Connecting mTORC1 signaling to SREBP-1 activation.
The implication of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) in promoting protein synthesis has been well described. Over the past years, several studies revealed that mTORC1 also plays a crucial role in promoting lipid biosynthesis and that such connection could be linked to diseases including obesity, nonalcoholic fatty liver disease (NAFLD), and cancer. Here, we review the mechanisms by which mTORC1 regulates lipid synthesis by focusing on the key signaling events that trigger hepatic de-novo lipogenesis in response to nutrients and insulin. mTORC1 promotes lipid synthesis by activating the transcription factor sterol regulatory element binding protein 1 (SREBP-1). Recent studies indicate that mTORC1 regulates SREBP-1 activation at multiple levels. Although mTORC1 was originally shown to be necessary and sufficient to activate SREBP-1 in vitro, new studies indicate that hyperactivation of mTORC1 is insufficient to trigger SREBP-1 activation and lipid biogenesis in vivo. These findings reveal that the molecular connection between mTORC1 and SREBP-1 is more complex than originally envisioned. The discovery of a connection between mTORC1 and SREBP-1 opens a new chapter in our understanding of the molecular mechanisms regulating de-novo lipogenesis. A better comprehension of these mechanisms is key for the development of new tools to treat NAFLD and its complications.