title: Inhibition of SCD1 impairs palmitate-derived autophagy at the step of autophagosome-lysosome fusion in pancreatic β-cells.
abstract: Autophagy is indispensable for the proper architecture and flawless functioning of pancreatic β-cells. A growing body of evidence indicates reciprocal communication between autophagic pathways, apoptosis, and intracellular lipids. The way in which elevated levels of free saturated or unsaturated FAs contribute to progressive β-cell failure remains incompletely understood. Stearoyl-CoA desaturase (SCD)1, a key regulatory enzyme in biosynthesis of MUFAs, was shown to play an important role in regulation of β-cell function. Here, we investigated whether SCD1 activity is engaged in palmitate-induced pancreatic β-cell autophagy. We found augmented apoptosis and diminished autophagy upon cotreatment of INS-1E cells with palmitate and an SCD1 inhibitor. Furthermore, we found that additional treatment of the cells with monensin, an inhibitor of autophagy at the step of fusion, exacerbates palmitate-induced apoptosis. Accordingly, diminished SCD1 activity affected the accumulation, composition, and saturation status of cellular membrane phospholipids and neutral lipids. Such an effect was accompanied by aberrant endoplasmic reticulum stress, mitochondrial injury, and decreases in insulin secretion and cell proliferation. Our data reveal a novel mechanism by which the inhibition of SCD1 activity affects autophagosome-lysosome fusion because of perturbations in cellular membrane integrity, thus leading to an aberrant stress response and β-cell failure.
authors: Laboratories of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors: Justyna
authors: J
authors: Janikiewicz
authors: Laboratories of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors: Katarzyna
authors: K
authors: Hanzelka
authors: Laboratories of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors: Anna
authors: A
authors: Dziewulska
authors: Laboratories of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors: Kamil
authors: K
authors: Kozinski
authors: Medical Molecular Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors: Pawel
authors: P
authors: Dobrzyn
authors: Functional and Structural Tissue Imaging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors: Tytus
authors: T
authors: Bernas
authors: Laboratories of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors: Agnieszka
authors: A
authors: Dobrzyn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007340:Insulinoma; D008247:Lysosomes / Q000378:metabolism; D008561:Membrane Fusion / Q000187:drug effects; D010168:Palmitates / Q000494:pharmacology*; D019308:Palmitic Acid / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D010168:Palmitates; D010743:Phospholipids; D019308:Palmitic Acid; D013230:Stearoyl-CoA Desaturase; C000594769:stearoyl-CoA desaturase SCD-1, rat
keywords: apoptosis; cardiolipin; diabetes; fatty acid/desaturases; insulin; pancreas; phospholipids