Aims: 

Hepatocytes express AQP9, a basolateral membrane channel permeable to water, glycerol and other small neutral solutes. Although liver AQP9 is downregulated by insulin and thought to mediate the hepatocyte glycerol uptake, its relevance in carbohydrate and fat physio-pathology remains uninvestigated. Here, we evaluate whether AQP9 acts as real glycerol channel and is involved in Non-Alcoholic Fatty Liver Disease (NAFLD), an emerging health problem worldwide characterized by exceedingly accumulation of triglycerides (steatosis) in hepatocytes.

Methods: 

Glycerol permeability (Pgly) of hepatocyte basolateral plasma membrane was assessed by stopped flow light scattering. The expression of AQP9 in ob/ob mice, an animal model of liver steatosis, or obese patients was assessed by qPCR, high-density oligonucleotide microarray, immunoblotting and immunocytochemistry.

Results: 

Both mRNA and protein levels of AQP9 were increased in the liver of fasted (vs fed) mice where a parallel increase in the hepatocyte basolateral membrane Pgly was also seen. Of note, both Pgly and AQP9 levels in the fatty liver of ob/ob mice were significantly lower than those of the control wild type counterpart. Similar AQP9 dysregulation was seen in liver biopsies by morbidly obese patients with insulin resistance or type 2 diabetes mellitus (T2DM) undergoing bariatric surgery.

Conclusions: 

Overall, these results prove functional relevance for AQP9 in liver glycerol uptake and suggest a compensatory mechanism to avoid further accumulation of triglycerides within the steatotic hepatocyte. AQP9 may prove useful to devise novel therapeutic strategies aimed at control of metabolic syndrome and related disorders such as liver steatosis and T2DM.