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    • Furthermore down regulation of Cpt a ApoE Fasn

    2021-02-25

    Furthermore, down-regulation of Cpt1a, ApoE, Fasn, Pxr, and Srebp-1 genes indicates a down-regulation of lipid metabolism associated genes while Fatp1 is up-regulated and indicates an increase in fatty Cy5.5 NHS ester transport genes involved in accumulation [84,85]. These changes in gene expression are consistent with increased liver lipids [86,87]. Interestingly, a drop in Srebp1 was also observed in steatotic HRN mice lacking all hepatic CYP activity [88], probably due to the increased retention of unsaturated fatty acids in the liver [89]. Typically, increases in free fatty acids are associated with increases in Srebp1 and Fasn [90] leading to increased Srebp1c activation that causes increased deposition of fat in the liver [91]. This suggests that there are other forces regulating the hepatic increase in triglycerides in Cyp3a-null mice or the down-regulation of Srebp is a compensatory response to the increased liver lipids. Overall, most but not all of these lipid markers are consistent with increased weight, liver triglycerides and polar lipids, and it is likely that decreased Cyp3a-mediated liver metabolism plays a role in the increased liver lipids through changes in metabolism. In addition to xenobiotics, CYP3A isoforms are involved in the metabolism of steroids, bile acids, and unsaturated fatty acids [30,49]. CYP3A4 has been shown to metabolize fatty acids such as arachidonic acid to generate epoxyeicosatrienoic acids (EETs) that have anti-inflammatory effects [92]. High-fat diets generate an endogenous fatty acid molecule, anandamide that can be converted to arachidonic acid by fatty acid amide hydrolase that can be further epoxygenated by Cyp3a to EETs. Anandamide and Cyp3a-mediated metabolites [36] bind cannabinoid receptors such as cannabinoid receptor 1 (CB1) in order to alter nociception, cognition, memory and orexigenic effects in the peripheral and central nervous system; however, there were no differences in food consumption between WT and Cyp3a-null mice. For example, CB1 regulates adiponectin activity in obese mice, and Rimonabant, a CB1 inverse agonist causes weight loss, increases Cpt1a, while decreasing Fasn in WT male mice, but not adiponectin-null mice [72]. Cannabinoid receptor 2 (CB2) is associated with immunosuppression and agonists reduce obesity [93]. Given that the fatty acid, anandamide and its Cyp3a metabolites are potent activators of CB1/2, it is possible that the loss of Cyp3a plays a role in perturbing fatty acid metabolism and epoxidation, including the production of anandamide and other fatty acid derivatives, that typically would act as signaling molecules [94,95], and reduce obesity. However, this does not explain why males and females react differently except for the possibility that the gender specific Cyp3a members in mice differentially metabolize steroids, arachidonic acid, anandamide, and other fatty acids. Murine 6β-hydroxylation of testosterone is significant higher in females than males demonstrating the higher Cyp3a activity in females than males [46]. Of course this difference in 6β-hydroxylation is lost in Cyp3a-null mice, indicating the differences between males and females for obesity and NAFLD is not directly caused by Cyp3a metabolism of steroids, but may be due to the metabolic differences that lead to sexually dimorphic differences in Cyp3a expression. It is possible that there are distinct differences in Cyp3a-mediated fatty acid metabolism in males compared to females as females express different Cyp3a isoforms, primarily Cyp3a41 and Cyp3a44. However, the substrate profiles for these murine isoforms are not known and that includes their metabolism of anandamide, arachidonic acid, and other PUFAs. Gender differences in PXR regulation and feedback within Cyp3a-null mice may also play a role in the sexually dimorphism of weight gain. For example, mPXR is associated with increased weight gain and hPXR with protection from weight gain in male mice with increased Cpt1a and PPARα levels [14]. In contrast, hPXR activation/presence causes greater weight gain than mPXR in female mice [39]. Because PXR positively regulates Cyp3a, the PXR studies are consistent with our studies in which loss of Cyp3a increased obesity in males and protected females. Therefore, while we don't know the exact mechanism of the sexually dimorphic weight gain in Cyp3a-null mice, it appears that differential PXR/Cyp3a activation and subsequent regulation of gene expression plays a role.