Figure 3.

Akt mTOR signaling Pathway in Lipid Synthesis. The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling regulate lipid metabolism. The most often dysregulated mechanism in cancer is PI3K signaling, which promotes growth, proliferation, and survival. When receptor tyrosine kinases are activated, PI3K is recruited to the plasma membrane and phosphorylates Phosphatidylinositol 4,5-bisphosphate (PIP2) to Phosphatidylinositol (3,4,5)-trisphosphate (PIP3). AKT binds to PIP3, allowing PDK1 and mTORC2 to activate. AKT stimulates lipogenesis directly by inhibiting Glycogen synthase kinase 3, activating ATP citrate lyase to make acetyl-CoA, and phosphorylating NADK to produce NADP+ for NADPH production. PI3K signaling is also intertwined with mTORC1 and mTORC2. mTORC1 controls lipogenesis by inhibiting lipin-1, a negative regulator of nuclear Sterol regulatory element-binding protein-1c, and activating the splicing factor Serine/threonine-protein kinase (SRPK2), boosting the production of lipogenic enzymes such as ATP citrate lyase (ACLY), Fatty acid synthase (FASN), and acetyl-CoA synthetase 2 (ACSS2). Finally, mTORC2 activation promotes lipogenesis via AKT-dependent and independent processes, with the latter involving phosphorylation of serum- and glucocorticoid-regulated kinase (SGK1) and Protein kinase C (PKCs), followed by sterol regulatory element binding protein-1c (SREBP1c) activation.