Lipid synthesis
De novo synthesis of fatty acids and cholesterol via SREBP. A growing cell needs membrane as much as it needs protein; both mTOR complexes feed this.
Making fat and membrane. Building new fats and cholesterol from scratch, mainly through a genetic switch called SREBP. A growing cell needs new membranes just as much as new proteins, and both mTOR complexes help fuel this.
mTORC1 acts via SREBP; mTORC2 contributes independently in liver, which is why hepatic Rictor loss and hepatic Raptor loss give different lipid phenotypes.
TL;DR. Lipid synthesis appears in 9 curated studies in Oliver's mTOR Atlas: 3 in animal models; 5 at the molecular level (cells, biochemistry, structure); 1 review. No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| mTORC2 activates Lipid synthesis mechanism: functional-consequence · this link in full · on the map table | mTORC2 also drives fat-making, which is one of the ways it is thought to help tumours grow. The cause-and-effect part was shown in mice; in people with liver cancer, the study only found that more fat-making went together with higher mTORC2 activity. Holds under: The causal part comes from mouse liver: one liver tumour model (GUR2017) that progresses from steatosis to hepatocellular carcinoma, and liver-specific Rictor knockout in otherwise normal mice (HAG2012), where loss of mTORC2 lowered lipogenesis through Akt and SREBP1c. GUR2017 also reports that in human HCC, increased lipogenesis correlated with elevated mTORC2 activity: correlative human data, not a test of this step. Not established as a general mTORC2 function outside liver. plausible in people, not shown directly · emerging, few independent studies | A | GUR2017, HAG2012 |
| SREBP1 / SREBP2 activates Lipid synthesis mechanism: transcriptional · this link in full · on the map table | SREBP is the master switch for making new fat from scratch. Holds under: Mammalian cell studies and a review (POR2008, PET2011, SHI2014). SREBP's role in lipid synthesis rests on cell-based work and does not measure it in people. plausible in people, not shown directly · settled in the literature | M | POR2008, PET2011, SHI2014, DUV2010, KID2013 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 3 |
| M | Molecular — cells, biochemistry, structure | 5 |
| R | Review — secondary literature, not a new result | 1 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | A | Impaired mTOR/SREBP1-Mediated Lipogenesis as a Mechanism of Hepatic Glycogen Accumulation in a Carnivorous Fish Model, Largemouth Bass (Micropterus salmoides) TAO2026 mTOR/SREBP1 signaling governs hepatic glucose partitioning; the insulin-responsive mTOR/SREBP1 axis promotes lipogenesis versus glycogen accumulation. In this model -- a carnivorous fish -- impairment of the axis is associated with hepatic glycogen overload mimicking glucose intolerance. |
| 2017 | A | mTORC2 Promotes Tumorigenesis via Lipid Synthesis GUR2017 mTORC2 promotes tumorigenesis through control of de novo lipid synthesis. |
| 2012 | A | Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c HAG2012 The authors deleted rictor, an essential mTORC2 component, only in mouse liver. In fed knockout mice the liver lost Akt Ser473 phosphorylation and had lower glucokinase and SREBP1c activity, so it kept making glucose (gluconeogenesis) while glycolysis and fat synthesis fell, as if it could not sense that the animal had eaten. The mice became hyperglycaemic and hyperinsulinaemic with low blood lipids. In mTORC2-deficient hepatocytes, constitutively active Akt2 restored both glucose flux and lipogenesis, while extra glucokinase restored glucose flux but not lipogenesis, placing Akt as the main route from hepatic mTORC2 to these outputs. Boundary: Mouse liver with lifelong genetic loss of mTORC2, plus cultured mouse hepatocytes. Not a drug study and not tested in people. Drafted from the abstract only. |
| 2023 | M | Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor NIC2023 Malonyl-CoA, an intermediate of fatty-acid biosynthesis, binds the mTOR catalytic pocket directly and acts as a conserved ATP-competitive inhibitor of mTORC1; when fatty acid synthase is downregulated, rising malonyl-CoA feeds back to dampen mTORC1 activity, linking lipogenic capacity to overall biosynthetic output. |
| 2014 | R | Making new contacts: the mTOR network in metabolism and signalling crosstalk SHI2014 Review of the mTOR network in metabolism and signalling crosstalk. |
| 2013 | M | Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity KID2013 Activating T cells switch on cholesterol and fatty acid synthesis genes within hours, and this paper showed the switch runs through PI3K and mTOR to SREBP: 100 nM rapamycin given 30 minutes before stimulation blocked the induction of the lipogenic programme, prevented processing of full-length SREBP and its accumulation in the nucleus, and reduced SREBP1 and SREBP2 occupancy at lipogenic promoters to background. Deleting Scap in T cells, which removes both SREBP1 and SREBP2 activity, left thymic and peripheral T-cell numbers normal but the cells could not blast: they entered G1 and stalled, failed to raise cholesterol and fatty acids after activation, and increased ECAR and OCR only modestly where controls rose about ten-fold and four-fold. Adding cholesterol conjugated to methyl-beta-cyclodextrin roughly doubled survival at 48 hours (21 to 45 percent) and restored growth, cell-cycle entry and ER expansion, which points to cholesterol as the limiting step. After LCMV-Armstrong infection the Scap-deficient mice had fewer virus-specific CD8 T cells with lower IFN-gamma and TNF, while homeostatic proliferation was unaffected. Boundary: mouse genetics and mouse cells; the mTOR step is shown with rapamycin pretreatment in cultured T cells, and the in vivo arm measures the consequence of losing SREBP activity rather than of inhibiting mTOR. |
| 2011 | M | mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway PET2011 mTORC1 controls lipin-1 nuclear localization to regulate SREBP and lipid synthesis. |
| 2010 | M | Activation of a metabolic gene regulatory network downstream of mTOR complex 1 DUV2010 Used cells with constitutively active mTORC1 (TSC2 loss) and rapamycin to map what mTORC1 switches on besides protein synthesis. Gene expression and metabolite profiling showed that mTORC1 activation is enough to drive glycolysis, the oxidative pentose phosphate pathway and de novo lipid synthesis. This ran through a transcriptional program of HIF1alpha and SREBP1/2 target genes; SREBP1 and 2 were needed for proliferation downstream of mTORC1, and their activation required S6K1. Boundary: cultured cells, mostly mouse fibroblasts with genetic mTORC1 activation; tissue and human relevance not tested here. |
| 2008 | M | SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth POR2008 mTORC1 activates SREBP to drive lipogenesis supporting Akt-dependent cell growth. |
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