肌營養(yǎng)不良癥小鼠模型的藥物代謝改變和脂肪肝易感性增加

IF 15.7 1區(qū) 綜合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Zachary Dewald, Oluwafolajimi Adesanya, Haneui Bae, Andrew Gupta, Jessica M. Derham, Ullas V. Chembazhi, Auinash Kalsotra

引用次數(shù): 0

摘要

1型肌營養(yǎng)不良癥（DM1）是一種高發(fā)的肌肉營養(yǎng)不良癥，是由DMPK基因中的（CTG）n重復(fù)擴(kuò)增引起的。對DM1的研究主要集中在肌肉和神經(jīng)組織的影響上；然而，DM1患者也會出現(xiàn)各種代謝和肝臟功能障礙，如對代謝功能障礙相關(guān)性脂肪肝（MAFLD）的易感性增加以及對某些藥物的敏感性增高。在這里，我們生成了一種肝臟特異性 DM1 小鼠模型，它再現(xiàn)了該疾病的分子和病理特征，包括對 MAFLD 的易感性以及對特定鎮(zhèn)痛藥和肌肉松弛劑代謝能力的降低。CUG-expanded（CUG）exp重復(fù)RNA在肝細(xì)胞內(nèi)的表達(dá)封存了肌球蛋白樣蛋白，并引發(fā)了廣泛的基因表達(dá)和RNA處理缺陷。從機(jī)理上講，我們證明乙酰-CoA羧化酶1的表達(dá)和替代剪接的增加驅(qū)動了DM1肝臟中脂質(zhì)的過度積累，而高脂、高糖飲食又加劇了這種積累。這些發(fā)現(xiàn)共同揭示了（CUG）exp RNA毒性會破壞正常的肝功能，使DM1肝臟易受損傷、MAFLD和藥物清除病理變化的影響，這些病理變化可能會危及患者的健康并使其治療復(fù)雜化。

本文章由計算機(jī)程序翻譯，如有差異，請以英文原文為準(zhǔn)。

Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy

Myotonic Dystrophy type 1 (DM1), a highly prevalent form of muscular dystrophy, is caused by (CTG)n repeat expansion in the DMPK gene. Much of DM1 research has focused on the effects within the muscle and neurological tissues; however, DM1 patients also suffer from various metabolic and liver dysfunctions such as increased susceptibility to metabolic dysfunction-associated fatty liver disease (MAFLD) and heightened sensitivity to certain drugs. Here, we generated a liver-specific DM1 mouse model that reproduces molecular and pathological features of the disease, including susceptibility to MAFLD and reduced capacity to metabolize specific analgesics and muscle relaxants. Expression of CUG-expanded (CUG)exp repeat RNA within hepatocytes sequestered muscleblind-like proteins and triggered widespread gene expression and RNA processing defects. Mechanistically, we demonstrate that increased expression and alternative splicing of acetyl-CoA carboxylase 1 drives excessive lipid accumulation in DM1 livers, which is exacerbated by high-fat, high-sugar diets. Together, these findings reveal that (CUG)exp RNA toxicity disrupts normal hepatic functions, predisposing DM1 livers to injury, MAFLD, and drug clearance pathologies that may jeopardize the health of affected individuals and complicate their treatment.

來源期刊

CiteScore

24.90

自引率

2.40%

發(fā)文量

6928

審稿時長

3.7 months

期刊介紹： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.

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