24-norursodeoxycholic acid (norUDCA), a side chain-modified ursodeoxycholic acid derivative, has dramatic therapeutic effects in experimental cholestasis and may be a promising agent for the treatment of cholestatic liver diseases. We aimed to better understand the physiologic and therapeutic properties of norUDCA and to test if they are related to its side chain length and/or relative resistance to amidation. For this purpose, Mdr2(-/-) mice, a model for sclerosing cholangitis, received either a standard diet or a norUDCA-, tauro norursodeoxycholic acid (tauro- norUDCA)-, or di norursodeoxycholic acid (di norUDCA)-enriched diet. Bile composition, serum biochemistry, liver histology, fibrosis, and expression of key detoxification and transport systems were investigated. Direct choleretic effects were addressed in isolated bile duct units. The role of Cftr for norUDCA-induced choleresis was explored in Cftr(-/-) mice. norUDCA had pharmacologic features that were not shared by its derivatives, including the increase in hepatic and serum bile acid levels and a strong stimulation of biliary HCO(3)(-)-output. norUDCA directly stimulated fluid secretion in isolated bile duct units in a HCO(3)(-)-dependent fashion to a higher extent than the other bile acids. Notably, the norUDCA significantly stimulated HCO(3)(-)-output also in Cftr(-/-) mice. In Mdr2(-/-) mice, cholangitis and fibrosis strongly improved with norUDCA, remained unchanged with tauro- norUDCA, and worsened with di norUDCA. Expression of Mrp4, Cyp2b10, and Sult2a1 was increased by norUDCA and di norUDCA, but was unaffected by tauro- norUDCA.The relative resistance of norUDCA to amidation may explain its unique physiologic and pharmacologic properties. These include the ability to undergo cholehepatic shunting and to directly stimulate cholangiocyte secretion, both resulting in a HCO(3)(-)-rich hypercholeresis that protects the liver from cholestatic injury.
Polycystic liver diseases are hereditary disorders that affect the biliary epithelium, often in conjunction with the renal tubule epithelium. Characterized by the progressive formation of cysts throughout the liver and kidney, they can often lead to severe life-threatening complications. Polycystins and fibrocystin, the defective proteins in the dominant and in the recessive form of the disease, respectively, are mainly expressed in the primary (nonmotile) cilia of cholangiocytes, the epithelial cells that line the intrahepatic biliary tree. Important clues for understanding the pathogenesis of cystic diseases come from understanding the biology and pathobiology of cholangiocytes. In this chapter, cholangiocyte function and morphology is first briefly described, with particular emphasis on the regulation of their secretory properties and the complex intercellular signaling. Then, we discuss a number of possible mechanisms leading to cyst formation and progressive growth of the cysts. In both autosomal dominant and recessive forms, liver cysts arise from an aberrant development of intrahepatic bile duct epithelium. During cyst expansion, different factors, including excessive fluid secretion, extracellular matrix remodeling, increased proliferation of the epithelial cells lining the cyst, and aberrant hypervascularization around the cyst wall, variably take part in promoting progressive cyst growth. Many of these factors act via autocrine mechanisms. Each of them represents a possible target for therapies aimed at reducing the growth of liver cysts.
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