Abstract
Background and aims: Liver toxicity is a well-documented and potentially fatal adverse complication of hyperthermia. However, the impact of hyperthermia on the hepatic metabolome has hitherto not been investigated. Methods: In this study, gas chromatography-mass spectrometry (GC-MS)-based metabolomics was applied to assess the in vitro metabolic response of primary mouse hepatocytes (PMH, n = 10) to a heat stress stimulus, i.e., after 24 h exposure to 40.5 °C. Metabolomic profiling of both intracellular metabolites and volatile metabolites in the extracellular medium of PMH was performed. Results: Multivariate analysis showed alterations in levels of 22 intra- and 59 extracellular metabolites, unveiling the capability of the metabolic pattern to discriminate cells exposed to heat stress from cells incubated at normothermic conditions (37 °C). Hyperthermia caused a considerable loss of cell viability that was accompanied by significant alterations in the tricarboxylic acid cycle, amino acids metabolism, urea cycle, glutamate metabolism, pentose phosphate pathway, and in the volatile signature associated with the lipid peroxidation process. Conclusion: These results provide novel insights into the mechanisms underlying hyperthermia-induced hepatocellular damage.
Highlights
Thermoregulation is a complex process, crucial for body homeostasis and survival, that is meticulously orchestrated by the thermoregulatory center in the hypothalamus [1]
Our analysis revealed that phenylalanine and tyrosine metabolism, aspartate metabolism, urea cycle, tricarboxylic revealed that phenylalanine and tyrosine metabolism, urea cycle, tricarboxylic acid (TCA)
Work, different gas chromatography-mass spectrometry (GC-MS) approaches were implemented to study the intracellular and extracellular different GC-MS approaches were implemented to study the intracellular and extracellular metabolome in order to better characterize the changes caused by hyperthermia in mice isolated metabolome in order to better characterize the changes caused by hyperthermia in mice isolated hepatocytes
Summary
Thermoregulation is a complex process, crucial for body homeostasis and survival, that is meticulously orchestrated by the thermoregulatory center in the hypothalamus [1]. A wide variety of xenobiotics can affect the thermal homeostasis, triggering or exacerbating the hyperthermia-induced damage, both by the increased metabolic heat production (e.g., sympathomimetic agents) or by an impairment of heat-dissipating effector mechanisms (e.g., anticholinergic agents) [3]. This disruption will affect many other homeostatic systems and may result in several life-threatening complications such as disseminated intravascular coagulation, hyperkalemia, metabolic acidosis, multi-organ failure, and rhabdomyolysis [4,5,6]. Conclusion: These results provide novel insights into the mechanisms underlying hyperthermia-induced hepatocellular damage
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