Gut microbiota of miR-30a-5p-deleted mice aggravate high-fat diet-induced hepatic steatosis by regulating arachidonic acid metabolic pathway

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2024-10-03 DOI:10.1002/ctm2.70035

Ruiying Wang, Xiaocheng Zhang, Yutian Wang, Yijun Lin, Yuling Zhou, Yan Wang, Gang Li

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引用次数: 0

Abstract

Background

Patients with non-alcoholic fatty liver disease (NAFLD) often exhibit hepatic steatosis and dyslipidemia. Studies have shown that intestinal microorganisms are closely related to the occurrence of NAFLD and atherosclerosis. Our previous study has underscored the protective role of microRNA-30a-5p (miR-30a-5p) against atherosclerosis.

Methods and Results

In the present study, we aimed to elucidate the effect and underlying mechanism of the intestinal microorganisms of miR-30a-5p knockout (KO) mice on NAFLD. Our findings demonstrated that KO exacerbated high-fat diet (HFD)-induced hepatic steatosis and disrupted liver function, as evidenced by elevated levels of total cholesterol, low-density lipoprotein, alanine aminotransferase, aspartate transaminase, and total bile acids in serum. Fecal microbiota from HFD-fed KO mice induced hepatic steatosis, dyslipidemia, and higher levels of enzymes indicative of liver damage in wild-type mice. Remarkably, KO mice significantly intensified the above effects. 16s rDNA sequencing and metabolomics of the intestinal microbiota in the HFD-treated KO and WT mice showed that the loss of miR-30a-5p resulted in intestinal microbiota imbalance and was highly related to the arachidonic acid metabolic pathway. Targeted metabolomic in the liver tissues unveiled upregulation of COX-related (PGF2a, 8-iso-PGF2a and PGF2) and LOX-related (LTB4, LTD4, 12S-HETE and 15S-HETE) factors in HFD-treated KO mice. Immunohistochemistry and transcriptional analyses showed that miR-30a-5p affected arachidonic acid metabolism through the LOX/COX pathways. Besides, COX/LOX pathways and hepatic steatosis were reversed after reintroducing miR-30a-5p in HFD-treated KO mice.

Conclusions

This study reveals the pivotal mechanism by which miR-30a-5p and intestinal microbes regulate hepatic steatosis and abnormal lipid metabolism, offering promising avenues for NAFLD and atherosclerosis therapeutics.

Highlights

MiR-30a-5p deletion aggravated hepatic steatosis and lipid disorder induced by an HFD in mice. Gut microbiota participated in the regulation of hepatic steatosis in the context of miR-30a-5p. Gut microbiota metabolism-related arachidonic acid metabolic pathway contributed to miR-30a-5p-regulated hepatic steatosis and lipid disorder. Reintroducing miR-30a-5p reversed hepatic steatosis and arachidonic acid metabolism disorder caused by HFD and miR-30a-5p deletion.

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miR-30a-5p缺失小鼠的肠道微生物群通过调节花生四烯酸代谢途径加重高脂饮食诱发的肝脂肪变性。

背景：非酒精性脂肪肝（NAFLD）患者通常表现出肝脂肪变性和血脂异常。研究表明，肠道微生物与非酒精性脂肪肝和动脉粥样硬化的发生密切相关。我们之前的研究强调了微RNA-30a-5p（miR-30a-5p）对动脉粥样硬化的保护作用：本研究旨在阐明 miR-30a-5p 基因剔除（KO）小鼠肠道微生物对非酒精性脂肪肝的影响及其内在机制。我们的研究结果表明，KO会加剧高脂饮食（HFD）诱导的肝脂肪变性和肝功能紊乱，表现为血清中总胆固醇、低密度脂蛋白、丙氨酸氨基转移酶、天门冬氨酸转氨酶和总胆汁酸水平升高。来自喂食高氟日粮的 KO 小鼠的粪便微生物群会诱发肝脂肪变性、血脂异常以及野生型小鼠肝损伤酶水平升高。值得注意的是，KO 小鼠明显加剧了上述影响。高密度脂蛋白胆固醇（HFD）处理的 KO 小鼠和 WT 小鼠肠道微生物群的 16s rDNA 测序和代谢组学研究表明，miR-30a-5p 的缺失导致肠道微生物群失衡，并与花生四烯酸代谢途径高度相关。肝脏组织中的靶向代谢组学显示，在HFD处理的KO小鼠中，COX相关因子（PGF2a、8-iso-PGF2a和PGF2）和LOX相关因子（LTB4、LTD4、12S-HETE和15S-HETE）上调。免疫组化和转录分析表明，miR-30a-5p 通过 LOX/COX 途径影响花生四烯酸代谢。此外，在 HFD 处理的 KO 小鼠中重新引入 miR-30a-5p 后，COX/LOX 通路和肝脏脂肪变性得到逆转：这项研究揭示了miR-30a-5p和肠道微生物调控肝脂肪变性和脂质代谢异常的关键机制，为非酒精性脂肪肝和动脉粥样硬化的治疗提供了前景广阔的途径：MiR-30a-5p缺失会加重高脂饮食诱导的小鼠肝脂肪变性和脂质紊乱。肠道微生物群参与了 miR-30a-5p 对肝脏脂肪变性的调控。肠道微生物群代谢相关的花生四烯酸代谢途径导致了miR-30a-5p调控的肝脂肪变性和脂质紊乱。重新引入miR-30a-5p可逆转高脂饮食和miR-30a-5p缺失导致的肝脏脂肪变性和花生四烯酸代谢紊乱。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.