Metabolomic-based investigation of Yinlan alleviating hyperlipidemia by inhibiting blood stasis and phlegm turbidity through the PXR-CYP3A4-ABCB1-FXR pathway期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

Metabolomic-based investigation of Yinlan alleviating hyperlipidemia by inhibiting blood stasis and phlegm turbidity through the PXR-CYP3A4-ABCB1-FXR pathway

Affiliation:	1. The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou, 510095, China;2. Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd., Guangzhou, 510095, China

Abstract:	Yinlan lipid regulatory capsule (YL) is a composite traditional Chinese medicine (TCM) new drug to alleviate hyperlipidemia, while its therapeutic mechanism in vivo was not clarified with nontargeted metabolomics investigation. An animal model was established in rats fed a high-fat diet, and their body weights, body mass index (BMI) and blood cholesterol levels were measured. Serum, liver and kidney tissue samples were also extracted for PXR-CYP3A4-ABCB1-FXR signaling pathway research using PCR and UHPLC–MS. The obtained plasma samples were analyzed by UHPLC-Q-TOF-MS metabolomic investigation, which revealed PXR-CYP3A4-related metabolites and changes induced by YL. Finally, the key metabolites were chosen as index components, and their levels in the serum, liver, small intestine and bile were used for simultaneous UHPLC–MS-MS determination. The results indicated that YL was effective in rebalancing blood TG and TC levels (compared to controls). With respect to the PXR-CYP3A4-ABCB1 pathway, as a result of YL’s effect, gene expression or activity of the two targets decreased significantly in both the liver and kidney. The same trend was observed in the serum samples mentioned above. Metabolomics screening and data revealed that 44 metabolites can be regarded as biomarkers related to hyperlipidemia, fatty acids synthesis, and body energy consumption, as well as synthesis, transportation and exertion of cholesterol. YL’s treatment focused on 26 of them, primarily bile acids, indicating that the antihyperlipidemic effect of this drug lies in its inhibitory activity of cholesterol metabolism. Subsequent analysis of those in vivo components revealed that significant increases (compared to the model group) occurred in the blood, liver, small intestine and bile in groups that received medium and high doses of YL (while the low dose was relatively unchanged). Those target components exhibit a close relationship with PXR and/or CYP3A4. The use of YL repressed PXR expression and subsequently decreased CYP3A4 activity. As a result, synthesis of related bile acids increased, while cholesterol levels decreased, consequently leading to the attenuation of hyperlipidemia. This study comprehensively investigated the antihyperlipidemia mechanism of YL based on its repression of PXR-CYP3A4 activity and related metabolite yield, establishing an accurate method for evaluating the therapeutic effect of YL.

Keywords:	Yinlan lipid regulatory capsule Hyperlipidemia PXR-CYP3A4 Metabolomics ABCB1"} {"#name":"keyword" "$":{"id":"k0030"} "$$":[{"#name":"text" "_":"ATP binding cassette subfamily B member 1 ADP"} {"#name":"keyword" "$":{"id":"k0040"} "$$":[{"#name":"text" "_":"Adenosine diphosphate α-MCA"} {"#name":"keyword" "$":{"id":"k0050"} "$$":[{"#name":"text" "_":"alpha-Muricholic acid AMP"} {"#name":"keyword" "$":{"id":"k0060"} "$$":[{"#name":"text" "_":"Adenosine monophosphate ATP Adenosine Triphosphate BA"} {"#name":"keyword" "$":{"id":"k0070"} "$$":[{"#name":"text" "_":"bile acid β-MCA"} {"#name":"keyword" "$":{"id":"k0080"} "$$":[{"#name":"text" "_":"beta-Muricholic acid CA"} {"#name":"keyword" "$":{"id":"k0090"} "$$":[{"#name":"text" "_":"Cholic acid CYP3A4"} {"#name":"keyword" "$":{"id":"k0100"} "$$":[{"#name":"text" "_":"cytochrome P450 enzyme type 3A4 CDCA"} {"#name":"keyword" "$":{"id":"k0110"} "$$":[{"#name":"text" "_":"Chenodeoxycholic acid DCA"} {"#name":"keyword" "$":{"id":"k0120"} "$$":[{"#name":"text" "_":"Deoxycholic acid ESI"} {"#name":"keyword" "$":{"id":"k0130"} "$$":[{"#name":"text" "_":"electrospray ionization FXR"} {"#name":"keyword" "$":{"id":"k0140"} "$$":[{"#name":"text" "_":"farnesoid X receptor GCA"} {"#name":"keyword" "$":{"id":"k0150"} "$$":[{"#name":"text" "_":"Glycocholic acid GDCA"} {"#name":"keyword" "$":{"id":"k0160"} "$$":[{"#name":"text" "_":"Glycodeoxycholic acid GHCA"} {"#name":"keyword" "$":{"id":"k0170"} "$$":[{"#name":"text" "_":"Glycohyocholic acid GHDCA"} {"#name":"keyword" "$":{"id":"k0180"} "$$":[{"#name":"text" "_":"Glycochenodeoxycholie acid GUDCA"} {"#name":"keyword" "$":{"id":"k0190"} "$$":[{"#name":"text" "_":"Glycoursodeoxycholic acid HDCA"} {"#name":"keyword" "$":{"id":"k0200"} "$$":[{"#name":"text" "_":"Hyodeoxycholic acid 3-keto-LCA"} {"#name":"keyword" "$":{"id":"k0210"} "$$":[{"#name":"text" "_":"3-keto-Lithocholic Acid LCA"} {"#name":"keyword" "$":{"id":"k0220"} "$$":[{"#name":"text" "_":"Lithocholic Acid OPLS-DA"} {"#name":"keyword" "$":{"id":"k0230"} "$$":[{"#name":"text" "_":"orthogonal projections of latent structures discriminant analysis PCA"} {"#name":"keyword" "$":{"id":"k0240"} "$$":[{"#name":"text" "_":"principal components analysis PLS-DA"} {"#name":"keyword" "$":{"id":"k0250"} "$$":[{"#name":"text" "_":"partial least squares discrimination analysis PXR"} {"#name":"keyword" "$":{"id":"k0260"} "$$":[{"#name":"text" "_":"pregnane X receptor TCCA"} {"#name":"keyword" "$":{"id":"k0270"} "$$":[{"#name":"text" "_":"Trichloroisocyanuric acid TC"} {"#name":"keyword" "$":{"id":"k0280"} "$$":[{"#name":"text" "_":"total cholesterol TCDCA"} {"#name":"keyword" "$":{"id":"k0290"} "$$":[{"#name":"text" "_":"Taurochenodeoxycholic acid TCM"} {"#name":"keyword" "$":{"id":"k0300"} "$$":[{"#name":"text" "_":"traditional Chinese medicine TDCA"} {"#name":"keyword" "$":{"id":"k0310"} "$$":[{"#name":"text" "_":"Tauroursodeoxycholic acid THCA"} {"#name":"keyword" "$":{"id":"k0320"} "$$":[{"#name":"text" "_":"Tetrahydrocannabinol acid TG"} {"#name":"keyword" "$":{"id":"k0330"} "$$":[{"#name":"text" "_":"triglyceride THDCA"} {"#name":"keyword" "$":{"id":"k0340"} "$$":[{"#name":"text" "_":"Taurosulodeoxycholic acid TIC"} {"#name":"keyword" "$":{"id":"k0350"} "$$":[{"#name":"text" "_":"total ion current TUDCA"} {"#name":"keyword" "$":{"id":"k0360"} "$$":[{"#name":"text" "_":"Taurocholic acid UDCA"} {"#name":"keyword" "$":{"id":"k0370"} "$$":[{"#name":"text" "_":"Ursodeoxycholic acid YL"} {"#name":"keyword" "$":{"id":"k0380"} "$$":[{"#name":"text" "_":"Yinlan lipid regulatory capsule
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