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

Abstract

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.

Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance

“…The increased mTORC1 activity in Grb14i mice can therefore be also driven by p62 in addition to insulin receptor stimulation, contributing to the positive feedback loop. After a nutritional challenge, insulin-dependent de novo fatty acid synthesis and liver lipid accumulation are mediated by the activation of SREBP-1c in an mTORC1-dependent manner (51,52). The observation that p62 is not phosphorylated by mTORC1 in liver of refed control mice is thus consistent with the activation of the lipogenic pathway in this situation.…”

Myelination and mTOR

“…Such mechanisms have been shown to be responsible for similar paradoxical findings upon disruption of the TSC complex in other cell types by affecting mTORC1‐independent targets of these pathways (Byles et al, 2013; Tang et al, 2014; Yecies et al, 2011) (Figure 4). Indeed, similar to other cell types, hyperactivation of mTORC1 after deletion of TSC1 or TSC2 suppressed Akt activity in both SCs and OLs (Beirowski et al, 2017; Figlia et al, 2017; Lebrun‐Julien et al, 2014).…”

mTORC1 signaling activates NRF1 to increase cellular proteasome levels

“…[9][10][11]35 The result is a measureable increase in rates of lipid synthesis within 6 hours of mTORC1 activation; for instance, as observed in primary hepatocytes stimulated with insulin. 34 As described above, the activation of SREBP also leads to the transcriptional activation of NRF1, resulting in a substantial increase in its abundance in cells and tissue by 6 hours.…”

“…33 It has become clear that the SREBPs are a major transcriptional effector of mTORC1 signaling in multiple cellular settings. [9][10][11]34,35 Lipids serve as a major source of stored energy that can be mobilized quickly, and growing cells have an increased demand for lipids for the production of new membranes. mTORC1 plays a central role in the control of cell growth, and evidence indicate that the activation of SREBPdependent lipid synthesis is one essential downstream factor in its promotion of growth.…”