Pathophysiology of Bile Secretion
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1 Pathophysiology of Bile Secretion Martin C. Carey, D.Sc., M.D. Division of Gastroenterology, Brigham and Women s Hospital and Department of Medicine, Harvard Medical School Boston, MA, U.S.A.
2 Functions of Bile Promotes exocrine lipid secretion, especially cholesterol elimination Facilitates dietary lipid absorption, obligatory for sterol and fat-soluble vitamin absorption Enhancement of dietary protein and carbohydrate digestion Conduit for endobiotic and xenobiotic excretion Distributes immunoglobins and antioxidants throughout the gut
3 Solute Composition of Human Bile Cholates Phospholipids Mostly PC 22% Primary Bile Salts (68%) Chenodeoxycholates Deoxycholates Secondary Secondary Cholesterol (4%) Bilirubin Conjugates (0.3%) Protein (4.5%) Ursodeoxycholates Lithocholates
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5 Via Aquaporins and Intercellular Spaces *Via 7 AQUAPORINS and INTERCELLULAR SPACES
6 Vectorial Bile Salt Transport by the Hepatocyte Basolateral membrane BS BS X - NTCP OATP s BS MRP4 GSH BS X - MRP3 OSTα/ OSTβ Canalicular membrane Glucuronosides BSEP ABCG2 MRP2 BS sulfates BS amidates BS glucuronosides
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9 NPC1L1 L Yu et al, J Biol Chem, 2006
10 OSTα/β
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13 Hepatocellular Trafficking BLOOD HEPATOCYTE Sinusoidal Membrane ABCB4 BILE ABCG5/G8 ABCB11 Canalicular Membrane
14 Bile Salt-Canalicular Membrane Interactions Promote Biliary Vesicle Formation ABCB11 ABCB4 ABCB11 Crawford et al, J Lipid Res, 1995 Crawford et al, J Clin Invest, 1997
15 Transport of Bile Salts and Phospholipids Across the Canalicular Membrane HEPATOCYTE BILE ABCB4 ATP ABCB11 Canalicular Membrane
16 Model for Flipping of Cholesterol into Bile Wittenburg and Carey, J Clin Invest, 2002
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18 Lipid Particles in Human Biles Physiological Range Unsaturated Bile Supersaturated Bile Simple and Mixed Micelles Simple and Mixed Micelles plus Vesicles CHOLESTEROL SATURATION INDEX CH BS PL
19 The Ying-Yang of Gallbladder Filling and Relaxation Liver FGF15/19 Ileum BS GB CCK CCK Duodenum M Choi et al, Nat Med, 2006
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22 FABP6 + OSTα OSTβ
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25 Functions of the Nuclear Bile Salt Receptor FXR Nuclear Receptor FXR (bile salt-activated receptor; previously called farnesoid X receptor) Ligand Primary bile salts (but not UDCA) GW ethyl CDCA Effect of activation P1: H: BS biosynthesis (via SHP) P2: H: BS N-acylamidation (conjugation) P2: IE: BS binding in ileoctes by FABP6 P3: H: BS uptake by basolateral NTCP P3: H: BS secretion by canalicular BSEP P3: IE: BS uptake by apical ASBT P3: H, IE, C: BS efflux by basolateral OSTα/β Abbreviations: H, hepatocyte; IE, ileal enterocyte; C, cholangiocyte. P1, phase 1 biotransformation (hydroxylation and related pathways); P2, phase 2 biotransformation (conjugation pathways); P3, phase 3 transporter activity.
26 Membrane Transporter Defects in Hereditary Cholestatic Disorders Progressive Familial Intrahepatic Cholestasis (PFIC) Disease PFIC1 (low γ-gt) PFIC2 (low γ-gt) PFIC3 (high γ-gt) Benign Recurrent Intrahepatic Cholestasis (BRIC) Dubin-Johnson syndrome Molecular Change Mutation of FIC1 gene (Chr 18q21-22) Mutation of BSEP gene (Chr 2q24); canalicular BSEP protein absent Mutation of MDR3 gene (Chr 7q21); canalicular MDR3 protein absent Mutation of FIC1 gene (Chr 18q21-22) Mutation of MRP2 gene (Chr 10q23-24); canalicular MRP2 protein absent Boyer, 1999
27 Pathophysiology of Bile Secretory Failure (Cholestasis) Biliary Lipids in the Systemic Circulation: Bilirubin conjugates (MRP3) Icterus (jaundice), bilirubinuria Biliary phospholipids (MDR3) Lipoprotein X (LpX) a vesicular LDL Biliary cholesterol (ABCG5/8) LpX hypercholesterolemia Bile salts (MRP4) Cholemia, choluria, pruritus, bradycardia
28 Pathophysiology of Bile Secretory Failure (Cholestasis) Deficit of Biliary Lipids in the Alimentary Tract Fat malabsorption: Principally lipovitamins, cholesterol, monoacylglycerides, but not long-chain fatty acids Delayed formation of chylomicrons and large particles Acholic stools Delayed peristalsis Constipation Changed ecology of gut flora defective small intestinal antimicrobiosis, including FXR-mediated secretion of antimicrobial factors Dysregulation of gene expression via nuclear receptors
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30 Etiology of Cholesterol Cholelithiasis Genetic predisposition Monogenic Polygenic Cholelithogenic environment Diet / Drugs Adiposity / Weight loss Gestation / Estrogens / Progestogens? Enteric microflora, enterohepatic Helicobacter spp. infection? Acquired immune response
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32 That s all from me, folks!
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