Stearoyl CoA Desaturase 1 and Inositol-Requiring Protein 1α Determine the Efficiency of Oleic Acid in Alleviating Silica Nanoparticle-Induced Insulin Resistance

Despite the widespread use of silica nanoparticles (SiNPs), their metabolic impact and mechanisms of action have not been well studied. Exposure to SiNPs induces insulin resistance (IR) in hepatocytes by endoplasmic reticulum (ER) stress via inositol-requiring protein 1 alpha (IRE1 alpha) activation of c-Jun N-terminal kinases (JNK). It has been well established that stearoyl CoA desaturase (SCD1) and its major product oleic acid elicited beneficial effects in restoring ER homeostasis. However, the potential coordination of SCD1 and IRE1 alpha in determining SiNP regulation of insulin signaling is unclear. Herein, we investigated the effects of SCD1 and oleic acid on IR induced by SiNPs or thapsigargin in hepatocytes. SCD1 overexpression or oleic acid efficiently reversed SiNP-induced ER stress and IR, whereas the effects of thapsigargin treatment could not be restored. Thapsigargin diminished SCD1 protein levels, leading to the accumulation of IRE1 alpha and sustained activation of the IRE1 alpha/JNK pathway. Moreover, knockdown of activating transcription factor 4 (ATF4) upstream of SCD1 suppressed SiNP-induced SCD1 expression, rescued the activated IRE1 alpha, and inhibited insulin signaling but was not able to restore the effects of thapsigargin. Collectively, downregulation of SCD1 and excess accumulation of IRE1 alpha protein prevented the beneficial effects of exogenous oleic acid on IR induced by ER stress. Our results provide valuable mechanistic insights into the synergic regulation of IR by SiNPs and ER stress and suggest a combinational strategy to restore ER homeostasis by targeting SCD1 and IRE1 alpha proteins, as well as supplementation of unsaturated fatty acids.

Automated summary

The study suggests that stearoyl-CoA desaturase 1 (SCD1) and oleic acid can effectively reverse silica nanoparticle (SiNP)-induced endoplasmic reticulum stress and insulin resistance, while the effects of thapsigargin treatment cannot be restored. Moreover, downregulation of SCD1 and excessive accumulation of IRE1 alpha protein prevent the beneficial effects of exogenous oleic acid on insulin resistance induced by endoplasmic reticulum stress.