title: Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice.
abstract: 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.
  
  
  
  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.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH.|Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq.
authors.forename: Munaf
authors.initials: M
authors.lastname: Zalzala
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH.
authors.forename: Jiesi
authors.initials: J
authors.lastname: Xu
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Intercept Pharmaceuticals, New York, NY.
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH.
authors.forename: Yoon-Kwang
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH. lyin@neomed.edu.
authors.forename: Liya
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH. yzhang@neomed.edu.
authors.forename: Yanqiao
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D007408:Intestinal Absorption; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002784:Cholesterol; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated