Diet-induced non-alcoholic fatty liver disease affects expression of major cytochrome P450 genes in a mouse model

Chiba, Tsuyoshi; Noji, Keiko; Shinozaki, Shohei; Suzuki, Sachina; Umegaki, Keizo; Shimokado, Kentaro

doi:10.1111/jphp.12646

Cited by 21 publications

(12 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In NAFLD rat models induced by a choline-deficient diet, CYP1A2 metabolic activity was significantly down-regulated (Lee et al, 2013). In contrast, high-fat diet induced CYP1A2 mRNA was found in NAFLD mice (Chiba et al, 2016). Overall, CYP1A2…”

Section: Discussionmentioning

confidence: 94%

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Sun

Zhang

et al. 2021

Drug Metab Dispos

View full text Add to dashboard Cite

Cytochrome P450 1A2 (CYP1A2) as one of the most important CYP isoforms is involved in the biotransformation of many important endogenous and exogenous substances. CYP1A2 also plays an important role in the development of many diseases because it is involved in the biotransformation of precancerous substances and poisons. Although the generation of Cyp1a2 knockout (KO) mouse model has been reported, there are still no relevant rat models for the study of CYP1A2-mediated pharmacokinetics and diseases. In this report, CYP1A2 KO rat model was established successfully by CRISPR/Cas9 without any detectable off-target effect. Compared with wild-type rats, this model showed a loss of CYP1A2 protein expression in the liver. The results of pharmacokinetics in vivo and incubation in vitro of specific substrates of CYP1A2 confirmed the lack of function of CYP1A2 in KO rats. In further studies of potential compensatory effects, we found that CYP1A1 was significantly up-regulated, and CYP2E1, CYP3A2 and LXRβ were down-regulated in KO rats. In addition, CYP1A2 KO rats exhibited a significant increase in serum cholesterol and free testosterone, accompanied by mild liver damage and lipid deposition, suggesting that CYP1A2 deficiency affects lipid metabolism and liver function to a certain extent. In summary, we successfully constructed the CYP1A2 KO rat model, which provides a useful tool for studying the metabolic function and physiological function of CYP1A2.

show abstract

Section: Discussionmentioning

confidence: 94%

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Sun

Zhang

et al. 2021

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…Cytochrome P450 of the liver plays a pivotal role in the process of lipid metabolism and lipid biosynthesis [40]. Several studies have shown that regulating the activity of cytochrome P450 can affect the development of NAFLD through different mechanisms, such as oxidative stress [41][42][43]. By analyzing the TCGA RNASeq LIHC database and 52 targets of EH against HCC, we obtained an enriched GO term network.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Mechanisms Underlying the Hepatoprotective Effects of Ecliptae herba on Hepatocellular Carcinoma

Pan

Zheng³

et al. 2021

Evidence-Based Complementary and Alternative Medicine

View full text Add to dashboard Cite

Background. The number of hepatocellular carcinoma (HCC) cases worldwide has increased significantly. As a traditional Chinese medicine (TCM) with a long history, Ecliptae herba (EH) has been widely used in HCC patients in China, but its hepatoprotective mechanism is still unclear. Methods. In this study, we applied a network pharmacology-based strategy and experimental verification to systematically unravel the underlying mechanisms of EH against HCC. First, six active ingredients of EH were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) by the ADME method. Subsequently, 52 potential targets of 6 active ingredients acting on HCC were screened from various databases, including TCMSP, DGIdb, SwissTargetPrediction, CTD, and GeneCards. Then, by constructing protein-protein interaction (PPI) network from STRING, we displayed the intricate connections among these 52 targets through Cytoscape software. We also applied enrichment analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, to provide an outline and set of concepts for describing gene functions and the advanced functions of biological systems of these 52 targets from genomic and molecular level information. Finally, molecular docking and biological experiments were used to reconfirm these results. Results. We hypothesized that EH might exert anti-HCC activity by acting on hub genes, including RELA, MMP9, PTGS2, ESR1, EGFR, AR, AKT1, HIF1A, AHR, CYP3A4, ABCG2, and MMP2. Moreover, based on GO and KEGG analysis, we speculated that EH may exert hepatoprotective effects on HCC through the following mechanisms: regulation of the PI3K-AKT signaling pathway to promote apoptosis and inhibit the abnormal proliferation of HCC, downregulation of HIF-1A expression by activating the HIF-1 signaling pathway, prevention of HCC by regulating lipid metabolism, and inhibition of nonalcoholic fatty liver disease (NAFLD) by the cytochrome P450 subfamily. Subsequent biological experiments verified that EH inhibits the PI3K-AKT signaling pathway through its active ingredients, quercetin, and wedelolactone, thereby inhibiting the proliferation of HCC cells and promoting the apoptosis of HCC cells. Conclusions. The network pharmacological strategy provides an efficient method to systematically explore the pharmacological mechanism of EH in HCC. Our study demonstrated that the anti-HCC proliferation activity of EH is mainly exerted by two active ingredients (quercetin and wedelolactone), which inhibit the proliferation of HCC cells (HepG2 and Huh-7) by inhibiting PI3K-AKT signaling.

show abstract

“…Even less is known about the effect of high sucrose intake on hepatic P450 expression. An early study showed that high sucrose feeding decreased total CYP content [ 37 ], whereas another study in rodents showed that a high-fat-high-sucrose diet increased Cyp1a2 , Cyp1a1 , Cyp2b10 and Cyp2c29 expression while decreasing Cyp3a11 expression [ 38 ]. Moreover, the mechanism(s) by which dietary components affect P450 expression are unclear at the moment, as well as the functional consequences for P450 function.…”

Section: Discussionmentioning

confidence: 99%

Effects of meal composition and meal timing on the expression of genes involved in hepatic drug metabolism in rats

et al. 2017

View full text Add to dashboard Cite

IntroductionWith chronotherapy, drug administration is synchronized with daily rhythms in drug clearance and pharmacokinetics. Daily rhythms in gene expression are centrally mastered by the suprachiasmatic nucleus of the hypothalamus as well as by tissue clocks containing similar molecular mechanisms in peripheral organs. The central timing system is sensitive to changes in the external environment such as those of the light-dark cycle, meal timing and meal composition. We investigated how changes in diet composition and meal timing would affect the daily hepatic expression rhythms of the nuclear receptors PXR and CAR and of enzymes involved in P450 mediated drug metabolism, as such changes could have consequences for the practice of chronotherapy.Materials and methodsRats were subjected to either a regular chow or a free choice high-fat-high-sugar (fcHFHS) diet. These diets were provided ad libitum, or restricted to either the light phase or the dark phase. In a second experiment, rats had access to chow either ad libitum or in 6 meals equally distributed over 24 hours.ResultsPxr, Alas1 and Por displayed significant day-night rhythms under ad libitum chow fed conditions, which for Pxr was disrupted under fcHFHS diet conditions. Although no daily rhythms were detected in expression of CAR, Cyp2b2 and Cyp3a2, the fcHFHS diet did affect basal expression of these genes. In chow fed rats, dark phase feeding induced a diurnal rhythm in Cyp2b2 expression while light phase feeding induced a diurnal rhythm in Car expression and completely shifted the peak expression of Pxr, Car, Cyp2b2, Alas1 and Por. The 6-meals-a-day feeding only abolished the Pxr rhythm but not the rhythms of the other genes.ConclusionWe conclude that although nuclear receptors and enzymes involved in the regulation of hepatic drug metabolism are sensitive to meal composition, changes in meal timing are mainly effectuated via changes in the molecular clock.

show abstract

Diet-induced non-alcoholic fatty liver disease affects expression of major cytochrome P450 genes in a mouse model

Abstract: Drug metabolism may be impaired in NAFLD, and each Cyp subtype is regulated in a different manner.

Cited by 21 publications

References 49 publications

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Pharmacological Mechanisms Underlying the Hepatoprotective Effects of Ecliptae herba on Hepatocellular Carcinoma

Effects of meal composition and meal timing on the expression of genes involved in hepatic drug metabolism in rats

Contact Info

Product

Resources

About