Figure 3.

Bile acid synthesis regulates cholesterol homeostasis in hepatocytes. Cholesterol homeostasis is maintained by dietary uptake of cholesterol, de novo cholesterol synthesis from acetyl-CoA, and conversion of cholesterol to bile acids. Oxysterols are derived from cholesterol and bile acids. When intracellular cholesterol/oxysterol levels are high, steroid response element binding protein 2 (SREBP-2) precursor (125 kDa) interacts with insulin induced gene 1/2 (Insig1/2) and is retained in endoplasmic reticulum (ER) membrane. When intracellular oxysterol levels are low, SREBP cleavage and activating protein (SCAP) escorts SREBP-2 precursor to the Golgi apparatus, where sterol sensitive proteases S1P and S2P are activated to cleave a N-terminal fragment (65 kDa), which is translocated to the nucleus to bind to the steroid response elements in the gene promoters of all cholesterogenic genes and stimulates de novo cholesterol synthesis. Oxysterols activate LXRα, which induces CYP7A1 gene transcription to stimulate bile acid synthesis in mice, but not humans. Bile acids (CDCA) activate farnesoid X receptor (FXR) to inhibit CYP7A1 gene transcription and bile acid synthesis. This may lead to increased cholesterol levels and inhibited de novo cholesterol synthesis and absorption of dietary cholesterol.