进行性家族性肝内胆汁淤积症 3 的分子基础。 蛋白质组学研究。

IF 5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
BioFactors Pub Date : 2024-01-29 DOI:10.1002/biof.2041
Laura Guerrero, Lorena Carmona-Rodríguez, Fátima Milhano Santos, Sergio Ciordia, Luiz Stark, Loreto Hierro, Pablo Pérez-Montero, David Vicent, Fernando J. Corrales
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引用次数: 0

摘要

进行性家族性肝内胆汁淤积症 3 型(PFIC3)是一种严重的罕见肝病,患病儿童的比例在 1/50,000 到 1/100,000 之间。在生理状态下,胆汁由肝脏产生并储存在胆囊中,然后流向小肠,发挥消化脂肪的作用。为防止组织受损,胆汁酸(BA)被保存在磷脂胶束中。磷脂酰胆碱转运体 ABCB4(MDR3)发生突变会导致游离胆汁酸在肝内积聚,从而造成肝损伤。PFIC3 通常在早期发病,进展迅速,预后不良。目前,除了熊去氧胆酸盐(ursodeoxycholate)的姑息治疗外,该病唯一的治疗方法就是肝移植,而这对年龄较小的患者来说确实具有挑战性。为了深入了解 PFIC3 的发病机制,我们对人类肝脏样本进行了蛋白质组学和磷酸化蛋白质组学的综合研究,然后在 PFIC3 鼠模型中验证了新出现的功能假说。我们确定了 6246 个蛋白质组,其中 324 个蛋白质在对照组和 PFIC3 之间有差异表达。通过磷酸化蛋白质组学分析,我们鉴定出 5090 个磷酸化肽,其中 215 个对应 157 个蛋白质组,在 PFIC3(包括 MDR3)中出现不同程度的磷酸化。炎症、代谢重编程、细胞骨架和细胞外基质重塑以及细胞增殖等重要细胞过程和结构的调控被确定为该疾病的主要驱动因素。我们的研究结果提供了一个强有力的分子背景,大大有助于更好地理解 PFIC3,并提供了可能对患者的临床治疗有用的新概念。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Molecular basis of progressive familial intrahepatic cholestasis 3. A proteomics study

Molecular basis of progressive familial intrahepatic cholestasis 3. A proteomics study

Molecular basis of progressive familial intrahepatic cholestasis 3. A proteomics study

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe rare liver disease that affects between 1/50,000 and 1/100,000 children. In physiological conditions, bile is produced by the liver and stored in the gallbladder, and then it flows to the small intestine to play its role in fat digestion. To prevent tissue damage, bile acids (BAs) are kept in phospholipid micelles. Mutations in phosphatidyl choline transporter ABCB4 (MDR3) lead to intrahepatic accumulation of free BAs that result in liver damage. PFIC3 onset usually occurs at early ages, progresses rapidly, and the prognosis is poor. Currently, besides the palliative use of ursodeoxycholate, the only available treatment for this disease is liver transplantation, which is really challenging for short-aged patients. To gain insight into the pathogenesis of PFIC3 we have performed an integrated proteomics and phosphoproteomics study in human liver samples to then validate the emerging functional hypotheses in a PFIC3 murine model. We identified 6246 protein groups, 324 proteins among them showing differential expression between control and PFIC3. The phosphoproteomic analysis allowed the identification of 5090 phosphopeptides, from which 215 corresponding to 157 protein groups, were differentially phosphorylated in PFIC3, including MDR3. Regulation of essential cellular processes and structures, such as inflammation, metabolic reprogramming, cytoskeleton and extracellular matrix remodeling, and cell proliferation, were identified as the main drivers of the disease. Our results provide a strong molecular background that significantly contributes to a better understanding of PFIC3 and provides new concepts that might prove useful in the clinical management of patients.

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来源期刊
BioFactors
BioFactors 生物-内分泌学与代谢
CiteScore
11.50
自引率
3.30%
发文量
96
审稿时长
6-12 weeks
期刊介绍: BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.
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