Is the pathway of energy metabolism modified in advanced cirrhosis? (2014)

A switch in the source of ATP production and a loss in capacity to perform glycolysis are hallmarks of hepatocyte failure in advance liver diseaseJournal of HepatologyVol. 60Issue 6PreviewThe cause of hepatic failure in the terminal stages of chronic injury is unknown. Cellular metabolic adaptations in response to the microenvironment have been implicated in cellular breakdown. Full-Text PDF Reply to: “Is the pathway of energy metabolism modified in advanced cirrhosis?”Journal of HepatologyVol. 61Issue 2PreviewWe would like to thank Ganapathy-Kanniappan et al., for relating to our work to suggest an interesting hypothesis for the origin of hepatocellular carcinoma (HCC). Based on the recent and historical findings that HCC is associated with elevated glycolysis [1,2], they propose an interesting hypothesis that metabolic adaptations in early stages of liver cirrhotic hepatocytes could be linked to the origin of tumorigenesis in liver and that end-stage failing cirrhotic hepatocytes undergoes metabolic adaptations leading to HCC. Full-Text PDF Open Access The role of metabolic alterations and adaptations is becoming increasingly evident in the pathogenesis of cirrhosis and hepatocellular carcinoma (HCC) [1Krahenbuhl S. Reichen J. Adaptation of mitochondrial metabolism in liver cirrhosis. Different strategies to maintain a vital function.Scand J Gastroenterol Suppl. 1992; 193: 90-96Crossref PubMed Scopus (23) Google Scholar, 2Geschwind J.F. Georgiades C.S. Ko Y.H. Pedersen P.L. Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma.Expert Rev Anticancer Ther. 2004; 4: 449-457Crossref PubMed Scopus (110) Google Scholar, 3Aram G. Potter J.J. Liu X. Wang L. Torbenson M.S. Mezey E. Deficiency of nicotinamide adenine dinucleotide phosphate, reduced form oxidase enhances hepatocellular injury but attenuates fibrosis after chronic carbon tetrachloride administration.Hepatology. 2009; 49: 911-919Crossref PubMed Scopus (39) Google Scholar, 4Ganapathy-Kanniappan S. Kunjithapatham R. Geschwind J.F. Glyceraldehyde-3-phosphate dehydrogenase: a promising target for molecular therapy in hepatocellular carcinoma.Oncotarget. 2012; 3: 940-953Crossref PubMed Scopus (57) Google Scholar]. Using a rat model of cirrhosis, Nishikawa et al. [[5]Nishikawa T. Bellance N. Damm A. Bing H. Zhu Z. Handa K. et al.A switch in the source of ATP production and a loss in capacity to perform glycolysis are hallmarks of hepatocyte failure in advance liver disease.J Hepatol. 2014; 60: 1203-1211Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar] demonstrate that early stage cirrhotic hepatocytes switch to glycolysis to meet their energy requirements as a result of a decline in oxidative phosphorylation, but that this mechanism fails in late cirrhosis. Since HCC typically arises in the background of liver cirrhosis [[6]Fattovich G. Stroffolini T. Zagni I. Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors.Gastroenterology. 2004; 127: S35-S50Abstract Full Text Full Text PDF PubMed Scopus (1884) Google Scholar] and also encompasses a glycolytic phenotype [[7]Beyoglu D. Idle J.R. The metabolomic window into hepatobiliary disease.J Hepatol. 2013; 59: 842-858Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar], it would be important to determine how this is related to the altered metabolism of cirrhotic hepatocytes. Since early cirrhotic cells are more glycolytic than advanced or failing cirrhotic cells, it remains unclear as to whether the progression of HCC is facilitated by metabolically active early cirrhotic cells or represents an escape mechanism of late cirrhotic hepatocytes which are unable to sustain their energy demands. The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.