Bavachinin causes cholestasis by down-regulating BAAT expression and disrupting glycocholic acid synthesis in human liver organoids

IF 3.9 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology Pub Date : 2025-04-09 DOI:10.1016/j.fct.2025.115438

Xue Wang , Yu Su , Xiaomeng Chen , Lin Liu , Xinyan Zhao , Jidong Jia

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Abstract

Psoraleae Fructus (Bu Gu Zhi, BGZ) is extensively utilized for dermatological and osseous disorders in China. BGZ-induced liver injury has become one of the major concerns, which predominantly cause cholestasis, with the pathogenesis not being fully elucidated. Currently, studies on hepatotoxic mechanisms of BGZ have mainly been conducted on 2D cell culture systems or rodent models, which may not fully encapsulate human pathophysiology. Therefore, we generated human liver organoids (HLOs) from healthy donor(s) for living-related liver transplantation to explore the hepatotoxic mechanism. We identified bavachinin (BVC) as the most hepatotoxic component for cholestasis. After validating by CLF tests, we identified BVC caused cholestasis by down-regulating BAAT, which catalyzes the amidation of bile acids. We also found that up-regulating BAAT with harmaline could mitigate cholestasis and enhance cell viabilities in HLOs. We further demonstrated that glycocholic acid (GCA) levels decreased in BVC-treated HLOs. Supplementation of GCA to BVC-treated HLOs significantly improved cell viabilities. Collectively, our data suggested that BVC impaired the GCA synthesis by down-regulating the expression of BAAT, thereby inducing cholestasis.

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巴伐利亚蛋白通过下调人肝类器官中BAAT的表达和破坏糖胆酸的合成而引起胆汁淤滞

在中国，车前子被广泛用于治疗皮肤病和骨科疾病。BGZ诱导的肝损伤已成为人们关注的主要问题之一，主要导致胆汁淤积，其发病机制尚未完全阐明。目前，有关BGZ肝毒性机制的研究主要是在二维细胞培养系统或啮齿类动物模型上进行的，可能无法完全涵盖人体的病理生理学。因此，我们从健康的活体肝移植供体中提取了人肝脏器官组织（HLOs）来探索其肝脏毒性机制。我们发现巴伐醌（BVC）是胆汁淤积症中最具肝脏毒性的成分。通过CLF测试验证后，我们发现BVC通过下调催化胆汁酸酰胺化的BAAT导致胆汁淤积。我们还发现，用哈玛灵上调 BAAT 可以缓解胆汁淤积，并提高 HLO 细胞的存活率。我们进一步证实，在 BVC 处理的 HLO 中，甘油胆酸（GCA）水平下降。在 BVC 处理的 HLO 中补充 GCA 能显著提高细胞活力。总之，我们的数据表明，BVC 通过下调 BAAT 的表达来影响 GCA 的合成，从而诱导胆汁淤积。

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来源期刊

Food and Chemical Toxicology 工程技术-毒理学

CiteScore

10.90

自引率

4.70%

发文量

651

审稿时长

31 days

期刊介绍： Food and Chemical Toxicology (FCT), an internationally renowned journal, that publishes original research articles and reviews on toxic effects, in animals and humans, of natural or synthetic chemicals occurring in the human environment with particular emphasis on food, drugs, and chemicals, including agricultural and industrial safety, and consumer product safety. Areas such as safety evaluation of novel foods and ingredients, biotechnologically-derived products, and nanomaterials are included in the scope of the journal. FCT also encourages submission of papers on inter-relationships between nutrition and toxicology and on in vitro techniques, particularly those fostering the 3 Rs. The principal aim of the journal is to publish high impact, scholarly work and to serve as a multidisciplinary forum for research in toxicology. Papers submitted will be judged on the basis of scientific originality and contribution to the field, quality and subject matter. Studies should address at least one of the following: -Adverse physiological/biochemical, or pathological changes induced by specific defined substances -New techniques for assessing potential toxicity, including molecular biology -Mechanisms underlying toxic phenomena -Toxicological examinations of specific chemicals or consumer products, both those showing adverse effects and those demonstrating safety, that meet current standards of scientific acceptability. Authors must clearly and briefly identify what novel toxic effect (s) or toxic mechanism (s) of the chemical are being reported and what their significance is in the abstract. Furthermore, sufficient doses should be included in order to provide information on NOAEL/LOAEL values.