[Frontiers in Bioscience 8, s1166-1174, September 1, 2003]
THE MOLECULAR AND METABOLIC BASIS OF BILIARY CHOLESTEROL SECRETION AND GALLSTONE DISEASE
Silvana Zanlungo and Flavio Nervi
Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile.
FIGURES
Figure 1. The four pathogenic steps in cholesterol gallstone disease. The first abnormality is the secretion by the liver of higher than normal amounts of biliary cholesterol in the form of unilamellar phosphatidylcholines vesicles. Second, bile salts - dependent micellar solubilization of vesicular cholesterol is incomplete as a function of gallbladder emptying. Third, cholesterol crystal formation is accelerated by the presence of mucin and other still unknown pronucleating factors. Fourth, the majority of subjects with biliary cholesterol supersaturation present a chronic cholecystitis prior to the formation of gallstones. Gallbladder emptying is abnormal in some gallstone patients.
Figure 2. Hepatic cholesterol transport pathways and biliary lipid secretion. Hepatocytes acquire cholesterol by three ways: synthesis in the endoplasmic reticulum (ER), receptor-mediated internalization of chylomicron remnants (CM), VLDL, and LDL, and selective cholesterol uptake from HDL mediated by SR-BI. Particles internalized by LDLR are hydrolyzed in lysosomes releasing free cholesterol, which could be transported with the aid of NPC1 to the plasma membrane and to the interior of the hepatocyte. Cholesterol obtained from HDL is selectively transferred to the hepatocyte and is used as a preferentially source of cholesterol secreted into bile. Cholesterol synthesized in the (ER) and reaching the ER from other sources could be esterified in cholesterol ester-rich droplets, metabolized to bile acids or secreted into bile. SCP2 could delivers cholesterol destined for biliary secretion to the canalicular membrane. Biliary lipid secretion is mediated by different ABC transporters: ABCG5/G8 for cholesterol, ABCB4 for phospholipids (PL) and ABCB11 for bile salts (BS).