title: Critical role of SCD1 in autophagy regulation via lipogenesis and lipid rafts-coupled AKT-FOXO1 signaling pathway.
abstract: 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 tsc2(-/-) 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 tsc2(-/-) MEFs compared with Tsc2(+/+) 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 tsc2(-/-) 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 tsc2(-/-) 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.
authors.affiliation: Department of Physiology; Yong Loo Lin School of Medicine; National University of Singapore; Singapore; NUS Graduate School for Integrative Sciences and Engineering; National University of Singapore; Singapore.
authors.forename: Shi-Hao
authors.initials: SH
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Molecular Developmental Biology; Institute of Genetics and Developmental Biology; Chinese Academy of Sciences; Beijing, China.
authors.forename: Guanghou
authors.initials: G
authors.lastname: Shui
authors.affiliation: Department of Physiology; Yong Loo Lin School of Medicine; National University of Singapore; Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Physiology; Yong Loo Lin School of Medicine; National University of Singapore; Singapore.
authors.forename: Yin
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pathology; National University Hospital of Singapore; Singapore.
authors.forename: Jingxiang
authors.initials: J
authors.lastname: Huang
authors.affiliation: Zhejiang University School of Public Health; Hangzhou, Zhejiang, China.
authors.forename: Dajing
authors.initials: D
authors.lastname: Xia
authors.affiliation: NUS Graduate School for Integrative Sciences and Engineering; National University of Singapore; Singapore; Department of Biochemistry; Yong Loo Lin School of Medicine; National University of Singapore; Singapore.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.affiliation: Department of Physiology; Yong Loo Lin School of Medicine; National University of Singapore; Singapore; NUS Graduate School for Integrative Sciences and Engineering; National University of Singapore; Singapore.
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D050155:Lipogenesis / Q000235:genetics / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000214:Acyl Coenzyme A; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D046912:Multiprotein Complexes; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C017725:stearoyl-coenzyme A; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: AKT; FOXO1; SCD1; TSC2; autophagy; lipid rafts; lipogenesis