Every cell in the human body needs energy to sustain its metabolic functions. To this respect, glucose regulation is essential, especially the gluconeogenesis pathway that converts non-hexose precursors, such as glycerol, lactate, pyruvate and glucogenic amino acids into glucose moieties. It is known that gluconeogenesis mainly occurs in the liver and, to a lesser extent, in kidneys. During fasting and under stress conditions, renal gluconeogenesis may account for 40% of systemic gluconeogenesis. To this respect, our lab is interested in liver-to-kidney crosstalk. To do so, we intend to build an in vitro model allowing the communication between hepatocytes and renal cells. Initially, we decided to use the HepG2 hepatocyte cell line mainly for its ease of implementation as well as for the numerous publications demonstrating their usefulness in various applications.

We started with the assessment of their metabolic skills by using a ¹H-NMR -based metabolomic approach. The gluconeogenesis pathway was stimulated by adding a cocktail of known precursors (lactate, pyruvate, cAMP and dexamethasone). However, the metabolomic findings revealed that HepG2 cells essentially displayed a Warburg-like profile, as expected for cancer cells, but with very limited or no gluconeogenesis activity even under stimulation.

In conclusion, the HepG2 cell line does not seem like a reliable ally to study gluconeogenesis and another model is needed. Primary hepatocytes could represent a valuable alternative. However, their use should be coupled with MS-based metabolomic instead of NMR due to a limitation in cell number.