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Deletion of protein kinase Cepsilon in mice has limited effects on liver metabolite levels but alters fasting ketogenesis and gluconeogenesis

Abstract

AIMS/HYPOTHESIS: Protein kinase Cepsilon (PKCepsilon) is emerging as a key mediator of lipid-induced insulin resistance in liver and hepatic lipid metabolism itself. We investigated whether PKCepsilon plays a role in other metabolic processes, to further examine its suitability as a therapeutic target. METHODS: We measured amino acid, organic acid and sugar levels by liquid and gas chromatography-mass spectrometry of liver extracts from chow and fat-fed wild-type (WT) and PKCepsilon-deficient (Prkce (-/-)) mice. Fed and fasting glucose, ketone and fatty acid levels were measured in blood. Triacylglycerol levels and gluconeogenic and ketogenic enzyme expression were measured in liver. The effect of fasting on epididymal fat pad mass was also determined. RESULTS: Metabolomic analysis indicated that the short-term high-fat diet affected over 20 compounds, including a 50% reduction in the glucogenic amino acid alanine. Prkce deletion resulted only in a reduction of 4-hydroxyproline and aspartate and an increase in glutamate. However, upon fasting, Prkce (-/-) mice were better able to maintain blood glucose levels and also exhibited lower levels of the ketone beta-hydroxybutyrate compared with WT mice. Upon fasting, Prkce deletion also resulted in lower liver and plasma lipids and a smaller reduction in fat pad mass. CONCLUSIONS/INTERPRETATION: Metabolomic analysis provided new insights into the effects of a high-fat diet on liver metabolite levels. Glucose homeostasis under fasting conditions is improved in Prkce (-/-) mice, which, in turn, may reduce the mobilisation of lipid from adipose tissue, reducing the availability of ketogenic substrate in the liver. Together with the protection against fat-diet-induced glucose intolerance previously observed in the fed state, these findings indicate PKCepsilon as a unique therapeutic target for the improvement of glucose homeostasis.

Type Journal
Authors Raddatz, K.; Frangioudakis, G.; Diakanastasis, B.; Liao, B. M.; Leitges, M.; Schmitz-Peiffer, C.
Garvan Authors A/Prof Carsten Schmitz-Peiffer
Publisher Name DIABETOLOGIA
Published Date 2012-10-01 00:00:00
Published Volume 55
Published Issue 10
Published Pages 2789-93
URL http://www.ncbi.nlm.nih.gov/pubmed/22814763
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?11384_12063/12_Raddatz_Diabet_.pdf