Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity

Abstract

Multiple factors in addition to over consumption lead to obesity and non-alcoholic fatty liver disease (NAFLD) in the United States and worldwide. CYP2B6 is the only human detoxification CYP whose loss is associated with obesity, and Cyp2b-null mice show greater diet-induced obesity with increased steatosis than wildtype mice. However, a putative mechanism has not been determined. LC-MS/MS revealed that CYP2B6 metabolizes PUFAs, with a preference for metabolism of ALA to 9-HOTrE and to a lesser extent 13-HOTrE with a preference for metabolism of PUFAs at the 9- and 13-positions. To further study the role of CYP2B6 in vivo, humanized-CYP2B6-transgenic (hCYP2B6-Tg) and Cyp2b-null mice were fed a 60% high-fat diet for 16 weeks. Compared to Cyp2b-null mice, hCYP2B6-Tg mice showed reduced weight gain and metabolic disease as measured by glucose tolerance tests, however hCYP2B6-Tg male mice showed increased liver triglycerides. Serum and liver oxylipin metabolite concentrations increased in male hCYP2B6-Tg mice, while only serum oxylipins increased in female hCYP2B6-Tg mice with the greatest increases in LA oxylipins metabolized at the 9 and 13-positions. Several of these oxylipins, specifically 9-HODE, 9-HOTrE, and 13-oxoODE, are PPAR agonists. RNA-seq data also demonstrated sexually dimorphic changes in gene expression related to nuclear receptor signaling, especially CAR > PPAR with qPCR suggesting PPARγ signaling is more likely than PPARα signaling in male mice. Overall, our data indicates that CYP2B6 is an anti-obesity enzyme, but probably to a lesser extent than murine Cyp2b’s. Therefore, the inhibition of CYP2B6 by xenobiotics or dietary fats can exacerbate obesity and metabolic disease potentially through disrupted PUFA metabolism and the production of key lipid metabolites.

The promotion of fatty acid β-oxidation by hesperidin via activating SIRT1/PGC1α to improve NAFLD induced by a high-fat diet

“…S4A, B and C †), suggesting that AMPK is the upstream protein of SIRT1 and is positively correlated with it. It has been shown that 13-OxoODE is an activator of PPARα 52 and can affect PPARα expression; while nicotinamide affects lipid metabolism by increasing fatty acid β-oxidation activity. 53 Here, 13-OxoODE and nicotinamide were significantly…”

RNA-seq transcriptome profiling of pigs’ liver in response to diet with different sources of fatty acids

“…Other studies have related CYP7A1 to lipid metabolism (Wang et al, 2020;Lyu et al, 2022), which highlights the importance of our study when verifying that the diet with oils modified the expression in pigs. In humans, CYP2B6 is the only hepatic isoform of CYP2B that plays a role in the metabolism of numerous xenobiotic and endobiotic compounds (Heintz et al, 2022). Cholesterol and dietary fats modulate CYP7A1 activity and gene expression in humans, but the exact mechanism by which fatty acids can regulate CYP7A1 expression remains to be elucidated (Fu et al, 2011).…”

Detoxification Cytochrome P450s (CYPs) in Families 1–3 Produce Functional Oxylipins from Polyunsaturated Fatty Acids

“…Mice that lack the three primarily hepatic Cyp2b members, Cyp2b9, Cyp2b10, and Cyp2b13 (Cyp2b-null or Cyp2b9/10/13-null) show greater susceptibility to high-fat diet induced obesity coupled with increased steatosis in males [44,57]. The presence of human CYP2B6 in Cyp2b-null mice (hCYP2B6-Tg) reduced obesity in the females; however suprisingly, human CYP2B6 increased steatosis in association with several oxylipins including 9-HODE and 13-KODE from linoleic acid, and 12,13-DHET, 14,15-EET, and 14,15-DHET from arachidonic acid [8]. Whether these oxylipins are directly involved in obesity or steatosis is unknown.…”

“…Products produced include the thromboxanes, prostaglandins, leukotrienes, lipoxins, and the less studied and more recently measured CYP-derived oxylipins such as the epoxides and diols produced from those epoxides by soluble epoxide hydrolase (sEH). These oxylipins may have powerful activity at multiple receptors [3]; however, some oxylipins have little function or no verified function and the roles of several oxylipins have been poorly defined [1,8].…”

“…Humanized CYP2B6-Tg mice produce 9-HODE and 13-HODE at greater levels than Cyp2b-null mice. This is associated with reduced diet-induced obesity, but also increased steatosis [8]. The level of HODEs has also been shown to decrease in response to ischemia in wildtype mice and mice that overexpress endothelial CYP2J2 [83], but the implications of this is not known.…”