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Movie: Structural view of a novel transcriptional repressor. The orphan nuclear receptor SHP is a central regulator of bile acid and lipid metabolism, but the mechanism by which it represses expression of a number of genes in the liver was unknown. The movie shows the three-dimensional ribbon model of SHP (green) in complex with the interacting domain of a transcriptional repressor called EID1 (red). The x-ray crystal structure of this complex revealed an unexpected cofactor-binding site on SHP that is different from that of other nuclear receptors, which normally recruit transcription cofactors at the C-terminal helix (orange). By revealing this novel mode of repression, the SHP crystal structure provides a rational template for drug design to treat metabolic diseases arising from bile acid and cholesterol imbalances.
Glutamine and glutamate as vital metabolites - SciELO
Bile acid synthesis regulates cholesterol homeostasis in hepatocytes. Cholesterol homeostasis is maintained by dietary uptake of cholesterol, 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 cholesterol synthesis. Oxysterols activate LXRα, which induces gene transcription to stimulate bile acid synthesis in mice, but not humans. Bile acids (CDCA) activate farnesoid X receptor (FXR) to inhibit gene transcription and bile acid synthesis. This may lead to increased cholesterol levels and inhibited cholesterol synthesis and absorption of dietary cholesterol.
Bile acids are steroid-derived molecules synthesized in the liver, secreted from hepatocytes into the bile canaliculi, and subsequently stored in the gall bladder. During the feeding, bile flows into the duodenum, where it contributes to the solubilization and digestion of lipid-soluble nutrients. After a meal, bile-acid levels increase in the intestine, liver, and also in the systemic circulation. Therefore, serum bile-acid levels serve as an important sensing mechanism for nutrient and energy. Recent studies have described bile acids as versatile signaling molecules endowed with systemic endocrine functions. Bile acids are ligands for G-protein coupled receptors (GPCRs) such as TGR5 (also known as GPBAR1, M-BAR, and BG37) and nuclear hormone receptors including farnesoid X receptor (FXR; also known as NR1H4). Acting through these diverse signaling pathways, bile acids regulate triglyceride, cholesterol, glucose homeostasis, and energy expenditure. These bile-acid-controlled signaling pathways have become the source of promising novel drug targets to treat common metabolic and hepatic diseases.