Understanding the role of LIPA mediated lipophagy in pancreatic beta cells.

Human beta cells also showed an increase in area and/or number or neutral lipid depots per cell (p<0.05 by student’s t test). In addition, triglycerides (TG) content was increased in both models of LIPA suppressed cells compared to controls (p<0.05). LIPA downregulation (siRNA) did not change cholesterol and cholesteryl esters’ contents in INS-1 cells.

These results confirm that LIPA mediated lipophagy is crucial for primarily for triglycerides turn over in beta cells. Furthermore, siLIPA INS-1 cells showed a decrease in peri-nuclear lysosome compared to control (distance from nucleus <5 microns, p<0.05 by student’s t test) and an increase in peripheral lysosome (distance from nucleus 15-20 microns, p<0.05 by student’s t test) indicating LIPA activity regulates lysosome distribution within cells.

Chronic (48 hrs) suppression or downregulation of LIPA led to a significant reduction in glucose-stimulated insulin secretion (GSIS) in both INS-1 cells and human islets (p<0.05). Our findings highlight the important role of LIPA in maintaining beta cell functionality. Considering that the mitochondria is essential for insulin secretion, we assessed the parameters of mitochondrial health in siLIPA/Lali2 INS-1 cells compared to control.

Interestingly, we observed a decrease in mitochondrial content and oxidative respiration along with an increase in mitochondrial fragmentation, indicating that mitochondrial health and function are impaired in siLIPA INS-1 cells. Collectively, we show that LIPA activity contributes to triglycerides metabolism in beta cells and is sensitive to aging and GLT stress. The reduction of LIPA activity negatively affects insulin secretion and mitochondria health by which it might impair insulin secretion.

Pancreatic beta cells are central to insulin secretion and glucose homeostasis, and their dysfunction underlies the pathogenesis of diabetes. Lysosomal Acid Lipase (LIPA) mediates breakdown of neutral lipids within lysosomes, yet its specific function in islet biology remains poorly understood. In this study we investigated the role of LIPA in INS-1 rat insulinoma cells and human beta cells.

We observed a negative correlation of LIPA activity with age in human beta cells (r=-0.64, p<0.05). Additionally, LIPA activity in INS-1 cells decreased after 72 hrs of glucolipotoxic (GLT) media conditions in INS-1 suggesting that LIPA activity is sensitive to aging and chronic nutrient load in human islets and rat beta cells respectively. LIPA inhibition (Lalistat2)/downregulation(siRNA/ShRNA) showed increase in size and number of neutral lipid depot in INS-1 cells (p<0.05 by student’s t test).

Human beta cells also showed an increase in area and/or number or neutral lipid depots per cell (p<0.05 by student’s t test). In addition, triglycerides (TG) content was increased in both models of LIPA suppressed cells compared to controls (p<0.05). LIPA downregulation (siRNA) did not change cholesterol and cholesteryl esters’ contents in INS-1 cells.

These results confirm that LIPA mediated lipophagy is crucial for primarily for triglycerides turn over in beta cells. Furthermore, siLIPA INS-1 cells showed a decrease in peri-nuclear lysosome compared to control (distance from nucleus <5 microns, p<0.05 by student’s t test) and an increase in peripheral lysosome (distance from nucleus 15-20 microns, p<0.05 by student’s t test) indicating LIPA activity regulates lysosome distribution within cells.

Chronic (48 hrs) suppression or downregulation of LIPA led to a significant reduction in glucose-stimulated insulin secretion (GSIS) in both INS-1 cells and human islets (p<0.05). Our findings highlight the important role of LIPA in maintaining beta cell functionality. Considering that the mitochondria is essential for insulin secretion, we assessed the parameters of mitochondrial health in siLIPA/Lali2 INS-1 cells compared to control.

Interestingly, we observed a decrease in mitochondrial content and oxidative respiration along with an increase in mitochondrial fragmentation, indicating that mitochondrial health and function are impaired in siLIPA INS-1 cells. Collectively, we show that LIPA activity contributes to triglycerides metabolism in beta cells and is sensitive to aging and GLT stress. The reduction of LIPA activity negatively affects insulin secretion and mitochondria health by which it might impair insulin secretion.