The Effect of CYP7A1 Polymorphisms on Lipid Responses to Fenofibrate

Shen, Jian; Arnett, Donna K.; Parnell, Laurence D.; Lai, Chao‐Qiang; Straka, Robert J.; Hopkins, Paul N.; An, Ping; Feitosa, Mary F.; Ordovás, José M.

doi:10.1097/fjc.0b013e31823de86b

Cited by 18 publications

(10 citation statements)

References 35 publications

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“…Polymorphisms in the promoter of this gene are associated with defects in bile acid synthesis. They affect lipid responses to the lipid-lowering drug fenofibrate [ 32 ]. Mice deficient in CYP7A1 also exhibited changes in cholesterol and bile acid metabolism in the liver [ 33 ], while overexpression of CYP7A1 in the liver resulted in improved metabolic homeostasis in CYP7A1 transgenic mice [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

MiRNA-17 encoded by the miR-17-92 cluster increases the potential for steatosis in hepatoma cells by targeting CYP7A1

Gong

Liu

2018

Cell Mol Biol Lett

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BackgroundThe miRNA cluster miR-17-92 is known to act as an oncogene in various cancers. Members of this cluster were also found to be involved in some other pathological process, such as steatosis, which is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether miR-17, one of the most functional miRNAs in the miR-17-92 family, participates in the process of steatosis in hepatoma cells.MethodsWe developed both a miR-17-expressing transgenic mouse model and a miR-17-expressing HepG2 cell model, the latter was established via stable transfection. Real-time PCR and western blot were applied to measure the expression levels of miR-17 and the potential target gene CYP7A1. The luciferase assay was used to confirm direct binding of miR-17 and CYP7A1. The oleic acid induction assay and Oil-Red-O staining were performed to support the determination of steatotic changes in HepG2 cell.ResultsExtensive steatotic changes were observed in the livers of transgenic mice. Fewer were seen in the wild-type animals. CYP7A1 was confirmed as a target gene of miR-17, and the expression of CYP7A1 was found to be negatively regulated in both the transgenic mice liver cells and the miR-17-expressing HepG2 cells. CYP7A1 was found to participate in miR-17-induced steatosis, as its repressed expression in miR-17 HepG2 cells exacerbated steatotic change. Re-introduction of CYP7A1 into miR-17 HepG2 cell partially alleviated steatosis.ConclusionsmiR-17 is a novel regulator of CYP7A1 signaling in hepatic lipid metabolism, suggesting a potential therapeutic approach for fatty liver.Electronic supplementary materialThe online version of this article (10.1186/s11658-018-0083-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

MiRNA-17 encoded by the miR-17-92 cluster increases the potential for steatosis in hepatoma cells by targeting CYP7A1

Gong

Liu

2018

Cell Mol Biol Lett

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“…It should be noted that nearly all patients were treated with statins in our study, which might influence the results of the analysis of the association between the studied genetic variant and cholesterol level in CAD group. CYP7A1 gene polymorphisms may also modify response of organism to lipid lowering drugs [ 25 , 26 ], which may be another reason of the obtained results. Nevertheless, it is difficult to explain the lack of association between the rs7833904 polymorphism and cholesterol level in the control group; however, our findings are in line with Xiang et al [ 19 ] who observed an association of rs1023652 polymorphism (being with complete linkage disequilibrium with the rs7833904) with HDCA amount, but not with the concentrations of total cholesterol and 7 α -hydroxy-4-cholesten-3-one (7HCO, the known marker of the primary bile acids synthesis).…”

Section: Discussionmentioning

confidence: 99%

CYP7A1Gene Polymorphism Located in the 5′ Upstream Region Modifies the Risk of Coronary Artery Disease

et al. 2015

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Background. 7-Alpha cholesterol hydroxylase (CYP7A1), the first enzyme of classic conversion pathway leading from cholesterol to bile acids synthesis, is encoded by CYP7A1 gene. Its single nucleotide polymorphisms (SNPs) influence serum lipid levels and may be related to impaired lipid profile leading to coronary artery disease (CAD). The aim of the present study was to analyze the possible association between the rs7833904 CYP7A1 polymorphism and premature CAD. Material and Methods. Serum lipid levels and rs7833904 SNP were determined in 419 subjects: 200 patients with premature CAD and 219 age and sex matched controls. Results. The A allele carrier state was associated with CAD (OR = 1.76, 95% CI; 1.14–2.71, P = 0.014). The effect was even stronger in the male subgroups (OR = 2.16, 95% CI; 1.28–3.65, P = 0.003). There was no effect in the females. Risk factors of CAD and clinical phenotype of atherosclerosis were not associated with genotype variants of the rs7833904 SNP. Lipid profiles also did not differ significantly between individual genotypes. Conclusion. The CYP7A1 rs7833904 polymorphism may modify the risk of CAD. This effect is especially strong in male subjects. The studied polymorphism does not significantly influence serum lipid levels, in the present study.

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“…3D-F, Additional le 2). Among that, Lrp5 [15], Cyp7a1 [16], Nfkbiz [17], Sigmar1 [18], Fabp7 [19], and Hao1 [20] (Additional le 3) have been reported in in ammatory response and lipid metabolic process, suggesting these genes may play an important role in modulating sepsis-induced system in ammation in WT and LBP-de cient rats after LPS injection.…”

Section: Systemic Administration Of Bacterial Lps Induces Global Chanmentioning

confidence: 99%

RNA-seq profiles of LPS-induced transcriptional changes in LBP-deficient rat and its possible implications for the liver dysregulation during sepsis

Song

Meng

et al. 2020

Preprint

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Abstract Background Sepsis is an organ dysfunction caused by the dysregulated inflammatory response to infection. LBP binds to LPS, and modulates the inflammatory response. Rare systematic study has been reported to detect the effect of LBP gene during the LPS-induced sepsis. Herein, we explored the RNA sequencing technology to profile the transcriptomic changes in liver tissue between LBP-deficient rats and WT rats at multiple timepoints after LPS administration. Results We compared the serum ALT levels using the biochemistry analyzer and proceeded RNA sequencing of liver tissue to search differentially expressed genes and enriched biological processes and pathways between LBP-deficient and WT groups at 0 h, 6 h, and 24 h. In total, 168, 284, and 307 differential expressed genes (DEGs) were identified at 0 h, 6 h, and 24 h respectively, including Lrp5, Cyp7a1, Nfkbiz, Sigmar1, Fabp7, and Hao1, which are related to the inflammatory or lipid-related process. Functional enrichment analysis revealed that inflammatory response to LPS mediated by Ifng, Cxcl10, Serpine1, and Lbp was enhanced at 6 h, while lipid-related metabolism associated with C5, Cyp4a1, and Eci1 was enriched at 24 h after LPS administration in the WT samples. The inflammatory process was not found when the LBP gene was knocked out, lipid-related metabolic process and PPAR signaling pathway mediated by Dhrs7b and Tysnd1 were significantly activated in LBP-deficient samples. Conclusions Our study suggested that the invading LPS may interplay with LBP to activate NF-κB signaling pathway and trigger uncontrolled inflammatory response. However, when inhibiting the activity of NF-κB, lipid-related metabolism would make bacteria removal via the effect on PPAR signaling pathway in the absence of LBP gene. Moreover, we further found the potent implications of targeting the LBP gene may as a biomarker for inflammatory conditions induced by metabolic disorders.

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The Effect of CYP7A1 Polymorphisms on Lipid Responses to Fenofibrate

Cited by 18 publications

References 35 publications

MiRNA-17 encoded by the miR-17-92 cluster increases the potential for steatosis in hepatoma cells by targeting CYP7A1

MiRNA-17 encoded by the miR-17-92 cluster increases the potential for steatosis in hepatoma cells by targeting CYP7A1

CYP7A1Gene Polymorphism Located in the 5′ Upstream Region Modifies the Risk of Coronary Artery Disease

RNA-seq profiles of LPS-induced transcriptional changes in LBP-deficient rat and its possible implications for the liver dysregulation during sepsis

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