Sexually dimorphic effects of CYP2B6 in the development of fasting-mediated steatosis in mice: Role of the oxylipin products 9-HODE and 9-HOTrE

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CYP2B6 is a sexually dimorphic, anti-obesity CYP enzyme responsible for the metabolism of xeno- and endobiotics, including the metabolism of polyunsaturated fatty acids (PUFAs) into 9-HODE and 9-HOTrE. hCYP2B6-Tg mice are sensitive to diet-induced hepatic steatosis despite their resistance to obesity. The purpose of this work is to determine if 9-HODE, 9-HOTrE, or other factors contribute to the steatosis observed in hCYP2B6-Tg mice. Cyp2b-null mice were injected with either 9-HODE or 9-HOTrE for 2 days then subjected to a 20-h fast. In addition, hCYP2B6-Tg mice and Cyp2b-null mice were compared after a 20-h fast. Serum lipids were moderately increased by 9-HODE or 9-HOTrE, especially in females, after 9-HODE (TG, VLDL) and 9-HOTrE (HLD, LDL, cholesterol) treatment. In addition, hCYP2B6-Tg mice exhibited increased steatosis compared to Cyp2b-null mice. Serum cholesterol, triglycerides, HDL, and VLDL were increased in hCYP2B6-Tg males. Serum triglycerides and VLDL were decreased in hCYP2B6-Tg females, suggesting greater hepatic retention of lipids in females. Hepatic oxylipin profiles revealed 8 perturbed oxylipins in hCYP2B6-Tg mice and only 1 in males compared to Cyp2b-null mice. RNA-seq was also performed and while the oxylipins showed little to moderate affects, there were profound differences between hCYP2B6-Tg mice and Cyp2b-null mice. Earlier studies under normal diet conditions found few changes in gene expression. In addition, greater changes were found in females in terms of number of genes and GO terms perturbed. There were only a few overlapping GO terms between sexes and lipid metabolic processes was enriched in hCYP2B6-Tg male mice but repressed in hCYP2B6-Tg females compared to Cyp2b-nulls. In conclusion, hCYP2B6-Tg mice are sensitive to steatosis in males and females although the responses are different. The oxylipins 9-HODE and 9-HOTrE are unlikely to be a sole or major cause of CYP2B6’s pro-steatotic effects based on RNAseq, liver steatosis, and serum triglyceride perturbations.

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