S-9-PAHSA regulates glycolipid metabolism by enhancing autophagy and upregulating PI3K/AKT pathway

Abstract The disorders of glucolipid metabolism are prevalent in patients with type 2 diabetes mellitus (T2DM). Since the effects of Palmitic-Acid-Hydroxy-Stearic Acid (PAHSA) on T2DM were not fully understood, the study aimed to investigate the role of S-9- PAHSA in diabetes and the possible mechanisms. Male C57BL6 mice were fed with a high-fat diet (HFD) and injected with streptozotocin (STZ) to establish the diabetic mice model, and then administered with low- or high-dose S-9-PAHSA. Insulin, glycosylated serum protein (GSP), glucagon-like peptide-1 (GLP-1), and oxidized lowdensity lipoprotein (ox-LDL) were assessed by ELISA. SH-SY 5Y cells were incubated in a diabetic environment and treated with S-9-PAHSA, R-9-PAHSA, or 9-PAHSA. Cell viability, cell proliferation, apoptosis, lactate dehydrogenase (LDH), and reactive oxygen species (ROS) were measured by corresponding kits. Protein expressions were determined by western blot. The results showed high-does S-9-PAHSA improved insulin resistance and lowered ox-LDL. Compared with the control group, the significantly up-regulated expression of p62 and down-regulated expression of beclin 1 were found in diabetic mice and could be reversed by S-9-PAHSA. In vitro, S-9- PAHSA increased cell viability and proliferation while reducing LDH and ROS. S-9- PAHSA could reduce the expression of cleaved caspase-3 and TUNEL-positive cells, and increase the ratio of LC3II/I after high glucose and fatty acid stimulation in vitro. Downward trends were observed in PI3K and the phosphorylation of AKT in diabetic environments, which could be slightly restored by S-9-PAHSA. In conclusion, S-9- PAHSA could regulate glycolipid metabolism both in vivo and in vitro, indicating the vital role of S-9-PAHSA in T2DM.