Adenovirus-mediated human aquaporin-1 expression in hepatocytes improves lipopolysaccharide-induced cholestasis

MARRONE, JULIETA; DANIELLI, MAURO; GASPARI, CÉSAR I.; MARINELLI, RAÚL A.

IUBMB LIFE

JOHN WILEY & SONS INC

Año: 2017 vol. 69 p. 978 - 984

1521-6543

Lipopolysaccharides (LPS) are known to cause cholestasis insepsis. There is evidence that a defective expression of canalicularaquaporin water channels contributes to bile secretoryfailure in LPS-induced cholestasis. Thus, we studied whetherthe hepatic adenovirus-mediated transfer of human aquaporin-1 gene (haqp1) can improve the cholestasis induced by LPS.Adenoviral vector encoding hAQP1 (AdhAQP1) or control vectorwas administered to rats by retrograde intrabiliary infusion.Hepatocyte canalicular hAQP1 expression was assessedby liver immunostaining and immunoblotting in purifiedplasma membranes. LPS reduced bile flow and biliary bileacid excretion by 30% and 45%, respectively. AdhAQP1-treatment normalized both bile flow and biliary bile acid excretionin LPS-induced cholestasis. Moreover, markedly elevatedserum bile acid levels in cholestatic rats, were also normalizedwith the AdhAQP1 hepatic transduction. Bile flow and serumor biliary bile acids in normal rats were not significantlyaltered by AdhAQP1. AdhAQP1 delivery unaffected the downregulatedprotein expression of canalicular bile salt exportpump (BSEP/ABCB11) in cholestasis, but improved its transportactivity restoring reduced canalicular cholesterol content.Our data suggest that the adenovirus-mediated hepatocytehAQP1 expression improves LPS-induced cholestasis in ratsby stimulating the BSEP/ABCB11-mediated biliary bile acidexcretion; a finding that might contribute to the understandingand treatment of sepsis-associated cholestatic diseases.