Donghui Zhang , Xinya Liu , Lanchao Sun , Daochuan Li , Jingyue Du , Huizi Yang , Dianke Yu , Chuanhai Li
{"title":"Fine particulate matter disrupts bile acid homeostasis in hepatocytes via binding to and activating farnesoid X receptor","authors":"Donghui Zhang , Xinya Liu , Lanchao Sun , Daochuan Li , Jingyue Du , Huizi Yang , Dianke Yu , Chuanhai Li","doi":"10.1016/j.tox.2024.153850","DOIUrl":null,"url":null,"abstract":"<div><p>Fine particulate matter (PM<sub>2.5</sub>)-induced metabolic disorders have attracted increasing attention, however, the underlying molecular mechanism of PM2.5-induced hepatic bile acid disorder remains unclear. In this study, we investigated the effects of PM<sub>2.5</sub> components on the disruption of bile acid in hepatocytes through farnesoid X receptor (FXR) pathway. The receptor binding assays showed that PM<sub>2.5</sub> extracts bound to FXR directly, with half inhibitory concentration (IC<sub>50</sub>) value of 21.7 μg/mL. PM<sub>2.5</sub> extracts significantly promoted FXR-mediated transcriptional activity at 12.5 μg/mL. In mouse primary hepatocytes, we found PM<sub>2.5</sub> extracts (100 μg/mL) significantly decreased the total bile acid levels, inhibited the expression of bile acid synthesis gene (Cholesterol 7 alpha-hydroxylase, Cyp7a1), and increased the expression of bile acid transport genes (Multidrug resistance associated protein 2, Abcc2; and Bile salt export pump, Abcb11). Moreover, these alterations were significantly attenuated by knocking down FXR in hepatocytes. We further divided the organic components and water-soluble components from PM<sub>2.5</sub>, and found that two components bound to and activated FXR, and decreased the bile acid levels in hepatocytes. In addition, benzo[<em>a</em>]pyrene (B[<em>a</em>]P) and cadmium (Cd) were identified as two bioactive components in PM<sub>2.5</sub>-induced bile acid disorders through FXR signaling pathway. Overall, we found PM<sub>2.5</sub> components could bind to and activate FXR, thereby disrupting bile acid synthesis and transport in hepatocytes. These new findings also provide new insights into PM<sub>2.5</sub>-induced toxicity through nuclear receptor pathways.</p></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8000,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0300483X24001318","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Fine particulate matter (PM2.5)-induced metabolic disorders have attracted increasing attention, however, the underlying molecular mechanism of PM2.5-induced hepatic bile acid disorder remains unclear. In this study, we investigated the effects of PM2.5 components on the disruption of bile acid in hepatocytes through farnesoid X receptor (FXR) pathway. The receptor binding assays showed that PM2.5 extracts bound to FXR directly, with half inhibitory concentration (IC50) value of 21.7 μg/mL. PM2.5 extracts significantly promoted FXR-mediated transcriptional activity at 12.5 μg/mL. In mouse primary hepatocytes, we found PM2.5 extracts (100 μg/mL) significantly decreased the total bile acid levels, inhibited the expression of bile acid synthesis gene (Cholesterol 7 alpha-hydroxylase, Cyp7a1), and increased the expression of bile acid transport genes (Multidrug resistance associated protein 2, Abcc2; and Bile salt export pump, Abcb11). Moreover, these alterations were significantly attenuated by knocking down FXR in hepatocytes. We further divided the organic components and water-soluble components from PM2.5, and found that two components bound to and activated FXR, and decreased the bile acid levels in hepatocytes. In addition, benzo[a]pyrene (B[a]P) and cadmium (Cd) were identified as two bioactive components in PM2.5-induced bile acid disorders through FXR signaling pathway. Overall, we found PM2.5 components could bind to and activate FXR, thereby disrupting bile acid synthesis and transport in hepatocytes. These new findings also provide new insights into PM2.5-induced toxicity through nuclear receptor pathways.
期刊介绍:
Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.