title: Loss of ULK1 increases RPS6KB1-NCOR1 repression of NR1H/LXR-mediated Scd1 transcription and augments lipotoxicity in hepatic cells.
abstract: Lipotoxicity caused by saturated fatty acids (SFAs) induces tissue damage and inflammation in metabolic disorders. SCD1 (stearoyl-coenzyme A desaturase 1) converts SFAs to mono-unsaturated fatty acids (MUFAs) that are incorporated into triglycerides and stored in lipid droplets. SCD1 thus helps protect hepatocytes from lipotoxicity and its reduced expression is associated with increased lipotoxic injury in cultured hepatic cells and mouse models. To further understand the role of SCD1 in lipotoxicity, we examined the regulation of Scd1 in hepatic cells treated with palmitate, and found that NR1H/LXR (nuclear receptor subfamily 1 group H) ligand, GW3965, induced Scd1 expression and lipid droplet formation to improve cell survival. Surprisingly, ULK1/ATG1 (unc-51 like kinase) played a critical role in protecting hepatic cells from SFA-induced lipotoxicity via a novel mechanism that did not involve macroautophagy/autophagy. Specific loss of Ulk1 blocked the induction of Scd1 gene transcription by GW3965, decreased lipid droplet formation, and increased apoptosis in hepatic cells exposed to palmitate. Knockdown of ULK1 increased RPS6KB1 (ribosomal protein S6 kinase, polypeptide 1) signaling that, in turn, induced NCOR1 (nuclear receptor co-repressor 1) nuclear uptake, interaction with NR1H/LXR, and recruitment to the Scd1 promoter. These events abrogated the stimulation of Scd1 gene expression by GW3965, and increased lipotoxicity in hepatic cells. In summary, we have identified a novel autophagy-independent role of ULK1 that regulates NR1H/LXR signaling, Scd1 expression, and intracellular lipid homeostasis in hepatic cells exposed to a lipotoxic environment.
authors.affiliation: a Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School , Singapore.
authors.forename: Rohit Anthony
authors.initials: RA
authors.lastname: Sinha
authors.affiliation: a Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School , Singapore.
authors.forename: Brijesh K
authors.initials: BK
authors.lastname: Singh
authors.affiliation: a Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School , Singapore.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: a Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School , Singapore.
authors.forename: Sherwin
authors.initials: S
authors.lastname: Xie
authors.affiliation: a Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School , Singapore.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Farah
authors.affiliation: a Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School , Singapore.|b Department of Physiology , Universitas Padjadjaran , Bandung , Indonesia.
authors.forename: Ronny
authors.initials: R
authors.lastname: Lesmana
authors.affiliation: a Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School , Singapore.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohba
authors.affiliation: c Stroke Trial Unit, National Neuroscience Institute Singapore , Singapore.
authors.forename: Madhulika
authors.initials: M
authors.lastname: Tripathi
authors.affiliation: a Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School , Singapore.
authors.forename: Sujoy
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: d Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School , Boston , MA USA.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hollenberg
authors.affiliation: a Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School , Singapore.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Yen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D051379:Mice; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; C539127:NCOR1 protein, human; C539128:Ncor1 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1; D034741:RNA, Small Interfering; D019308:Palmitic Acid; C523776:SCD1 protein, human; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D000071189:Autophagy-Related Protein-1 Homolog; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C484754:ULK1 protein, human; C112444:Ulk1 protein, mouse; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1
keywords: LXR; NASH; NCOR1; RPS6KB1; SCD1; ULK1; autophagy; lipid droplets; lipotoxicity