Epigenetic regulation of thyroid hormone action in human metabolic dysfunction-associated steatohepatitis.

IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM
European Thyroid Journal Pub Date : 2024-09-21 Print Date: 2024-10-01 DOI:10.1530/ETJ-24-0080
Alison-Michelle Naujack, Christin Krause, Jan H Britsemmer, Natalie Taege, Jens Mittag, Henriette Kirchner
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引用次数: 0

Abstract

Objective: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by inflammation, fibrosis, and accumulation of fatty acids in the liver. MASH disease progression has been associated with reduced thyroid hormone (TH) signaling in the liver, including reduced expression of deiodinase type I (DIO1) and TH receptor beta (THRB). However, the underlying mechanisms mediating these effects remain elusive. Here, we hypothesized that epigenetic mechanisms may be involved in modulating hepatic TH action.

Methods: Liver samples from patients with and without MASH were analyzed by qRT-PCR and correlated with clinical parameters. Luciferase reporter assays and overexpression of miRNA in HepG2 cells were used to validate the functional binding of miRNA to predicted targets. DNA methylation was analyzed by bisulfite pyrosequencing.

Results: miR-34a-5p was upregulated in MASH patients and correlated positively with the clinical parameters of MASH. Using in silico and in vitro analysis, we demonstrate that miR-34a-5p is capable of targeting several modulators of local hepatic TH action, as evidenced by the functional binding of miR-34a-5p to the seed sequence in the THRB and DIO1 genes. Consequently, overexpression of miR-34a-5p in HepG2 cells reduced the expression of THRA, THRB, DIO1, and SLC10A1, thus potentially mediating an acquired hepatic resistance to TH in MASH. As an additional regulatory mechanism, DNA methylation of THRB intron 1 was increased in MASH and negatively correlated with THRB expression.

Conclusion: miR-34a-5p constitutes a possible epigenetic master regulator of hepatic TH action, which together with THRB-specific DNA methylation could explain a possible developing TH resistance in the liver during MASH progression on the molecular level.

人类代谢功能障碍相关性脂肪性肝炎中甲状腺激素作用的表观遗传调控。
目的:代谢功能障碍相关性脂肪性肝炎(MASH)以肝脏炎症、纤维化和脂肪酸蓄积为特征。MASH 疾病的进展与肝脏中甲状腺激素(TH)信号传导的减少有关,包括脱碘酶 I 型(DIO1)和 TH 受体 beta(THRB)表达的减少。然而,介导这些效应的潜在机制仍然难以捉摸。在此,我们假设表观遗传机制可能参与了肝脏 TH 作用的调节:方法:通过 qRT-PCR 分析患有和未患有 MASH 患者的肝脏样本,并将其与临床参数相关联。荧光素酶报告实验和 miRNA 在 HepG2 细胞中的过表达被用来验证 miRNA 与预测靶点的功能性结合。结果:miR-34a-5p在MASH患者中上调,并与MASH的临床参数呈正相关。我们利用硅学和体外分析证明,miR-34a-5p 能够靶向肝脏局部 TH 作用的几个调节因子,这从 miR-34a-5p 与 THRB 和 DIO1 基因中的种子序列的功能性结合中得到了证明。因此,miR-34a-5p 在 HepG2 细胞中的过表达降低了 THRA、THRB、DIO1 和 SLC10A1 的表达,从而可能介导了 MASH 对 TH 的获得性肝抗性。结论:miR-34a-5p可能是肝脏TH作用的表观遗传主调节因子,它与THRB特异性DNA甲基化可从分子水平上解释MASH进展过程中肝脏可能出现的TH耐药性。
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来源期刊
European Thyroid Journal
European Thyroid Journal Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
6.70
自引率
2.10%
发文量
156
期刊介绍: The ''European Thyroid Journal'' publishes papers reporting original research in basic, translational and clinical thyroidology. Original contributions cover all aspects of the field, from molecular and cellular biology to immunology and biochemistry, from physiology to pathology, and from pediatric to adult thyroid diseases with a special focus on thyroid cancer. Readers also benefit from reviews by noted experts, which highlight especially active areas of current research. The journal will further publish formal guidelines in the field, produced and endorsed by the European Thyroid Association.
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