1. Figure 5 Sterol regulatory element-binding
protein regulation of tissue cholesterol and plasma LDL levels
Figure 5 | Sterol regulatory element-binding protein regulation of tissue cholesterol and plasma LDL levels. Cellular cholesterol levels are maintained by cholesterol biosynthetic and LDL receptor (LDLR) pathways that are regulated at the transcriptional level by the sterol-sensing sterol regulatory element-binding protein 2 (SREBP2)–SREBP cleavage-activating protein (SCAP)–insulin-induced gene proteins (INSIGs) complex. Statins inhibit 3-hydroxy-3-methylglutaryl CoA reductase (HMGCoAR), which leads to feedback upregulation of both pathways to sustain cellular cholesterol levels and decreased plasma cholesterol levels. In addition to the classic sterol regulation system, epigenetic regulation by microRNAs (miRs) and PCSK9 regulation of protein levels can occur. Upregulated PCSK9 enhances LDLR degradation and limits cholesterol accumulation. Some miRs (including miR-33a, which is controlled by SREBP2) suppress HDL formation, whereas other miRs (such as miR-33b, which is controlled by SREBP1) suppress fatty acid metabolism. Some miRs work through positive and others through negative feedback loops. miRs regulate the subtle balance between cholesterol homeostasis and other cellular processes. Sterol regulation is the dominant form of SREBP control, but nutritional states have some influence through the mTORC1–SREBP2–LDLR and mTORC1–PKCδ–HNF1α–PCSK9 pathways. Black arrows and T bars denote stimulatory and inhibitory actions, respectively.
Shimano, H. & Sato, R. (2017) SREBP-regulated lipid metabolism: convergent physiology — divergent pathophysiology
Nat. Rev. Endocrinol. doi: /nrendo