Role of human CYP2B6 in vivo in diet-induced obesity

To investigate the role of human CYP2B6 in vivo under high-fat diet conditions, we compared our previously developed Cyp2b triple knockout mouse lacking Cyp2b9, Cyp2b10, and Cyp2b13 (via CRISPER/Cas9; Cyp2b-null), to our newly developed humanized-CYP2B6-transgenic (hCYP2B6-Tg) mouse model (on a Cyp2b-null background). hCYP2B6-Tg and Cyp2b-null mice were fed a high-fat diet consisting of 60% fat for 16 weeks. RNA was extracted from the livers of female and male mice from both treatment groups and used for RNA seqencing. RNAseq and in gene ontology (GO) analysis indicate human CYP2B6 is important in protein processing and phosphorylation, hepatic circadian regulation, and lipid metabolism under HFD conditions.Circadian rhythm-associated genes were up-regulated in HFD-fed hCYP2B6-Tg mice compared to Cyp2b-null mice. Circadian regulation plays an important role in liver metabolism and metabolic disease. In addition, female hCYP2B6-Tg mice had several down-regulated genes involved in lipid metabolism compared to Cyp2b-null mice, notably Angptl8 (logFC = -1.24), a critical modulator of lipid metabolism that has been associated with metabolic disease. Genes identified by RNAseq analysis may contribute to the overall healthier metabolic profile of HFD-fed humanized mice compared to Cyp2b-null mice. Use RNA-sequencing to investigate the role of human CYP2B6 in diet-induced obesity on a transcriptomic level, by comparing the livers of Cyp2b-null and hCYP2B6-Tg mice fed a high-fat diet for 16 weeks using Illumina technology.