Aquaporin Gene Transfer for hepatocelular cholestasis

MARRONE J; DANIELLI, M; GASPARI CI; CAPIGLIONI AM; MARINELLI RA

BIOCHIMIE

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

Lugar: Paris; Año: 2021

0300-9084

Bile secretion by hepatocytes is an osmotic process. The output of bile salts and other organic anions (e.g.glutathione), through the bile salt transporter BSEP/ABCB11 and the organic anion transporter MRP2/ABCC2, respectively, are considered to be the major osmotic driving forces for water secretion into bilecanaliculi mainly via aquaporin-8 (AQP8) channels. The down-regulated canalicular expression of thesekey solute transporters and AQP8 would be a primary event in the establishment of hepatocellularcholestasis. Recent studies in animal models of hepatocellular cholestasis show that the hepatic deliveryof AdhAQP1, an adenovector encoding for the archetypical water channel human aquaporin-1 (hAQP1),improves bile secretion and restores to normal the elevated serum bile salt levels. AdhAQP1-transducedhepatocytes show that the canalicularly-expressed hAQP1 not only enhances osmotic membrane waterpermeability but also induces the transport activities of BSEP/ABCB11 and MRP2/ABCC2 by redistributionin canalicular cholesterol-rich microdomains likely through interactions with the cholesterol-bindingprotein caveolin-1. Thus, the hepatic gene transfer of hAQP1 improves the bile secretory failure in hepatocellularcholestasis by increasing both biliary output and choleretic efficiency of key osmotic solutes,such as, bile salts and glutathione. The study of hepatocyte aquaporins has provided new insights intothe mechanisms of bile formation and cholestasis, and may lead to innovative treatments for cholestaticliver diseases.