Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways
By J. Yecies, Hui H. Zhang, Suchithra Menon, Sihao Liu, Derek W. Yecies, A. Lipovsky, Cem Z. Gorgun, D. Kwiatkowski, G. Hotamışlıgil, Chih‐Hao Lee and 1 more. Cell Metabolism, 2011
637 citations recorded by the source corpus.
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.
Subfields: Biochemistry, Molecular Biology, Surgery
View Paper: https://www.semanticscholar.org/paper/9ad0cd162a897a219cf5739c64e40e5ae24cd659
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Citations in the corpus
- The PI3K/AKT pathway in obesity and type 2 diabetes (2018, background): “AKT suppresses the expression of INSIG2A, a liver-specific transcript encoding the SREBP-1c inhibitor INSIG2, through an mTORC1-independent pathway [98].”
- Mechanisms of Hepatic Triglyceride Accumulation in Nonalcoholic Fatty Liver Disease (2013, positive): “Within the insulin signaling pathway, the mammalian target of rapamycin complex 1 (mTORC1) and insulin induced gene 2A (INSIG2A) are required for stimulation of lipogenesis [39, 40], but apparently not for inhibition of gluconeogenesis [39], which is regulated by the transcription factor forkhead bo”
- Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis (2020, background): “To investigate if mTORC1 regulates ferroptosis through modulating cellular lipid metabolism, we examined a central regulator of lipid synthesis, SREBP1 (20, 21), which was recently demonstrated as a downstream target of mTORC1 activity (22, 25, 34, 35).”
- Reprogramming of fatty acid metabolism in cancer (2019, background): “124 In terms of cross-inhibition, ERK has been shown to phosphorylate the scaffold protein GRB2associated-binding protein 1 (GAB1), thus compromising the recruitment of PI3K to the plasma membrane and downstream activation of AKT.125 Therefore, in addition to its role in de novo lipogenesis, FASN is”
- mTOR signaling in growth control and disease (2012, positive): “In addition to its role in controlling the hepatic response to fasting, mTORC1 also promotes anabolism in the fed state by controlling hepatic lipogenesis through the regulation of SREBP1c (Li et al., 2010; Yecies et al., 2011).”
- Regulation of mTORC1 and its impact on gene expression at a glance (2013, background): “In addition to promoting expression of SREBPs, mTORC1 induces the processing and the nuclear accumulation of the mature and active form of these transcription factors (Düvel et al., 2010; Owen et al., 2012; Porstmann et al., 2008; Wang et al., 2011; Yecies et al., 2011).”