FXR regulation of bile acid synthesis, transport and absorption

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FXR plays a central role in regulation of bile acid synthesis and transport. FXR inhibits the CYP7A1 and CYP8B1 genes involved in bile acid synthesis. On the other hand, FXR stimulates bile acid conjugation by inducing BCAS and bile acid CoA:amino acid Nacetyltransferase (BAT). FXR markedly induces bile salt export pump (BSEP, ABCB11) (Ananthanarayanan et al. 2001), which is the principle bile acid transporter for excretion of bile acid conjugates. FXR also induces multidrug resistance associated protein 2 (MRP2, ABCC2) for transport of sulfate, glutathione or glucuronide conjugated anionic compounds including bile acids (Kast et al. 2002). Bile acids facilitate the biliary excretion of phosphatidylcholine by inducing multi-drug resistant protein 2 (MDR2), and cholesterol by inducing ABCG5 and G8 half transporters (Yu et al. 2002). Bile acids are quantitatively reabsorbed in the intestine, mostly in the ileum by an active transport process involving the apical sodium-dependent bile salt transporter (ASBT) (Wong et al. 1994). FXR induces ileum bile acid binding protein (IBABP) (Grober et al. 1999), which binds bile acids and protects enterocytes for cytotoxic effect of bile acids. Bile acids are excreted into portal circulation, transported back to the liver, and reabsorbed into hepatocytes by sinusoidal Na2+-dependent taurocholate cotransport peptide (NTCP). FXR inhibits NTCP and may protect hepatocytes from accumulating high levels of toxic bile acids during inflammation (Denson et al. 2001). FXR also induces organic anion transport protein 2 (OATP2), which takes up bile acids from the sinusoid. FXR induces DHEA-sulfate transferase (SULT2A1), which transfers a sulfate group to the secondary bile acids for rapid excretion into bile via MRP2. Guggulsterone, a FXR antagonist, has been used as a lipid-lowering drug in humans (Urizar and Moore 2003). Guggulsterone inhibits IBABP gene in the intestine (Urizar et al. 2002), and BSEP and CYP7A1 gene expression in the liver (Cui et al. 2003; Owsley and Chiang 2003; Wu et al. 2002). Selective FXR modulators may be useful for lipid-lowering (Dussault et al. 2002).

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