{Reference Type}: Journal Article
{Title}: Silencing the FABP3 gene in insulin-secreting cells reduces fatty acid uptake and protects against lipotoxicity.
{Author}: Hyder A;Sheta B;Eissa M;Schrezenmeir J;
{Journal}: Acta Diabetol
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jul 4
{Factor}: 4.087
{DOI}: 10.1007/s00592-024-02325-x
{Abstract}: <B>BACKGROUND: </B>Long-term exposure of pancreatic islets to fatty acids (FAs), common in obesity, metabolic syndrome, and type 2 diabetes, leads to a compensatory hyperactivity followed by inflammation, apoptosis, dysfunctional beta cells, and results in insulin dependence of the patient. Restriction of fatty uptake by islet beta cells may protect them from lipotoxicity.<BR><B>OBJECTIVE: </B>Pancreatic islet beta cells express the fatty acid binding protein 3 (FABP3) to bind FAs and to orchestrate lipid signals. Based on this, we investigated whether downregulation of FABP3, by Fabp3 silencing, might slow lipid metabolism and protect against lipotoxicity in insulin-secreting cells.<BR><B>RESULTS: </B>Neither Fabp3 silencing, nor overexpression affected the glucose-stimulated insulin secretion in absence of FAs. Fabp3 silencing decreased FA-uptake, lipid droplets formation, and the expression of the lipid accumulation-regulating gene Dgat1 in Ins1E cells. It reduced FA-induced inflammation by deactivation of NF-κB, which was associated with upregulation of IκBα and deactivation of the NF-κB p65 nuclear translocation, and the downregulation of the cytokines ILl-6, IL-1β, and TNFα. Ins1E cells were protected from the FA-induced apoptosis as assessed by different parameters including DNA degradation and cleaved caspase-3 immunoblotting. Furthermore, FABP3 silencing improved the viability, Pdx1 gene expression, and the insulin-secreting function in cells long-term cultured with palmitic acid. All results were confirmed by the opposite action rendered by FABP3 overexpression.<BR><B>CONCLUSIONS: </B>The present data reveals that pancreatic beta cells can be protected from lipotoxicity by inhibition of FA-uptake, intracellular utilization and accumulation. FABP3 inhibition, hence, may be a useful pharmaceutical approach in obesity, metabolic syndrome, and type 2 diabetes.