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Metabolites 2016, 6(1), 1; doi:10.3390/metabo6010001

Metabolic Flux Distribution during Defatting of Steatotic Human Hepatoma (HepG2) Cells

1
Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA
2
Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital and the Shriners Hospitals for Children, Boston, MA 02114, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Peter Meikle
Received: 2 December 2015 / Revised: 23 December 2015 / Accepted: 29 December 2015 / Published: 4 January 2016
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Abstract

Methods that rapidly decrease fat in steatotic hepatocytes may be helpful to recover severely fatty livers for transplantation. Defatting kinetics are highly dependent upon the extracellular medium composition; however, the pathways involved are poorly understood. Steatosis was induced in human hepatoma cells (HepG2) by exposure to high levels of free fatty acids, followed by defatting using plain medium containing no fatty acids, or medium supplemented with a cocktail of defatting agents previously described before. We measured the levels of 28 extracellular metabolites and intracellular triglyceride, and fed the data into a steady-state mass balance model to estimate strictly intracellular fluxes. We found that during defatting, triglyceride content decreased, while beta-oxidation, the tricarboxylic acid cycle, and the urea cycle increased. These fluxes were augmented by defatting agents, and even more so by hyperoxic conditions. In all defatting conditions, the rate of extracellular glucose uptake/release was very small compared to the internal supply from glycogenolysis, and glycolysis remained highly active. Thus, in steatotic HepG2 cells, glycolysis and fatty acid oxidation may co-exist. Together, these pathways generate reducing equivalents that are supplied to mitochondrial oxidative phosphorylation. View Full-Text
Keywords: fatty liver; steatosis; defatting; beta-oxidation; mass balances; liver transplantation; hepatocytes fatty liver; steatosis; defatting; beta-oxidation; mass balances; liver transplantation; hepatocytes
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Yarmush, G.; Santos, L.; Yarmush, J.; Koundinyan, S.; Saleem, M.; Nativ, N.I.; Schloss, R.S.; Yarmush, M.L.; Maguire, T.J.; Berthiaume, F. Metabolic Flux Distribution during Defatting of Steatotic Human Hepatoma (HepG2) Cells. Metabolites 2016, 6, 1.

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