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<p>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 H<sub>2</sub>O<sub>2</sub>, 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 adenovirus-mediated mitochondrial human AQP8 (hAQP8) expression significantly increased the expressions of SREBP-2, LXR, and ABCG5 and, consequently, the biliary excretion of cholesterol. A mitochondrial-targeted antioxidant, which has been shown to quench mitochondrial H<sub>2</sub>O<sub>2</sub> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月6日

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  • María Celeste Capitani,
  • Alejo M. Capiglioni,
  • Raúl A. Marinelli,
  • Julieta Marrone

摘要

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 adenovirus-mediated mitochondrial human AQP8 (hAQP8) expression significantly increased the expressions of SREBP-2, LXR, and ABCG5 and, consequently, the biliary excretion of cholesterol. A mitochondrial-targeted 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.