title: Specific alterations of carbohydrate metabolism are associated with hepatocarcinogenesis in mitochondrially impaired mice.
abstract: Friedreich's ataxia is an inherited neurodegenerative disease caused by the reduced expression of the mitochondrially active protein frataxin. We have previously shown that mice with a hepatocyte-specific frataxin knockout (AlbFxn(-/-)) develop multiple hepatic tumors in later life. In the present study, hepatic carbohydrate metabolism in AlbFxn(-/-) mice at an early and late life stage was analyzed. In young (5-week-old) AlbFxn(-/-) mice hepatic ATP, glucose-6-phosphate and glycogen levels were found to be reduced by ∼74, 80 and 88%, respectively, when compared with control animals. This pronounced ATP, G6P and glycogen depletion in the livers of young mice reverted in older animals: while half of the mice die before 30 weeks of age, the other half reaches 17 months of age and exhibits glycogen, G6P and ATP levels similar to those in age-matched controls. A key event in this respect seems to be the up-regulation of GLUT1, the predominant glucose transporter in fetal liver parenchyma, which became evident in AlbFxn(-/-) mice being 5-12 weeks of age. The most significant histological findings in animals being 17 or 22 months of age were the appearance of multiple clear cell, mixed cell and basophilic foci throughout the liver parenchyma as well as the development of hepatocellular adenomas and carcinomas. The hepatocarcinogenic process in AlbFxn(-/-) mice shows remarkable differences regarding carbohydrate metabolism alterations when compared with all other chemically and virally driven liver cancer models described up to now.
authors: Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173 Hannover, Germany. rene.thierbach@uni-jena.de
authors: René
authors: R
authors: Thierbach
authors: Simone
authors: S
authors: Florian
authors: Katharina
authors: K
authors: Wolfrum
authors: Anja
authors: A
authors: Voigt
authors: Gunnar
authors: G
authors: Drewes
authors: Urte
authors: U
authors: Blume
authors: Peter
authors: P
authors: Bannasch
authors: Michael
authors: M
authors: Ristow
authors: Pablo
authors: P
authors: Steinberg
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D050260:Carbohydrate Metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D000096923:Frataxin
chemical_list: D000255:Adenosine Triphosphate; D051246:Glucose Transport Proteins, Facilitative; D019298:Glucose-6-Phosphate; D006003:Glycogen; D006006:Glycogen Synthase; D038362:Glycogen Synthase Kinase 3; D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins; D000096923:Frataxin