Figure 2.

Transcriptional factors and oncogenic signaling pathways in lipid metabolism of cancer. Sterol regulatory element‐binding proteins (SREBPs) act as transcriptional factors that control the expression of most lipogenic enzymes involved in cholesterol and fatty acid biosynthesis. When lipid levels decrease, SREBPs are released from the SCAP‐INSIG complex in the endoplasmic reticulum and translocate to the Golgi, where they are cleaved by site‐1 and site‐2 proteases to release their active N terminus (mature SREBPs). Mature SREBPs move into the nucleus and bind to sterol response elements (SRE) in downstream target gene promoters to initiate transcription. The PI3K‐AKT‐mTOR pathway is frequently dysregulated in human cancers and can be activated by growth factor receptor tyrosine kinases (RTKs). The mTOR complexes participate in lipogenesis regulation through SREBP‐dependent or independent mechanisms. The mTOR‐dependent sequestration of Lipin‐1 in the cytoplasm enhances SREBP‐transcriptional activity in the nucleus, while the mTORC1/S6K1/SRPK2/U1‐70K axis increases mRNA splicing of lipogenic genes, such as FASN and ACLY. Liver X receptor (LXR) is an additional regulator of lipogenesis and a nuclear transcription factor receptor that senses oxysterols, cholesterol derivatives, to form the LXR‐RXRα complex. This complex induces the expression of genes involved in cholesterol efflux, such as ABCA1, and several lipogenic genes, including FASN and SCD. Peroxisome proliferator‐activated receptors (PPARs) are regulators of lipid metabolism and play vital roles in lipid β‐oxidation and storage in harsh environments when cellular energy is needed.