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Fat induces glucose metabolism in nontransformed liver cells and promotes liver tumorigenesis

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic g...

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Main Authors: Broadfield, Lindsay A. (Author) , Duarte, João André Gonçalves (Author) , Schmieder, Roberta (Author) , Broekaert, Dorien (Author) , Veys, Koen (Author) , Planque, Mélanie (Author) , Vriens, Kim (Author) , Karasawa, Yasuaki (Author) , Napolitano, Francesco (Author) , Fujita, Suguru (Author) , Fujii, Masashi (Author) , Eto, Miki (Author) , Holvoet, Bryan (Author) , Vangoitsenhoven, Roman (Author) , Fernandez-Garcia, Juan (Author) , Elsen, Joke Van (Author) , Dehairs, Jonas (Author) , Zeng, Jia (Author) , Dooley, James (Author) , Rubio, Rebeca Alba (Author) , Pelt, Jos van (Author) , Grünewald, Thomas G. P. (Author) , Liston, Adrian (Author) , Mathieu, Chantal (Author) , Deroose, Christophe M. (Author) , Swinnen, Johannes V. (Author) , Lambrechts, Diether (Author) , Bernardo, Diego di (Author) , Kuroda, Shinya (Author) , Bock, Katrien De (Author) , Fendt, Sarah-Maria (Author)
Format: Article (Journal)
Language:English
Published: March 9, 2021
In: Cancer research
Year: 2021, Volume: 81, Issue: 8, Pages: 1988-2001
ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-20-1954
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/0008-5472.CAN-20-1954
Verlag, lizenzpflichtig, Volltext: https://cancerres.aacrjournals.org/content/81/8/1988
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Author Notes:Lindsay A. Broadfield, João André Gonçalves Duarte, Roberta Schmieder, Dorien Broekaert, Koen Veys, Mélanie Planque, Kim Vriens, Yasuaki Karasawa, Francesco Napolitano, Suguru Fujita, Masashi Fujii, Miki Eto, Bryan Holvoet, Roman Vangoitsenhoven, Juan Fernandez-Garcia, Joke Van Elsen, Jonas Dehairs, Jia Zeng, James Dooley, Rebeca Alba Rubio, Jos van Pelt, Thomas G.P. Grünewald, Adrian Liston, Chantal Mathieu, Christophe M. Deroose, Johannes V. Swinnen, Diether Lambrechts, Diego di Bernardo, Shinya Kuroda, Katrien De Bock, and Sarah-Maria Fendt

MARC

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245 1 0 |a Fat induces glucose metabolism in nontransformed liver cells and promotes liver tumorigenesis  |c Lindsay A. Broadfield, João André Gonçalves Duarte, Roberta Schmieder, Dorien Broekaert, Koen Veys, Mélanie Planque, Kim Vriens, Yasuaki Karasawa, Francesco Napolitano, Suguru Fujita, Masashi Fujii, Miki Eto, Bryan Holvoet, Roman Vangoitsenhoven, Juan Fernandez-Garcia, Joke Van Elsen, Jonas Dehairs, Jia Zeng, James Dooley, Rebeca Alba Rubio, Jos van Pelt, Thomas G.P. Grünewald, Adrian Liston, Chantal Mathieu, Christophe M. Deroose, Johannes V. Swinnen, Diether Lambrechts, Diego di Bernardo, Shinya Kuroda, Katrien De Bock, and Sarah-Maria Fendt 
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520 |a Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC. - Significance: With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, nontransformed livers that fat induces glucose metabolism similar to an oncogenic transformation. 
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700 1 |a Liston, Adrian  |e VerfasserIn  |4 aut 
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