Disorders of Bile Acid Transport

Bile salts take part in a rather efficient enterohepatic circulation in which most of the secreted bile salts are reclaimed by absorption in the terminal ileum. In the liver the sodium dependent taurocholate transporter (NTCP) at the basolateral (sinusoidal) membrane and the bile salt export pump...

Pathology of Cholestasis

C formation may give rise to extensive parenchymal changes, without significant alterations in biliary tree morphology. Sepsis or systemic inflammatory conditions also can cause severe hepatocellular cholestasis without obstruction, although there may be attendant inflammatory changes in portal t...

Bile Acid-Mediated Apoptosis in Cholestasis

H injury by inducing apoptosis. Toxic bile acids induce apoptosis by activating cell surface membrane death receptors. The activated death receptors stimulate a signaling cascade involving the pro-apoptotic Bcl-2 poteins Bid and Bax. The proapoptotic Bcl-2 proteins initiate mitochondrial injury, ...

Hepatocyte Transplantation and Liver-Directed Gene Therapy

The research on liver-directed gene therapy and hepatocyte transplantation has progressed in parallel. Hepatocytes, with or without genetic modification have been used to introduce normal genes into patients or animal models with inherited disorders, while gene transfer can be used to expand h...

Genetics, Mutations and Polymorphisms

Genetic approaches complement functional approaches to the study of hereditary disease, and have contributed substantially to our understanding of the biology of enterohepatic circulation in health and disease. The basic steps in genetic mapping of a disease gene are reviewed here. They includ...

Fat Absorption and Lipid Metabolism in Cholestasis

The liver has a central role in control of various aspects of lipid metabolism. Primarily, the liver produces bile, constituents of which are required for efficient intestinal fat absorption. Additionally, biliary secretion of cholesterol (either as such, or after metabolism in the form of bil...

Hepatocellular Transport Systems: Basolateral Membrane

The basolateral membrane of hepatocytes is equipped with efficient transport systems for uptake of bile salts (Ntcp/NTCP) and xenobiotics (Oatps/OATPs). Under physiological conditions these transporters are important for ongoing bile formation and for efficient hepatic detoxification. Especial...

Genetic Defects in Biliary Lipid Transport

In terms of solute mass, lipids are the second most important component of bile. Biliary lipids mainly consist of phospholipid (almost exclusively phosphatidylcholine; PC) and cholesterol. The ratio in which these two lipids are secreted varies considerably between species. In rodents th...

Gap Junctions in the Liver

Gap junctions are hexameric hemichannels that are inserted into the plasma membrane and allow for direct exchange of cytosolic contents among adjacent cells. Connexin 26 and connexin 32 are the specific types of gap junctions found in hepatocytes, and connexin 43 is the predominant gap junctio...

Medical Therapy of Cholestatic Liver Diseases

Cholestasis and its sequelae are the hallmark of chronic cholestatic liver diseases and can be a feature of virtually all liver diseases at some point. Ursodeoxycholic acid (UDCA), a dihydroxy bile acid, is the only drug approved for the treatment of patients with primary biliary cirrhosis (PB...

Pathophysiological Basis of Pruritus and Fatigue in Cholestasis

Fatigue and pruritus are subjective complaints which are extremely common amongst patients with cholestasis, significantly impairing the quality of life of these patients. The genesis of these complaints appears to be complex and likely multi-factorial. Moreover, the central nervous syst...

Bone Disease in Chronic Cholestatic Liver Disease

Harold Dobnig and Astrid Fehrleiter

Patients with chronic cholestatic liver disease are especially prone to osteoporosis. Hepatic osteodystrophy typically presents as low turnover osteoporosis with initially normal bone resorption that becomes elevated as disease progresses. The mechanisms leading to low bone formation remain largely...

Acquired Alterations in Transporter Expression and Function in Cholestasis

Exposure to cholestatic injury (e.g., drugs, hormones, proinflammatory cytokines, biliary obstruction/destruction), hereditary mutations of transporter genes, or the combination of both result in decreased expression and function of hepatobiliary transport systems. These molecular changes may ...

Drug-induced cholestatic liver disease

Drug induced cholestatic liver disease is a subtype of liver injury that is characterized by predominant elevations of alkaline phosphatase and bilirubin secondary to the administration of a hepatotoxic agent. It can manifest itself as a cholestatic hepatitis or as bland cholestasis, depending...

Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disorder of the intrahepatic and/or extrahepatic bile ducts. PSC is characterized by concentric obliterative fibrosis and bile duct strictures. Its course is very variable and can in individual cases follow a benign course but...

Molecular Basis of Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) can be defined by the triad of positive PBC-specific autoantibodies (antimitochondrial antibodies (AMA) in >95%), cholestatic liver function tests and diagnostic or compatible liver histology. PBC is generally considered to be an autoimmune disease. To be accept...

Hepatic Copper Transport

Copper is an essential nutrient that is required in a number of critical metabolic path ways. This metal is absorbed in the stomach and duodenum, stored in the liver and excreted in the bile. The liver functions to maintain copper balance as the amount of copper excreted in the bile is directly...

Transport of Bilirubin and its Conjugates across Hepatocellular Membrane Domains and the Conjugated Hyperbilirubinemia of Dubin-Johnson Syndrome

Bilirubin, the end product of heme catabolism, needs to be taken up into hepatocytes and is then glucuronidated within the cells prior to its excretion via bile. Members of the SLC21A family in the sinusoidal membrane of hepatocytes selectively mediate the uptake of unconjugated bilirubin and ...

Hepatic Drug Metabolism

The liver plays an important role in the metabolism of xenobiotics and the metabolic reactions are mediated by many different kinds of enzymes. These enzymes mediate the detoxification in most cases, but are sometimes responsible for the bioactivation of xenobiotics. In this chapter, the pharm...

Transcriptional Regulation of Hepatobiliary Transporters

The expression and activities of hepatobiliary transporter genes is a critical component of liver function. Both sinusoidal and canalicular membrane transporters are responsible for the coordinated transport of a wide variety of organic anions, drugs, toxins, endobiotics and bile acids that ul...

The Pathobiology of cholangiocytes

In this chapter, we first review the bile duct structure, then the intracellular mechanisms involved in ductal secretion and absorption. The modulation of ductal secretion by hormones, enzymes and neuropeptides is described. Next we describe the specific transporters (e...

Cholestasis: An Intracellular "Traffic Jam"

Mutations in the coding region of BSEP which result in its absence from the bile canalicular membrane are manifested by progressive cholestasis and liver damage. We have proposed that defects in intracellular trafficking and/or posttranslational regulation of BSEP may produce a similar pheno...

The ABC of Canalicular Transport

Bile formation is a regulated process and depends on the coordinated action of a number of transporter proteins in the sinusoidal (basal) and canalicular (apical) domains of the hepatocyte. The secretion of substances in the canalicular lumen is mediated by a set of ATP-dependent transport pro...

Mechanisms of Bile Formation—An Introduction

The formation of bile is a unique and vital function of the liver. Failure to form bile results in progressive cholestatic liver injury and death. Knowledge of the mechanism of bile formation has progressed rapidly in the past decade and this introduction provides a background and historical p...

Signal Transduction in Bile Formation and Cholestasis

Bile formation involves vectorial transport of solutes from blood to bile and is dependent on coordinated activities of various solute transporters located at the basolateral and apical membranes of hepatocytes and cholangiocytes. Cholestasis results when the vectorial transport of solut...