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Metabolic Landscape of the Mouse Liver by Quantitative 31 P Nuclear Magnetic Resonance Analysis of the Phosphorome
Author(s) -
BernardoSeisdedos Ganeko,
Bilbao Jon,
FernándezRamos David,
LopitzOtsoa Fernando,
Gutierrez de Juan Virginia,
Bizkarguenaga Maider,
Mateos Borja,
Fondevila Marcos F.,
AbrilFornaguera Jordi,
Diercks Tammo,
Lu Shelly C.,
Nogueiras Rubén,
Mato José M.,
Millet Oscar
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31676
Subject(s) - steatosis , pentose phosphate pathway , gluconeogenesis , citric acid cycle , biology , metabolic pathway , steatohepatitis , biochemistry , phosphocholine , glycolysis , lipid metabolism , metabolism , hypermetabolism , medicine , chemistry , endocrinology , fatty liver , phospholipid , disease , membrane , phosphatidylcholine
Background and Aims The liver plays a central role in all metabolic processes in the body. However, precise characterization of liver metabolism is often obscured by its inherent complexity. Phosphorylated metabolites occupy a prominent position in all anabolic and catabolic pathways. Here, we develop a 31 P nuclear magnetic resonance (NMR)–based method to study the liver “phosphorome” through the simultaneous identification and quantification of multiple hydrophilic and hydrophobic phosphorylated metabolites. Approach and Results We applied this technique to define the metabolic landscape in livers from a mouse model of the rare disease disorder congenital erythropoietic porphyria (CEP) as well as two well‐known murine models of nonalcoholic steatohepatitis: one genetic, methionine adenosyltransferase 1A knockout mice, and the other dietary, mice fed a high‐fat choline‐deficient diet. We report alterations in the concentrations of phosphorylated metabolites that are readouts of the balance between glycolysis, gluconeogenesis, the pentose phosphate pathway, the tricarboxylic acid cycle, and oxidative phosphorylation and of phospholipid metabolism and apoptosis. Moreover, these changes correlate with the main histological features: steatosis, apoptosis, iron deposits, and fibrosis. Strikingly, treatment with the repurposed drug ciclopirox improves the phosphoromic profile of CEP mice, an effect that was mirrored by the normalization of liver histology. Conclusions In conclusion, these findings indicate that NMR‐based phosphoromics may be used to unravel metabolic phenotypes of liver injury and to identify the mechanism of drug action.