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Integrative Biology

Reduced hepatic aquaporin-9 and glycerol permeability are related to insulin resistance in non-alcoholic fatty liver disease

International Journal of Obesity volume 38, pages 1213–1220 (2014)Cite this article

Subjects

Abstract

Background/Objectives:

Glycerol represents an important metabolite for the control of lipid accumulation and hepatic gluconeogenesis. We investigated whether hepatic expression and functionality of aquaporin-9 (AQP9), a channel mediating glycerol influx into hepatocytes, is impaired in non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in the context of insulin resistance.

Subjects/Methods:

Liver biopsies were obtained from 66 morbid obese patients undergoing bariatric surgery (66% women, mean body mass index (BMI) 46.1±1.0 kg m−2) with available liver echography and pathology analysis of the biopsies in this cross-sectional study. Subjects were classified according to normoglycemia (NG), impaired glucose tolerance (IGT) or type 2 diabetes (T2D). Hepatic expression of AQP9 was analyzed by real-time PCR, western blotting and immunohistochemistry, while glycerol permeability (Pgly) was measured by stopped-flow light scattering.

Results:

AQP9 was the most abundantly (P<0.0001) expressed aquaglyceroporin in human liver (AQP9>>>AQP3>AQP7>AQP10). Obese patients with T2D showed increased plasma glycerol as well as lower Pgly and hepatic AQP9 expression. The prevalence of NAFLD and NASH in T2D patients was 100 and 65%, respectively. Interestingly, AQP9 expression was decreased in patients with NAFLD and NASH as compared with those without hepatosteatosis, in direct relation to the degree of steatosis and lobular inflammation, being further reduced in insulin-resistant individuals. The association of AQP9 with insulin sensitivity was independent of BMI and age. Consistent with these data, fasting insulin and C-reactive protein contributed independently to 33.1% of the hepatic AQP9 mRNA expression variance after controlling for the effects of age and BMI.

Conclusions:

AQP9 downregulation together with the subsequent reduction in hepatic glycerol permeability in insulin-resistant states emerges as a compensatory mechanism whereby the liver counteracts further triacylglycerol accumulation within its parenchyma as well as reduces hepatic gluconeogenesis in patients with NAFLD.

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Acknowledgements

We gratefully acknowledge the valuable collaboration of all members of the Departments of Surgery, Anesthesia and the Nutrition Unit of the Clínica Universidad de Navarra for their technical support. We are also thankful to Prof. Piero Portincasa, Gabriella Garruti, Domenico Ferri, Giuseppa E Liquori and Maria Mastrodonato for valuable suggestions and stimulating discussions. This work was funded by the Instituto de Salud Carlos III and fondos FEDER (FIS PI10/01677 to AR and PI12/00515 to GF) and by grants from the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR; PRIN20089SRS2X_003, 2009–2012) and Fondazione Cassa di Risparmio di Puglia (Ricerca Scientifica e Tecnologica, 2010–2012) to GC and Plan de Investigación de la Universidad de Navarra (PIUNA) (2011–2013) to AR. CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn) is an initiative of the Instituto de Salud Carlos III, Spain.

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Author notes

  1. G Calamita and G Frühbeck: These authors contributed equally to this work.

Authors and Affiliations

  1. Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain

    A Rodríguez, L Méndez-Giménez & G Frühbeck

  2. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Pamplona, Spain

    A Rodríguez, V Valentí, F Rotellar & G Frühbeck

  3. Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy

    P Gena, A Rosito, M Svelto & G Calamita

  4. Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain

    V Valentí & F Rotellar

  5. Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain

    I Sola

  6. Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain

    R Moncada

  7. Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain

    C Silva, J Salvador & G Frühbeck

  8. Centro di Eccellenza di Genomica in campo Biomedico ed Agrario (CEGBA), Bari, Italy

    M Svelto & G Calamita

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Correspondence to G Calamita or G Frühbeck.

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Rodríguez, A., Gena, P., Méndez-Giménez, L. et al. Reduced hepatic aquaporin-9 and glycerol permeability are related to insulin resistance in non-alcoholic fatty liver disease. Int J Obes 38, 1213–1220 (2014). https://doi.org/10.1038/ijo.2013.234

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