Reply to: “Is the pathway of energy metabolism modified in advanced cirrhosis?”
Authors: Deepak Nagrath, Alejandro Soto-Gutierrez
Journal: Journal of Hepatology (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 Is the pathway of energy metabolism modified in advanced cirrhosis?Journal of HepatologyVol. 61Issue 2PreviewThe role of metabolic alterations and adaptations is becoming increasingly evident in the pathogenesis of cirrhosis and hepatocellular carcinoma (HCC) [1–4]. Using a rat model of cirrhosis, Nishikawa et al. [5] 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] and also encompasses a glycolytic phenotype [7], it would be important to determine how this is related to the altered metabolism of cirrhotic hepatocytes. Full-Text PDF Open Access We 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 [1Huang Q. Tan Y. Yin P. Ye G. Gao P. Lu X. et al.Metabolic characterization of hepatocellular carcinoma using nontargeted tissue metabolomics.Cancer Res. 2013; 73: 4992-5002Crossref PubMed Scopus (289) Google Scholar, 2Beyoglu D. Imbeaud S. Maurhofer O. Bioulac-Sage P. Zucman-Rossi J. Dufour J.F. et al.Tissue metabolomics of hepatocellular carcinoma: tumor energy metabolism and the role of transcriptomic classification.Hepatology. 2013; 58: 229-238Crossref PubMed Scopus (138) Google Scholar], 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. However, the mechanistic links between liver cirrhosis and HCC are unclear and identification of pathways connecting both remains elusive. The focus of our recent work was the study of adaptive energy metabolic changes during liver cirrhosis to understand hepatic failure in the terminal stages of chronic injury [[3]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 (83) Google Scholar]. Even though the letter to the editor from Ganapathy-Kanniappan et al., is not completely related to the study we designed, it is recognized that liver cirrhosis is considered as a precursor to HCC.In addition to hepatocytes, it is important to consider the role of the tumor microenvironment in regulating the metabolism of cancer cells. Recent studies have shown that cells in the tumor microenvironment generate energy rich metabolites (e.g., lactate, beta-hydroxybutyrate) that are used by cancer cells for meeting their energetic demand through mitochondrial tricarboxylic acid cycle [4Bonuccelli G. Whitaker-Menezes D. Castello-Cros R. Pavlides S. Pestell R.G. Fatatis A. et al.The reverse Warburg effect: glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts.Cell Cycle. 2010; 9: 1960-1971Crossref PubMed Scopus (170) Google Scholar, 5Migneco G. Whitaker-Menezes D. Chiavarina B. Castello-Cros R. Pavlides S. Pestell R.G. et al.Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: evidence for stromal-epithelial metabolic coupling.Cell Cycle. 2010; 9: 2412-2422Crossref PubMed Scopus (111) Google Scholar]. Based on the compelling recent results [[6]Chan I.S. Guy C.D. Chen Y. Lu J. Swiderska-Syn M. Michelotti G.A. et al.Paracrine hedgehog signaling drives metabolic changes in hepatocellular carcinoma.Cancer Res. 2012; 72: 6344-6350Crossref PubMed Scopus (42) Google Scholar], one possibility is that microenvironment may induce metabolic transformations in early cirrhotic hepatocytes and when in contact with stromal cells to sustain their nutrient demand. Early cirrhotic hepatocytes may alter the surrounding cells metabolic phenotype to secrete high-energy metabolites for their energetic requirements. Metabolic alterations and adaptations are thus an exciting area of investigation.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We 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 [1Huang Q. Tan Y. Yin P. Ye G. Gao P. Lu X. et al.Metabolic characterization of hepatocellular carcinoma using nontargeted tissue metabolomics.Cancer Res. 2013; 73: 4992-5002Crossref PubMed Scopus (289) Google Scholar, 2Beyoglu D. Imbeaud S. Maurhofer O. Bioulac-Sage P. Zucman-Rossi J. Dufour J.F. et al.Tissue metabolomics of hepatocellular carcinoma: tumor energy metabolism and the role of transcriptomic classification.Hepatology. 2013; 58: 229-238Crossref PubMed Scopus (138) Google Scholar], 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. However, the mechanistic links between liver cirrhosis and HCC are unclear and identification of pathways connecting both remains elusive. The focus of our recent work was the study of adaptive energy metabolic changes during liver cirrhosis to understand hepatic failure in the terminal stages of chronic injury [[3]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 (83) Google Scholar]. Even though the letter to the editor from Ganapathy-Kanniappan et al., is not completely related to the study we designed, it is recognized that liver cirrhosis is considered as a precursor to HCC. In addition to hepatocytes, it is important to consider the role of the tumor microenvironment in regulating the metabolism of cancer cells. Recent studies have shown that cells in the tumor microenvironment generate energy rich metabolites (e.g., lactate, beta-hydroxybutyrate) that are used by cancer cells for meeting their energetic demand through mitochondrial tricarboxylic acid cycle [4Bonuccelli G. Whitaker-Menezes D. Castello-Cros R. Pavlides S. Pestell R.G. Fatatis A. et al.The reverse Warburg effect: glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts.Cell Cycle. 2010; 9: 1960-1971Crossref PubMed Scopus (170) Google Scholar, 5Migneco G. Whitaker-Menezes D. Chiavarina B. Castello-Cros R. Pavlides S. Pestell R.G. et al.Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: evidence for stromal-epithelial metabolic coupling.Cell Cycle. 2010; 9: 2412-2422Crossref PubMed Scopus (111) Google Scholar]. Based on the compelling recent results [[6]Chan I.S. Guy C.D. Chen Y. Lu J. Swiderska-Syn M. Michelotti G.A. et al.Paracrine hedgehog signaling drives metabolic changes in hepatocellular carcinoma.Cancer Res. 2012; 72: 6344-6350Crossref PubMed Scopus (42) Google Scholar], one possibility is that microenvironment may induce metabolic transformations in early cirrhotic hepatocytes and when in contact with stromal cells to sustain their nutrient demand. Early cirrhotic hepatocytes may alter the surrounding cells metabolic phenotype to secrete high-energy metabolites for their energetic requirements. Metabolic alterations and adaptations are thus an exciting area of investigation. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.