes, acyl-CoA oxidase 1 (ACOX1) and cytochrome P450 4 A (CYP4A); these effects were enhanced by a PPARα agonist but reversed by inhibition. Immunofluorescence and coimmunoprecipitation confirmed that PPARα acts as a key mediator of ANXA1-regulated triglyceride metabolism in ISCs. CONCLUSION: ANXA1 promotes ISCs activation by enhancing triglyceride catabolism through the PPARα signaling pathway, suggesting a novel therapeutic target for islet fibrosis.