Hepatic glycerol metabolism is early reprogrammed in rat liver cancer development

Abstract

Evidence shows that oral glycerol supplementation during the early stages of rat liver cancer reduces the growth of preneoplastic lesions. Besides, human hepatocellular carcinoma (HCC) cells display decreased expression of glycerol channel aquaporin 9 (AQP9) and also diminished glycerol-3-phosphate (G3P) content. According to this, we analyzed glycerol metabolism during the initial stages of rat liver carcinogenesis. Wistar rats were subjected to a 2-phase model of hepatocarcinogenesis (initiated-promoted, IP group) or left untreated (control, C group). Different features of glycerol metabolism were compared between both groups. IP animals showed increased plasma free glycerol levels and liver AQP9 protein expression. Also, IP rats showed increased glycerol kinase (GK) and glycerol-3-phosphate dehydrogenase (GPDH) hepatic activities. Gluconeogenesis from glycerol both in vivo and in isolated perfused liver was higher in rats having liver preneoplasia. Nevertheless, preneoplastic foci notably reduced AQP9 and GK protein expressions, displaying a reduced ability to import glycerol and to convert it into G3P, as a way to preserve preneoplastic hepatocytes from the deleterious effect of G3P. In conclusion, the metabolic shift that takes place in the initial stages of liver cancer development comprises an increased hepatic utilization of glycerol for gluconeogenesis. Enhanced glucose production from glycerol is mostly carried out by the surrounding non-preneoplastic tissue and can be used as an energy source for the early transformed liver cells.