Comparison of HepaRG cells following growth in proliferative and differentiated culture conditions reveals distinct bioenergetic profiles
Abstract
HepaRG is a proliferative human hepatoma-derived cell line that can be differentiated into hepatocyte-like and biliary-like cells. Differentiated HepaRG cultures maintain key hepatic functions including drug transporters and xenobiotic-metabolizing enzymes. To gain insight into proliferative and differentiated HepaRG metabolism we profiled various bioenergetic parameters and investigated cell culture levels of adenosine triphosphate (ATP), lactate, and lactate dehydrogenase (LDH) activity. Compared to differentiated-derived HepaRG, cells from proliferative cultures had increased basal and ATP-linked respiration and decreased maximal and spare respiratory capacities. Basal ATP levels but not lactate or LDH activity were increased in samples from proliferative-derived compared to differentiated-derived HepaRG. Further extracellular acidification rate (ECAR) experiments revealed parameters associated with glycolysis and oxidative phosphorylation. Under basal conditions, cells derived from both cultures had similar ECARs; however, under stressed conditions, proliferative-derived HepaRG had increases in ECAR capacity and apparent glycolytic reserve. The biguanide metformin has been reported to protect differentiated HepaRG against acetaminophen (APAP)-induced cell injury, as well as offer protection against bioenergetic deficiencies; therefore, we studied the outcome of exposure to these drugs in both culture conditions. Proliferative- and differentiated-derived cells were found…
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