Aquaporin-9 facilitates liver regeneration following hepatectomy

Abstract

Aquaporin-9 (AQP9) is an aquaglyceroporin strongly expressed in the basolateral membrane of hepatocytes facing the sinusoids. AQP9 is permeable to hydrogen peroxide (H 2 O 2 ) and glycerol as well as to water. Here, we report impaired liver regeneration in AQP9 −/− mice which involves altered steady-state H 2 O 2 concentration and glucose metabolism in hepatocytes. AQP9 −/− mice showed remarkably delayed liver regeneration and increased mortality following 70% or 90% partial hepatectomy. Compared to AQP9 +/+ littermates, AQP9 −/− mice showed significantly greater hepatic H 2 O 2 concentration and more severe liver injury. Fluorescence measurements indicated impaired H 2 O 2 transport across plasma membrane of primary cultured hepatocytes from AQP9 −/− mice, supporting the hypothesis that AQP9 deficiency results in H 2 O 2 accumulation and oxidative injury in regenerating liver because of reduced export of intracellular H 2 O 2 from hepatocytes. The H 2 O 2 overload in AQP9 −/− hepatocytes reduced PI3K-Akt and insulin signaling, inhibited autophagy and promoted apoptosis, resulting in impaired proliferation and increased cell death. In addition, hepatocytes from AQP9 −/− mice had low liver glycerol and high blood glycerol levels, suggesting decreased glycerol uptake and gluconeogenesis in AQP9 −/− hepatocytes. Adeno-associated virus (AAV)-mediated expression of hepatic expression of aquaglyceroporins AQP9 and AQP3 in AQP9 −/− mice, but not water-selective channel AQP4, fully rescued the impaired liver regeneration phenotype as well as the oxidative injury and abnormal glucose metabolism. Our data revealed a pivotal role of AQP9 in liver regeneration by regulating hepatocyte H 2 O 2 homeostasis and glucose metabolism, suggesting AQP9 as a novel target to enhance liver regeneration following injury, surgical resection or transplantation.

Protective roles of peroxiporins AQP0 and AQP11 in human astrocyte and neuronal cell lines in response to oxidative and inflammatory stressors

“…AQP9 is permeable to H 2 O 2 , as well as glycerol and water, beneficial in liver regeneration. Impaired H 2 O 2 transport across plasma membranes of cultured AQP9 −/− hepatocytes resulted in H 2 O 2 accumulation and oxidative injury, whereas overexpression of AQP9 or AQP3 in AQP9 −/− mice fully rescued liver regeneration, oxidative protection and glucose metabolism [ 97 ]. Up-regulation of various AQP classes in inflammatory conditions is essential for immune cell migration and viability [ 98 ].…”

Overexpression of circ PTK2 suppresses the progression of nonalcoholic fatty liver disease via the miR‐200c/SIK2/PI3K/Akt axis

“…Mice were sacrificed for serum and liver tissue collection. In addition, primary cultured hepatocytes were collected from mice according to a previous reference 25 . The TG content was measured by a biochemical assay kit (Boyao, Shanghai, China).…”

Signaling pathways of liver regeneration: Biological mechanisms and implications

“…found that when PI3K-AKT and insulin signaling pathways were suppressed, autophagy was inhibited, apoptosis was enhanced, proliferation was impaired, and cell death was promoted in hepatocytes of aquaporin-9 knockout mice. 154 Lin et al. revealed that translation control tumor protein (TCTP) promoted LR in mice by activating PI3K/AKT signaling pathway through interaction with mTORC2.…”

“… Zhang et al. 154 TCTP promoted LR in mice by activating PI3K/AKT signaling pathway through interaction with mTORC2. Lin et al.…”