Aquaporins and glycerol metabolism in health and disease. Translational value in liver steatosis and obesity

CALAMITA G; PIERO PORTINCASA,; RODRIGUEZ A; MEACCI D; TRAGNI M; DEL VECCHIO T; RAUL A. MARINELLI; MARIA SVELTO; FRÜHBECK G; PATRICIA GENA

Utrecht

Congreso; 48th Annual Scientific Meeting of the European Society for Clinical Investigation; 2014

Background: The liver plays a central role in glycerol metabolism, since it is responsible for 70?90% of thewhole-body glycerol metabolism. Glycerol enters hepatocytes via AQP9, an aquaporin channel, and isconverted into glycerol-3-phosphate, a major precursor of gluconeogenesis and a direct source fortriacylglycerol (TG) synthesis. We investigated the implication of AQP9 in Non-Alcoholic Fatty LiverDisease (NAFLD), an emerging health problem worldwide, characterized by increased intrahepatic influx offatty acids, and overaccumulation of TGs and their intermediates. NAFLD is commonly encountered withthe metabolic syndrome, a variable aggregation of visceral adiposity, hypertension, dyslipidemia, insulinresistance or overt diabetes mellitus. NAFLD has potentials for inflammatory and fibrotic evolution,exposing populations at risk of liver cirrhosis, and hepatocellular carcinoma.Materials and methods: Obese leptin-deficient (ob/ob) mice, an animal model of NAFLD, were used tocorrelate liver AQP9 expression, glycerol permeability and fat accumulation in hepatosteatosis.Results: By qPCR, liver Aqp9 mRNA level of starved obese mice was comparable with the correspondingcontrol lean mice. By immunoblotting, the AQP9 protein at the hepatocyte sinusoidal plasma membrane ofobese mice was markedly lower (33%) than lean littermates. Results were confirmed byimmunohistochemistry. By stopped-flow light scattering, liver glycerol permeability of ob/ob mice wassignificantly lower (53%) than lean mice, a finding consistent with the down-regulation of AQP9 protein andincreased level of plasma glycerol characterizing ob/ob mice.Conclusions: Involvement of AQP9 in fatty liver disease is a novel finding with major translational value.Decreased hepatic AQP9 and glycerol permeability may constitute a defensive mechanism against enhancedglycerol accumulation. Reducing liver AQP9 and glycerol permeability may therefore represent a noveltherapeutic approach in counteracting hepatosteatosis.