Critical role of SCD1 in autophagy regulation via lipogenesis and lipid rafts-coupled AKT-FOXO1 signaling pathway

SCD1 (stearoyl-coenzyme A desaturase 1) is an endoplasmic reticulum-bound enzyme that catalyzes the formation of the first double bond at the cis-Δ9 position of saturated fatty acids (SFA) to form monounsaturated fatty acids (MUFA). Increasing evidence indicates that autophagy plays an important role in regulating lipid metabolism, while little is known about whether key enzymes of lipogenesis like SCD1 can regulate autophagy. In this study, we examined the role of SCD1 in autophagy using the <i>tsc2^−/−</i> mouse embryonic fibroblasts (MEFs) possessing constitutively active MTORC1 as a cellular model. We found that mRNA and protein levels of SCD1 are significantly elevated in the <i>tsc2^−/−</i> MEFs compared with <i>Tsc2^+/+</i> MEFs, resulting in significant increases in levels of various lipid classes. Furthermore, inhibition of SCD1 activity by either a chemical inhibitor or genetic knockdown resulted in an increase of autophagic flux only in the <i>tsc2^−/−</i> MEFs. Induction of autophagy was independent of MTOR as MTORC1 activity was not suppressed by SCD1 inhibition. Loss of phosphorylation on AKT Ser473 was observed upon SCD1 inhibition and such AKT inactivation was due to disruption of lipid raft formation, without affecting the formation and activity of MTORC2. Increased nuclear translocation of FOXO1 was observed following AKT inactivation, leading to increased transcription of genes involved in the autophagic process. The <i>tsc2^−/−</i> MEFs were also more susceptible to apoptosis induced by SCD1 inhibition and blockage of autophagy sensitized the cell death response. These results revealed a novel function of SCD1 on regulation of autophagy via lipogenesis and the lipid rafts-AKT-FOXO1 pathway.