fig5

Figure 5. Proposed mechanism of how cholestyramine interacts with the gut microbiota, changing intestinal and hepatic gene expression to reduce cholesterol levels. (1) Bile acids from the liver, stored in the gallbladder, are secreted into the ileum following food consumption; (2) In the ileum, primary bile acids are transformed into secondary bile acids by microbiota; (3) Cholestyramine sequesters bile acids in the ileum where Gcg is expressed; (4) Enterohepatic circulation causes bile acids to be delivered from the ileum directly to the liver, where they bind to hepatic Fxr (Nr1h4); (5) Decreased Fxr expression in the liver causes decreased expression of Shp in the liver; (6) Decreased expression of Shp in the ileum and decreased expression of Fgf15; (7) This eventually leads to decreased expression of Shp in the liver; (8) Decreased Shp (a Cyp7a1 inhibitor) in the liver causes increased expression of Cyp7a1; (9) Cyp7a1 converts cholesterol in the liver to bile acids. Gcg: Glucagon; Shp: small heterodimer protein; Fxr: farnesoid X receptor; Nr1h4: nuclear receptor subfamily 1 group H member 4; Fgf15: fibroblast growth factor 15; Cyp7a1: cytochrome P450 family 7 subfamily A member 1.