Current Drug Targets - Immune, Endocrine & Metabolic Disorders - Volume 5, Issue 2, 2005

New Insights Into Bile Formation: from Secretion to Therapeutic Implications

Biliary lipid secretion is driven by bile salts, the primary metabolites of cholesterol. Transport of bile salts as well as phospholipids and cholesterol is mediated by ATP Binding Cassette (ABC) transporters. Expression of these transporters is regulated in a coordinate fashion by a set of nuclear hormone receptors explaining the old observation of coupling between bile salt secretion and biliary lipid secretion. Although it is now cl Read More

Formation of bile and generation of bile flow are driven by the active secretion of bile salts (BS), lipids and electrolytes into the canalicular and bile duct lumens followed by the osmotic movement of water. Although the transporting proteins involved in solute secretion have been cloned and their coordinated interplay defined both in health and disease, boosted by the discovery of the aquaporin water channels, only recently Read More

The function of the gallbladder is not only to store bile, but also to concentrate it during the interdigestive phase by means of salt-dependent water reabsorption. On the contrary, secretions of water and salt take place during the digestive phase. Dysregulation of ion absorption or secretion are common in many gallbladder diseases, such as colelithiasis. Transepithelial absorptions are determined by the Na +/K+ pump on the ba Read More

At least one third of the bile flow is driven osmotically by the amount of hepatic glutathione excreted into canalicular spaces. Beyond the importance of this secretory mechanism for bile formation, the excretion of glutathione is an important way to discharge toxic anionic compounds deriving from liver metabolism of exogenous and endogenous substances. Thus, biliary secretion of glutathione and its conjugates really Read More

Family and twin studies as well as animal studies indicate that gallstone disease is, in part, genetically determined. Recently new single gene defects have been identified in specific patients with cholesterol and pigment gallstones. Examples include low phospholipid-associated cholelithiasis due to mutations of the gene encoding the hepatocanalicular phosphatidylcholine transporter, and pigment stones in association with mutation Read More

Fatty acid bile acid conjugates (FABACs) are novel synthetic lipid molecules, which were designed for the treatment of cholesterol gallstones. The rationale was to combine a cholesterol solubilizing moiety (a saturated fatty acid) with a bile acid (cholic acid) as a vehicle to enable secretion into bile and entry into the enterohepatic circulation. An amide bond was used to provide stability against intestinal degradation. Initial in vitr Read More

The first step in cholesterol gallstone disease is precipitation of cholesterol crystals in bile. In gallbladder bile, cholesterol is normally solubilized together with bile salts and phospholipids to form mixed micellar structures. When cholesterol in bile is in excess, vesicles (i.e. phospholipid-cholesterol globular structures: liquid crystals) form which become supersaturated in cholesterol. Early aggregation and precipitation of Read More

Gallstone disease in the Western world has an estimated prevalence of 10-15% and more than 75% are cholesterol-enriched gallstones. Defective gallbladder motility has been identified as an important pathogenic factor for cholesterol gallstone disease. Various agents may enhance or impair postprandial gallbladder motility, and their effects on interdigestive gallbladder and intestinal motility should also be taken into account. Read More

Acute biliary pancreatitis, caused by macroscopic cholesterol gallstones or microlithiasis, is often a severe disease with considerable morbidity and mortality. Formation of cholesterol gallstones and microlithiasis is caused by cholesterol crystallization from cholesterol supersaturated gallbladder bile. Particularly patients with fast and extensive crystallization, due to highly concentrated bile, low biliary phospholipid contents and gal Read More

Gene therapy constitutes a great promise for the treatment of inherited diseases as well as cancer. Although the principle is extremely elegant, reality proves that several important problems remain to be solved before gene therapy becomes a standard application for these conditions. Meanwhile, and because of these problems alternatives are being considered as well. For the treatment of hepatic inherited disorders, h Read More

Gallstone disease is exceptionally common, occurring especially in Western populations, with cholesterol gallstones predominating. Currently, it is believed that obesity is the most consistent and important risk factor for the development of cholesterol gallstones. Obesity has been shown to be associated with the supersaturation of bile with cholesterol because of increased hepatic secretion of the sterol. In accord with current i Read More

Several processes are involved in control of plasma cholesterol levels, e.g., intestinal cholesterol absorption, endogenous cholesterol synthesis and transport and bile acid synthesis. Adaptation of either of these processes allows the body to adapt to changes in dietary cholesterol intake. Disturbances herein may lead to hypercholesterolemia and increase the risk for atherosclerosis. Several approaches are available for pl Read More

Cardiovascular disease is a major cause of mortality and morbidity in individuals with obesity, type 2 diabetes and the metabolic syndrome. The mechanisms for this are partially understood, but include increased atherosclerosis, hypercoagulability and increased hypertension. Epidemiological data suggests however, that a component of the excess cardiovascular mortality occurs independently of underlying coronary artery dis Read More

The pathogenesis of type 1 diabetes is multifactorial, involving genetic susceptibility, autoimmune mechanisms, and environmental factors. This article will focus on two main strategies for altering the underlying disease process in type 1 diabetes. The first strategy is to identify individuals at risk for the development of diabetes and to halt the immune process before it leads to overt clinical disease. Promising in vitro and anim Read More

The innate immune system is the oldest mammalian defence against invading micro-organisms and provides the first line of defence against them, however until recently a detailed understanding of its complexity has been lacking. This review describes recent advances that have been made in understanding the components of the innate immune system, including the pathogen sensing mechanisms, receptor and intracellular si Read More