Biliary elimination of cholesterol can be modulated by hepatocyte mitochondrial Aquaporin-8 in mice

Sterol regulatory element-binding protein (SREBP) transcription factors directly or indirectly regulate key genes involved in hepatic cholesterol homeostasis, including biliary elimination. The ATP-binding cassette transporter G5 (ABCG5), located in hepatocyte canalicular plasma membranes, strongly controls the excretion of unesterified cholesterol into bile. Recently, we demonstrated in cultured hepatocytes that mitochondrial aquaporin-8 (mtAQP8), a channel protein capable of conducting H2O2, is involved in SREBP-controlled cholesterol synthesis. In this study, we evaluated whether hepatic mtAQP8 participates in modulating the biliary elimination of cholesterol. Using C57BL/6 mice, we found that adenovirus-induced mtAQP8 knockdown significantly downregulated the expression of sterol regulatory element-binding protein-2 (SREBP-2) and, through liver X receptor (LXR), that of ABCG5, which in turn decreased biliary cholesterol excretion. In contrast, mice with adenovirusmediated mitochondrial human AQP8 (hAQP8) expression significantly increased the expressions of SREBP-2, LXR, and ABCG5 and, consequently, the biliary excretion of cholesterol. A mitochondrialtargeted antioxidant, which has been shown to quench mitochondrial H2O2 release, did not affect mitochondrial hAQP8 expression, but prevented upregulation of SREBP-2, ABCG5, and biliary cholesterol excretion. Our data further support the involvement of mtAQP8 in hepatic cholesterol metabolism, suggesting that it modulates biliary cholesterol elimination through ABCG5 gene expression.