Yang Xu1, Fei Li2, Munaf Zalzala1,3, Jiesi Xu1, Frank J Gonzalez2, Luciano Adorini4, Yoon-Kwang Lee1, Liya Yin5, Yanqiao Zhang6. 1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH. 2. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD. 3. Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq. 4. Intercept Pharmaceuticals, New York, NY. 5. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH. lyin@neomed.edu. 6. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH. yzhang@neomed.edu.
Abstract
UNLABELLED: Activation of farnesoid X receptor (FXR) markedly attenuates development of atherosclerosis in animal models. However, the underlying mechanism is not well elucidated. Here, we show that the FXR agonist, obeticholic acid (OCA), increases fecal cholesterol excretion and macrophage reverse cholesterol transport (RCT) dependent on activation of hepatic FXR. OCA does not increase biliary cholesterol secretion, but inhibits intestinal cholesterol absorption. OCA markedly inhibits hepatic cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) partly through inducing small heterodimer partner, leading to reduced bile acid pool size and altered bile acid composition, with the α/β-muricholic acid proportion in bile increased by 2.6-fold and taurocholic acid (TCA) level reduced by 71%. Overexpression of Cyp8b1 or concurrent overexpression of Cyp7a1 and Cyp8b1 normalizes TCA level, bile acid composition, and intestinal cholesterol absorption. CONCLUSION: Activation of FXR inhibits intestinal cholesterol absorption by modulation of bile acid pool size and composition, thus leading to increased RCT. Targeting hepatic FXR and/or bile acids may be useful for boosting RCT and preventing the development of atherosclerosis. (Hepatology 2016;64:1072-1085).
UNLABELLED: Activation of farnesoid X receptor (FXR) markedly attenuates development of atherosclerosis in animal models. However, the underlying mechanism is not well elucidated. Here, we show that the FXR agonist, obeticholic acid (OCA), increases fecal cholesterol excretion and macrophage reverse cholesterol transport (RCT) dependent on activation of hepatic FXR. OCA does not increase biliary cholesterol secretion, but inhibits intestinal cholesterol absorption. OCA markedly inhibits hepatic cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) partly through inducing small heterodimer partner, leading to reduced bile acid pool size and altered bile acid composition, with the α/β-muricholic acid proportion in bile increased by 2.6-fold and taurocholic acid (TCA) level reduced by 71%. Overexpression of Cyp8b1 or concurrent overexpression of Cyp7a1 and Cyp8b1 normalizes TCA level, bile acid composition, and intestinal cholesterol absorption. CONCLUSION: Activation of FXR inhibits intestinal cholesterol absorption by modulation of bile acid pool size and composition, thus leading to increased RCT. Targeting hepatic FXR and/or bile acids may be useful for boosting RCT and preventing the development of atherosclerosis. (Hepatology 2016;64:1072-1085).
Authors: Brenton Flatt; Richard Martin; Tie-Lin Wang; Paige Mahaney; Brett Murphy; Xiao-Hui Gu; Paul Foster; Jiali Li; Parinaz Pircher; Mary Petrowski; Ira Schulman; Stefan Westin; Jay Wrobel; Grace Yan; Eric Bischoff; Chris Daige; Raju Mohan Journal: J Med Chem Date: 2009-02-26 Impact factor: 7.446
Authors: W M Pandak; C Schwarz; P B Hylemon; D Mallonee; K Valerie; D M Heuman; R A Fisher; K Redford; Z R Vlahcevic Journal: Am J Physiol Gastrointest Liver Physiol Date: 2001-10 Impact factor: 4.052
Authors: W M Pandak; P Bohdan; C Franklund; D H Mallonee; G Eggertsen; I Björkhem; G Gil; Z R Vlahcevic; P B Hylemon Journal: Gastroenterology Date: 2001-06 Impact factor: 22.682
Authors: Robert S Rosenson; H Bryan Brewer; W Sean Davidson; Zahi A Fayad; Valentin Fuster; James Goldstein; Marc Hellerstein; Xian-Cheng Jiang; Michael C Phillips; Daniel J Rader; Alan T Remaley; George H Rothblat; Alan R Tall; Laurent Yvan-Charvet Journal: Circulation Date: 2012-04-17 Impact factor: 29.690
Authors: Michael H Davidson; Jason Voogt; Jayraz Luchoomun; Julie Decaris; Salena Killion; Drina Boban; Alexander Glass; Hussein Mohammad; Yun Lu; Deona Villegas; Richard Neese; Marc Hellerstein; David Neff; Thomas Musliner; Joanne E Tomassini; Scott Turner Journal: Atherosclerosis Date: 2013-08-13 Impact factor: 5.162
Authors: Sunder Mudaliar; Robert R Henry; Arun J Sanyal; Linda Morrow; Hanns-Ulrich Marschall; Mark Kipnes; Luciano Adorini; Cathi I Sciacca; Paul Clopton; Erin Castelloe; Paul Dillon; Mark Pruzanski; David Shapiro Journal: Gastroenterology Date: 2013-05-30 Impact factor: 22.682
Authors: Ivo P van de Peppel; Anna Bertolini; Theo H van Dijk; Albert K Groen; Johan W Jonker; Henkjan J Verkade Journal: J Lipid Res Date: 2019-07-19 Impact factor: 5.922
Authors: Romeo Papazyan; Xueqing Liu; Jingwen Liu; Bin Dong; Emily M Plummer; Ronald D Lewis; Jonathan D Roth; Mark A Young Journal: J Lipid Res Date: 2018-03-20 Impact factor: 5.922
Authors: Lili Sheng; Prasant Kumar Jena; Ying Hu; Hui-Xin Liu; Nidhi Nagar; Karen M Kalanetra; Samuel William French; Samuel Wheeler French; David A Mills; Yu-Jui Yvonne Wan Journal: J Pathol Date: 2017-11-01 Impact factor: 7.996