Hepatic Transcriptomics Reveals that Lipogenesis Is a Key Signaling Pathway in Isocitrate Dehydrogenase 2 Deficient Mice

Abstract

Mitochondrial nicotinamide adenine dinucleotide phosphate (NADP(+))-dependent isocitrate dehydrogenase (IDH2) plays a key role in the intermediary metabolism and energy production via catalysing oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the tricarboxylic acid (TCA) cycle. Despite studies reporting potential interlinks between IDH2 and various diseases, there is lack of effort to comprehensively characterize signature(s) of IDH2 knockout (IDH2 KO) mice. A total of 6583 transcripts were identified from both wild-type (WT) and IDH2 KO mice liver tissues. Afterwards, 167 differentially expressed genes in the IDH2 KO group were short-listed compared to the WT group based on our criteria. The online bioinformatic analyses indicated that lipid metabolism is the most significantly influenced metabolic process in IDH2 KO mice. Moreover, the TR/RXR activation pathway was predicted as the top canonical pathway significantly affected by IDH2 KO. The key transcripts found in the bioinformatic analyses were validated by qPCR analysis, corresponding to the transcriptomics results. Further, an additional qPCR analysis confirmed that IDH2 KO caused a decrease in hepatic de novo lipogenesis via the activation of the fatty acid beta-oxidation process. Our unbiased transcriptomics approach and validation experiments suggested that IDH2 might play a key role in homeostasis of lipid metabolism.