Akt Stimulates Hepatic SREBP1c and Lipogenesis through Parallel mTORC1-Dependent and Independent Pathways

• Published in: Cell metabolism Vol. 14; no. 1; pp. 21 - 32
• Main Authors: Yecies, Jessica L., Zhang, Hui H., Menon, Suchithra, Liu, Sihao, Yecies, Derek, Lipovsky, Alex I., Gorgun, Cem, Kwiatkowski, David J., Hotamisligil, Gökhan S., Lee, Chih-Hao, Manning, Brendan D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.07.2011
• Subjects: Animals; Cells, Cultured; fatty liver; Hepatocytes - metabolism; insulin; Insulin - metabolism; insulin resistance; Lipogenesis; liver; Male; Mechanistic Target of Rapamycin Complex 1; Membrane Proteins - metabolism; Mice; Mice, Knockout; Multiprotein Complexes; phenotype; Proteins - metabolism; Proteins - physiology; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Sterol Regulatory Element Binding Protein 1 - antagonists & inhibitors; Sterol Regulatory Element Binding Protein 1 - metabolism; TOR Serine-Threonine Kinases; transcription factors; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2011.06.002

Through unknown mechanisms, insulin activates the sterol regulatory element-binding protein (SREBP1c) transcription factor to promote hepatic lipogenesis. We find that this induction is dependent on the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). To further define the role of mTORC1 in the regulation of SREBP1c in the liver, we generated mice with liver-specific deletion of TSC1 (LTsc1KO), which results in insulin-independent activation of mTORC1. Surprisingly, the LTsc1KO mice are protected from age- and diet-induced hepatic steatosis and display hepatocyte-intrinsic defects in SREBP1c activation and de novo lipogenesis. These phenotypes result from attenuation of Akt signaling driven by mTORC1-dependent insulin resistance. Therefore, mTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2. [Display omitted] ► mTORC1 is required for proper activation of hepatic SREBP1c by insulin ► LTsc1KO mice reveal that mTORC1 activation is not sufficient to induce hepatic SREBP1c ► An mTORC1-independent pathway is also required for hepatic SREBP1c induction by Akt ► Akt signaling suppresses Insig2a, a liver-specific inhibitor of SREBP1c