The metabolomics of a protein kinase C delta (PKCδ) knock-out mouse model

Abstract

Introduction PKCδ is ubiquitously expressed in mammalian cells and its dysregulation plays a key role in the onset of several incurable diseases and metabolic disorders. However, much remains unknown about the metabolic pathways and disturbances induced by PKC deficiency, as well as the metabolic mechanisms involved. Objectives This study aims to use metabolomics to further characterize the function of PKC from a metabolomics standpoint, by comparing the full serum metabolic profiles of PKC deficient mice to those of wild-type mice. Methods The serum metabolomes of PKCδ knock-out mice were compared to that of a wild-type strain using a GCxGC-TOFMS metabolomics research approach and various univariate and multivariate statistical analyses. Results Thirty-seven serum metabolite markers best describing the difference between PKCδ knock-out and wild-type mice were identified based on a PCA power value > 0.9, a t-test p-value < 0.05, or an effect size > 1. XERp prediction was also done to accurately select the metabolite markers within the 2 sample groups. Of the metabolite markers identified, 78.4% (29/37) were elevated and 48.65% of these markers were fatty acids (18/37). It is clear that a total loss of PKCδ functionality results in an inhibition of glycolysis, the TCA cycle, and steroid synthesis, accompanied by upregulation of the pentose phosphate pathway, fatty acids oxidation, cholesterol transport/storage, single carbon and sulphur-containing amino acid synthesis, branched-chain amino acids (BCAA), ketogenesis, and an increased cell signalling via N-acetylglucosamine. ConclusionThe charaterization of the dysregulated serum metabolites in this study, may represent an additional tool for the early detection and screening of PKCδ-deficiencies or abnormalities.

Metabolic reprogramming contributes to radioprotection by protein kinase Cδ

“…reported that enzymes required for glycolysis were decreased, while enzymes that regulate lipid biosynthesis were increased in hearts from PKCδ −/− mice ( 18 ). Similarly, loss of PKCδ correlated with a reduction in glycolytic metabolites and an increase in fatty acid metabolites in serum from PKCδ −/− mice ( 19 ). In hepatocytes, PKCδ has been linked to suppression of insulin signaling, activation of NADPH oxidase, and a concomitant increase of oxidative stress ( 20 ).…”

Counteracting Colon Cancer by Inhibiting Mitochondrial Respiration and Glycolysis with a Selective PKCδ Activator

“…There are some studies that have contributed to the elucidation of the function of PKCδ in glucose metabolism, under non-tumor conditions. In fact, in a recent work, data from metabolomic analysis demonstrated an inhibition of glycolysis and tricarboxylic acid cycle (TCA), which was associated with an upregulation of other metabolic pathways in PKCδ-deficient mice [ 42 ]. Additionally, regarding mitochondrial respiration, it was described that PKCδ is implicated in the stimulation of the pyruvate dehydrogenase complex activity, thereby increasing the flux of fuel entering the TCA cycle by converting pyruvate to acetyl CoA in the mitochondrial matrix [ 43 , 44 , 45 , 46 ].…”