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Role of Cyp2b in diet-induced nonalcoholic steatohepatitis (NASH)

ABSTRACT: To investigate the role of hepatic CYP2B in diet-induced nonalcoholic steatohepatitis (NASH), a Cyp2b triple knockout mouse lacking Cyp2b9, Cyp2b10, and Cyp2b13 was developed using CRISPER/Cas9. Wildtype (WT) and Cyp2b-null mice were fed a normal diet (ND) or a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD), containing 0.1% methionine and 62% fat for 8 weeks. RNA was extracted from the livers of female and male mice from all treatment groups and used for RNA seqencing. RNAseq data demonstrated that a lack of Cyp2b was protective in female but more harmful in male mice. Hepatic gene expression revealed a higher number of phase I-III xenobiotic metabolism and inflammatory response genes were down-regulated in CDAHFD-fed WT female and Cyp2b-null male mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE137449 | GEO | 2019/12/31

REPOSITORIES: GEO

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Project description:Cytochrome P450 2B6 (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. However, hCYP2B6-Tg mice are sensitive to diet-induced hepatic steatosis despite their resistance to obesity. The purpose of this manuscript was determine if 9-HODE, 9-HOTrE, or other factors contribute to the sexually dimorphic 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 fasting period of 20 hours to induce steatosis. Moderately increased serum lipids, especially in females, were observed after 9-HODE (TG, VLDL) and 9-HOTrE (HLD, LDL, cholesterol) treatment. No change in hepatic lipids and few changes in hepatic gene expression were observed in mice treated with either oxylipin, suggesting these oxylipins had little effect or their effects were extrahepatic. Therefore, to further investigate CYP2B6’s role in steatosis, hCYP2B6-Tg and Cyp2b-null mice were subjected to a 20-hour fast and compared. Both male and female 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. Hepatic oxylipin profiles revealed 8 perturbed oxylipins in hCYP2B6-Tg mice and only 1 in males when compared to Cyp2b-null mice. RNA-seq also demonstrated greater effects in females in terms of number of genes and GO terms perturbed. There were only a few overlapping GO terms 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. In addition, the oxylipins 9-HODE and 9-HOTrE are unlikely to be a major cause of CYP2B6’s pro-steatotic effects.

Project description:Perfluorooctanesulfonate (PFOS) is a widespread environmental pollutant with a long half-life and clearly negative outcomes on metabolic diseases such as fatty liver and diabetes. Male and female Cyp2b-null and humanized CYP2B6-transgenic (hCYP2B6-Tg) mice were treated with 0, 1, or 10 mg/kg/day PFOS for 21 days, and surprisingly it was found that PFOS was retained at greater concentrations in the serum and liver of hCYP2B6-Tg mice than Cyp2b-null mice with greater differences in the females. Thus, Cyp2b-null and hCYP2B6-Tg mice provide new models for investigating individual mechanisms for PFOS bioaccumulation and toxicity. Overt toxicity was greater in hCYP2B6-Tg mice (especially females) as measured by mortality; however, steato-sis occurred more readily in Cyp2b-null mice despite the lower PFOS liver concentrations. Tar-geted lipidomics and transcriptomics from PFOS treated Cyp2b-null and hCYP2B6-Tg mouse livers were performed and compared to PFOS retention and serum markers of toxicity by PCA. Several oxylipins, including prostaglandins, thromboxanes, and docosahexaenoic acid metabo-lites are associated or inversely associated with PFOS toxicity. Both lipidomics and tran-scriptomics indicate PFOS toxicity is associated with PPAR activity in all models. GO terms as-sociated with reduced steatosis were sexually dimorphic with lipid metabolism and transport increased in females and circadian rhythm associated genes increased in males. However, we can rule out that steatosis was initially protective from PFOS toxicity. Moreover, several transporters are associated with increased retention probably due to increased uptake. The strongest associa-tions are the organic anion transport proteins (Oatp1a4-6) genes and a long-chain fatty acid transport protein (fatp1), enriched in female hCYP2B6-Tg mice. PFOS uptake was also reduced in cultured murine hepatocytes by OATP inhibitors. The role of OATP1A6 and FATP1 in PFOS transport has not been tested. In summary, Cyp2b-null and hCYP2B6-Tg mice provided unique models for estimating the importance of novel mechanisms in PFOS retention and toxicity.

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Role of Cyp2b in diet-induced nonalcoholic steatohepatitis (NASH)

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