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Review
. 2009 Dec 1;19(22):R1046-52.
doi: 10.1016/j.cub.2009.09.058.

An emerging role of mTOR in lipid biosynthesis

Mathieu Laplante  1 , David M Sabatini
Affiliations
Review

An emerging role of mTOR in lipid biosynthesis

Mathieu Laplante et al. Curr Biol. .

Abstract

Lipid biosynthesis is essential for the maintenance of cellular homeostasis. The lipids produced by cells (glycerolipids, fatty acids, phospholipids, cholesterol, and sphingolipids) are used as an energy source/reserve, as building blocks for membrane biosynthesis, as precursor molecules for the synthesis of various cellular products, and as signaling molecules. Defects in lipid synthesis or processing contribute to the development of many diseases, including obesity, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, and cancer. Studies published over the last few years have shown that the target of rapamycin (TOR), a conserved serine/threonine kinase with an important role in regulating cell growth, controls lipid biosynthesis through various mechanisms. Here, we review these findings and briefly discuss their potential relevance for human health and disease.

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Figures

Figure 1
Figure 1. Overview of the mTOR signaling pathway
The mTOR kinase nucleates two characterized protein complexes termed mTORC1 and mTORC2. mTORC1 is composed of 5 subunits : (i) the mTOR catalytic subunit, (ii) Raptor, (iii) mLST8, (iv) PRAS40, and (v) Deptor. The mTORC2 complex contains 6 proteins (i) mTOR, (ii) Rictor, (iii) mSin1, (iv) Protor-1, (v) mLST8, and (vi) Deptor. mTORC1 is sensitive to nutrients and is inhibited by FKBP12-rapamycin. One of the most important sensors involved in the regulation of mTORC1 activity is TSC, which is a heterodimer composed of TSC1 and TSC2. TSC1/2 functions as a GTPase GAP for the small, Ras-related GTPase, Rheb. The active, GTP-bound form of Rheb directly interacts with mTORC1 to stimulate its activity. As a Rheb-specific GAP, TSC1/2 negatively regulates mTORC1 signaling by converting Rheb into its inactive GDP-bound state. Stimulation of cells with growth factors activates Akt, Erk, and Rsk, which inactivates TSC and promotes Rheb activation. Akt activation also promotes mTORC1 activity by phosphorylating PRAS40, a negative regulator of mTORC1. At the opposite, induction of Redd1 and AMPK by hypoxia and energy deficit activates TSC1/2 and turn down mTORC1 signaling. The activation of mTORC1 by amino acids is regulated by the Rag GTPase and is independent of TSC1/2. Activation of mTORC1 by growth factors or amino acids promotes protein synthesis via the phosphorylation of S6K1 and 4EBPs. High activation of S6K1 by mTORC1 induces a feedback inhibition loop in which S6K1 reduces growth factor signaling by promoting the phosphorylation and the degradation of IRS-1. mTORC2 is activated by growth factors and regulates many AGC kinases (Akt, SGK1, PKC-α) playing key roles in controlling cell survival, metabolism and cytoskeletal organization. This complex is insensitive to FKBP12-rapamycin but is inhibited by the newly characterized mTOR inhibitor Torin1. Akt, protein kinase B; AMPK, AMP-activated protein kinase; Deptor, DEP domain containing protein associated with mTOR; Erk, extracellular signal-regulated kinase; FKBP12, intracellular receptor for rapamycin; GAP, GTPase activating protein; IRS-1, insulin receptor substrate-1; mLST8, mammalian lethal with Sec13 protein 8; mSIN1, mammalian stress-activated protein kinase interacting protein PKC-α, protein kinase C-α; PRAS40, proline-rich Akt substrate 40kDa; Protor1, protein observed with rictor-1; Raptor, regulatory-associated protein of mTOR; Redd1, transcriptional regulation of DNA damage response-1; Rheb, Ras homolog enriched in brain; Rictor, rapamycin insensitive companion of mTOR; Rsk, ribosomal S6 kinase; SGK1, serum- and glucocorticoid-induced protein kinase 1; S6K1, p70 ribosomal S6 kinase 1; TSC1/2, tuberous sclerosis complex 1 and 2; 4EBPs, eukaryotic initiation factor 4E-binding proteins.
Figure 2
Figure 2. mTORC1 promotes de novo lipogenesis through the activation of SREBP-1
The activation of mTORC1 in response to growth factors induces many anabolic processes that favors cell growth and proliferation. In addition of promoting protein synthesis through the phosphorylation of S6K1 and 4EBPs, mTORC1 controls de novo lipid synthesis by regulating the activation state of SREBP-1. In details, growth factors activate Akt, Erk and Rsk, which induce TSC1/2 phosphorylation and lead to mTORC1 activation. Akt also directly promotes mTORC1 action through the phosphorylation of PRAS40. When activated, mTORC1 favors the cleavage of SREBP-1 by a mechanism that remains to be established. The cleaved form of SREBP-1 then translocates to the nucleus where it induces the expression of many lipogenic genes including ACC, ACLY, FASN, GPAT, GK and SCD1. Mutations in tumor suppressors or oncogenes that lead to the overactivation of Ras and insulin signaling pathways are commonly observed in cancer and are thought to promote cell growth and proliferation by inducing many anabolic processes including lipid biosynthesis. The induction of lipogenesis through the activation of SREBP-1 promotes cancer progression by providing the lipids required for membrane synthesis. The fact that mTORC1 promotes SREBP-1 activation indicates that this protein complex may play a central role in cancer cell growth/proliferation by relaying growth factor signals to lipid synthesis. ACC, acetyl-CoA carbolxylase; ACLY, acyl-CoA lyase; FASN, fatty acid synthase; ER, endoplasmic reticulum; SCD-1, stearoyl-CoA desaturase-1; GPAT, glycerol-3-phosphate acyltransferase; GK, glucokinase; GLUT4, glucose transporter 4; Grb2, growth factor receptor bound protein 2; NF-1, neurofibromatosis type 1; PDK1, phosphoinositide-dependent kinase 1; PTEN, phosphatase and tensin homologue deleted on chromosome 10; SOS, son of sevenless; nSREBP-1, nuclear form of sterol regulatory element-binding protein-1; TCA cycle, tricarboxilic acid cycle.
Figure 3
Figure 3. mTORC1 promotes adipogenesis and adipocyte maintenance through various mechanisms
Many evidences indicates that mTORC1 controls adipogenesis by activating PPAR-γ, a nuclear receptor controlling the expression of numerous genes involved in fatty acid uptake, synthesis, esterification, and storage. Many mechanisms are though to be involved in the regulation of PPAR-γ by mTORC1. Activation of mTORC1 induces the phosphorylation of 4E-BPs, which in turn releases eIF4E and increases the translation of C/EBP-α and -δ, which are key components required for the establishment of the adipogenic cascade. C/EBP-δ is known to drive the expression of C/EBP-α and PPAR-γ and to trigger the activation of a feed-forward loop in which these two transcription factors reciprocally induce their expression. When sufficient levels of PPAR-γ proteins are produced, this transcription factor promotes adipogenesis and lipid synthesis by inducing the expression of many lipogenic genes. SREBP-1 cleavage by mTORC1 may also contribute to the induction of adipognesis by directly favoring triglyceride synthesis and by promoting the production of endogenous ligands for PPAR-γ. More work is required to determine if SREBP-1-dependent production of PPAR-γ ligands plays a significant role in the activation of PPAR-γ by mTORC1. Lipin1, a phosphatidic acid phosphatase, was shown to play key role in adipogenesis by promoting triglyceride synthesis and by serving as a coactivator for PPAR-γ. Lipin1 is phosphorylated in response to insulin and amino acids in a rapamycin-sensitive fashion. Because rapamycin can inhibit mTORC2 activity in some cell types, it is unclear if lipin1 is a direct substrate of mTORC1 or mTORC2. The biological meaning of mTOR-mediated lipin1 phosphorylation remains to be characterized.
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