“Islets therapeutic checkpoint: Inhibition of stearoyl‐CoA desaturase impairs lipid droplet morphology and metabolism during palmitotoxicity of pancreatic β‐cells”

Study objective Hyperglycemia, chronic insulin resistance in peripheral tissues and progressive insufficiency of pancreatic β‐cell function constitute main components in pathogenesis of type 2 diabetes (T2D). Obesity‐associated elevated levels of circulating fatty acids (FA) and defects in lipid metabolism regulation trigger pancreatic β‐cell failure. The precise molecular mechanism of saturated and unsaturated FA‐derived β‐cell demise remains rudimentary. Ultimately, stearoyl‐CoA desaturase 1 (SCD1), the rate limiting enzyme catalyzing the biosynthesis of monounsaturated FA is indispensable in protection of β‐cells from lipotoxicity and provide them with substrates for signaling molecules and membrane building blocks. During metabolic overload, lipid droplets (LD) are dedicated to accumulate surplus lipids in pancreatic β‐cells. Therefore, the present study aims to determine whether diminished SCD1 activity affects LD biogenesis, content and disposal, hence leading towards deregulation of β‐cell metabolism and function during lipid oversupply. Methods The experiments were performed in INS‐1E cells, an insulinoma β‐cell line, treated independently or in combination with palmitate (16:0) and SCD1 inhibitor. Also, murine pancreatic islets from the wild type littermates and SCD1 −/− animals were analysed. The biochemical characteristics of LD was assessed by Oil Red O staining and BODIPY 493/503. The FA composition in constituent neutral lipids and phospholipids of LD was evaluated by the GC/MS. Results Accordingly, we demonstrate that inhibition of SCD1 activity diminished the accumulation of triacylglycerols, cholesteryl esters and phosphatidylcholine by over 45% (±0.02), 25% (±0.03) and 40% (±0.09), respectively in comparison to INS‐1E cells treated with palmitate independently. The number of LD/cell was reduced by over 30% (±0.08) within aforementioned experimental group. We observed significant changes in the diameter, compactness, and desaturation status of the LD in SCD1‐ablated and palmitic acid‐treated pancreatic β‐cells. Such an effect was linked to modified expression of adipose triglyceride lipase (ATGL), CTP:phosphocholine cytidylyltransferase (CCTα), lysophosphatidylcholine acyltransferase 2 (LPCAT), phospholipase D (PC‐PLD), acetyl‐CoA acetyltransferase 1 (ACAT1), and perilipins (PLIN). Overall lipidome of the LDs was enriched in 18:2n‐6 and 20:4n‐6 FAs. Pancreatic islets demonstrated to have more unsaturated profile of the PC class which was followed by changes in abundance of the proteins involved in phospholipid synthesis and remodeling. Conclusions Our results point out on the novel mechanism of SCD1‐mediated regulation of metabolic LD remodeling in pancreatic β‐cells, shedding a light on the foundations of lipotoxicity‐mediated β‐cell failure. Support or Funding Information This work was supported by the National Science Centre grants UMO 2015/19/D/NZ4/03705 (JJ) and UMO‐2017/27/N/NZ3/01987 (AMD), and by The National Centre for Research and Development grant STRATEGMED 3/305813/2/NCBR/2017 (AD).