Fig. 1.

Regulation of lipid metabolism in cancer cells. In cancer cells, glucose uptake and glycolysis are markedly up-regulated by RTKs via the PI3K/Akt/mTOR signaling pathway, generating large amounts of pyruvate. Pyruvate is converted to lactate and it also enters the mitochondria, where it forms citrate, which is transported by SLC25A1 from the mitochondria into the cytoplasm, where the citrate serves as a precursor for de novo synthesis of fatty acids and cholesterol. Glutamine can also enter into mitochondria and participate in energy production and lipid synthesis. Acetate is converted to acetyl-CoA by the ACSS2 enzyme, serving as another source of lipid synthesis. Glucose participates in the HBP to form glycans that will be added to proteins during glycosylation. Oncogenic EGFR signaling increases N-glycosylation of SCAP, which activates SREBP-1 and -2 [55, 58], which ultimately up-regulate expression of enzymes in lipogenesis pathways and expression of LDLR. The enzyme up-regulation promotes fatty acid and cholesterol synthesis, while the LDLR up-regulation increases cholesterol uptake [40]. The microRNA miRNA-29 regulates the SCAP/SREBP pathway via a novel negative feedback loop [101]. The transporter CD36 brings fatty acids into cancer cells. When cellular fatty acids and cholesterol are in excess, they can be converted to TG and CE by the enzymes DGAT1/2 and SOAT1/ACAT1, forming LDs. When present in excess, cholesterol can be converted to 22- or 27-hydroxycholesterol, which activate LXR to up-regulate ABCA1 expression, promoting cholesterol efflux. ABCA1 ATP-binding cassette transporters A, ACC acetyl-CoA carboxylase, ACLY ATP citrate lyase, ACSS2 acetyl-CoA synthetase 2, DGAT1/2 diacylglycerol O-acyltransferase 1/2, FAs fatty acids, FASN fatty acid synthase, HBP hexosamine biosynthesis pathway, HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase, HMGCS 3-hydroxy-3-methylglutaryl-CoA synthase, LD lipid droplet, LDLR low-density lipoprotein receptor, LXR liver X receptor, RTKs oncogenic tyrosine kinase receptors, SCAP SREBP cleavage-activating protein, SCD1 stearoyl-CoA desaturase 1, SLC25A1 solute carrier family 25 member 1, SOAT1 (also known as ACAT1) sterol O-acyltransferase, SREBPs sterol regulatory element-binding proteins, TG/CE triglycerides/cholesteryl esters