The multifaceted role of mTORC1 in the control of lipid metabolism

Abstract

The mechanistic target of rapamycin is a protein kinase that, as part of the mechanistic target of rapamycin complex 1 (mTORC1), senses both local nutrients and, through insulin signalling, systemic nutrients to control a myriad of cellular processes. Although roles for mTORC1 in promoting protein synthesis and inhibiting autophagy in response to nutrients have been well established, it is emerging as a central regulator of lipid homeostasis. Here, we discuss the growing genetic and pharmacological evidence demonstrating the functional importance of its signalling in controlling mammalian lipid metabolism, including lipid synthesis, oxidation, transport, storage and lipolysis, as well as adipocyte differentiation and function. Defining the role of mTORC1 signalling in these metabolic processes is crucial to understanding the pathophysiology of obesity and its relationship to complex diseases, including diabetes and cancer.

Figure 1

Upstream regulation from the mTORC1 and its downstream functions related to lipid metabolism. The presence of amino acids is required for the activation of mTORC1 by GTP-bound Rheb. Upstream from Rheb, the TSC–TBC complex receives signals about systemic and local nutrient and energy availability, in part through AMPK and Akt. These signals either activate or inhibit the ability of the TSC–TBC complex to act as a GAP for Rheb, thereby inhibiting or activating mTORC1, respectively. Activated mTORC1 leads to enhanced phosphorylation of IRS1, which serves as negative feedback to dampen the insulin response. mTORC1 has many roles in regulating lipid metabolism, including the promotion of lipid synthesis and storage and inhibition of lipid release and consumption, which are detailed in the text. AMPK, adenosine monophosphate-activated protein kinase; GAP, GTPase-activating protein; IRS1, insulin receptor substrate 1; IGF1, insulin-like growth factor 1; mTORC1, mechanistic target of rapamycin complex 1; Raptor, regulatory-associated protein of mTOR; TSC, tuberous sclerosis complex; TBC, Tre-2/Bub2/Cdc16 domain-containing protein.

Figure 2

The complex steps leading to SREBP activation and input from mTORC1 signalling. (A) SREBP processing and activation is regulated by mTORC1 through S6K and lipin 1 leading to the transcriptional induction of the SREBF1 and SREBF2 genes, encoding SREBP1 and SREBP2, respectively, and genes encoding many lipogenic enzymes involved in both fatty acid and sterol synthesis. The mTORC1-mediated transcriptional activation of SREBF1 could result from either autoregulation by SREBP1 or from an unknown parallel pathway downstream from mTORC1. (B) In the presence of sterols, SREBP resides in the endoplasmic reticulum bound to SCAP and the Insig proteins. When sterols become scarce SCAP undergoes a conformational change, which releases the SCAP–SREBP complex from the Insig, allowing its transport from the endoplasmic reticulum to the Golgi apparatus through COPII vesicles. Once in the Golgi, SREBP comes into contact with two site-specific proteases. S1P cleaves the luminal loop of SREBP and S2P cleaves the amino-terminal transmembrane region of SREBP, which releases the N-terminal region of SREBP containing the DNA-binding and -transactivating domains. The NLS-containing processed form of SREBP enters the nucleus to activate transcription of genes containing SREs in their promoters. Finally, the processed form of SREBP is unstable and subject to proteasome-mediated degradation. In some settings, SREBP processing has been found to require S6K1 downstream from mTORC1 and is therefore sensitive to rapamycin. However, the nuclear shuttling of SREBP has been found to require lipin 1 downstream from mTORC1, the phosphorylation of which is largely resistant to rapamycin but sensitive to mTOR kinase domain inhibitors (Sidebar A). The precise molecular mechanisms by which either of these two mTORC1 targets regulates SREBP activation are unknown. COPII, coatamer protein II; Insig, insulin-induced gene; lipin 1, phosphatidate phosphatase LPIN1; mTORC1, mechanistic target of rapamycin complex 1; NLS, nuclear localization signal; S1/2P, site 1/2 protease; S6K1, ribosomal S6 kinase 1; SCAP, SREBP cleavage-activating protein; SRE, sterol response element; SREBP1/2, sterol regulatory element-binding protein 1/2.

Figure 3

mTORC1 signalling has been implicated in promoting the three main steps of adipogenesis. Adipogenesis consists of the differentiation of a mesenchymal stem cell to a mature adipocyte, which makes up a significant part of adipose tissue in which energy is stored as lipids. The commitment of the mesenchymal stem cells to the adipocyte lineage is the first step of adipogenesis and is facilitated by S6K1 activity. C/EBP-β and -δ are the primary drivers of clonal expansion, which is crucial for preadipocyte maturation, and the former has been suggested to be activated by mTORC1 signalling. The terminal differentiation of preadipocytes to mature adipocytes is mediated by PPARγ and C/EBP-α. mTORC1 promotes this final step through both its inhibition of 4E-BP and its activation of PPARγ through a poorly understood mechanism. Although the precise molecular mechanisms have yet to be defined, rapamycin blocks adipogenesis. 4E-BP, eIF4E-binding protein; C/EBP-α/β/δ, CCAAT/enhancer-binding protein-α/β/δ; mTORC1, mechanistic target of rapamycin complex 1; PPARγ, peroxisome proliferator-activated receptor γ; S6K1, ribosomal S6 kinase 1.

Figure 4

The increase in insulin levels after a meal alters hepatic and adipose lipid metabolism, at least in part, through mTORC1 signalling (a working model). In the liver, mTORC1 promotes lipid synthesis through SREBP1c activation. In addition, mTORC1 signalling blocks lipid catabolism by blocking β-oxidation and ketogenesis in the liver. Consequently, mTORC1 activation in the liver promotes the synthesis of TAGs and perhaps cholesterol, which are incorporated into VLDL for transport to peripheral tissues. Evidence suggests that mTORC1 signalling positively influences LPL activity, which promotes lipid delivery to peripheral tissues by hydrolysing VLDL to IDL, which is then converted to LDL. Lipoprotein-bound TAGs are taken up by tissues, including adipocytes, through the LDLR. Both the expression and stability of LDLR, at least in the liver, are probably promoted by mTORC1 activation. In response to insulin, mTORC1 has been suggested to inhibit lipolysis in adipocytes by downregulating ATGL and HSL. Therefore, the systemic effects of postprandial mTORC1 activation are to promote the flux of carbon from glucose towards TAG storage in adipose tissue. See text for details regarding the evidence underlying this model. Ac-COA, acetyl-CoA; ATGL, adipose triglyceride lipase; DAG, diacylglycerol; GLUT4, glucose transporter type 4; HSL, hormone-sensitive lipase; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; LDLR, LDL receptor; LPL, lipoprotein lipase; mTORC1, mechanistic target of rapamycin complex 1; SREBP1c, sterol regulatory element-binding protein 1c; TAG, triacylglycerol; VLDL, very low density lipoprotein.