Role of Matrix Gla Protein in Transforming Growth Factor-β Signaling and Nonalcoholic Steatohepatitis in Mice.
Role of Matrix Gla Protein in Transforming Growth Factor-β Signaling and Nonalcoholic Steatohepatitis in Mice.
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DOI：
10.1016/j.jcmgh.2023.08.007
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发表时间：
2023
影响因子：
7.2
通讯作者：
Lusis, Aldons J.
中科院分区：
文献类型：
--
作者：
Hui, Simon T.;Gong, Lili;Swichkow, Chantle;Blencowe, Montgomery;Kaminska, Dorota;Diamante, Graciel;Pan, Calvin;Dalsania, Meet;French, Samuel W.;Magyar, Clara E.;Pajukanta, Paivi;Pihlajamaki, Jussi;Bostrom, Kristina I.;Yang, Xia;Lusis, Aldons J.
非酒精性脂肪性肝炎（NASH）是一种复杂的疾病，其发病和进展涉及遗传和环境因素。我们分析了遗传多样性小鼠队列（杂交小鼠多样性小组）中的NASH表型，以确定导致疾病易感性的基因。一个“系统遗传学”的方法，涉及整合遗传，转录组学，和表型数据，被用来确定候选基因和途径的NASH小鼠模型。使用杂合MGP敲除（Mgp+/-）小鼠验证基质Gla蛋白（MGP）的因果作用。通过使用功能丧失方法在LX-2星状细胞系中检查MGP在转化生长因子-β（TGF-β）信号传导中的机制作用。MGP的局部顺式作用调节与纤维化相关，表明在NASH中的因果作用，并且这在2种饮食诱导的NASH模型中使用功能丧失实验进行了验证。使用单细胞RNA测序，发现Mgp主要在小鼠肝星状细胞和树突状细胞中表达。星形LX-2细胞中MGP表达的敲低导致对TGF-β刺激的迟钝反应。这与调节性SMAD磷酸化和TGF-β受体ALK 1表达减少以及抑制性SMAD 6表达增加有关。发现肝脏MGP表达与NASH患者肝脏纤维化的严重程度显著相关，表明与人类疾病相关。MGP调节肝纤维化和肝星状细胞中的TGF-β信号传导，并促成NASH发病机制。
Nonalcoholic steatohepatitis (NASH) is a complex disease involving both genetic and environmental factors in its onset and progression. We analyzed NASH phenotypes in a genetically diverse cohort of mice, the Hybrid Mouse Diversity Panel, to identify genes contributing to disease susceptibility. A “systems genetics” approach, involving integration of genetic, transcriptomic, and phenotypic data, was used to identify candidate genes and pathways in a mouse model of NASH. The causal role of Matrix Gla Protein (MGP) was validated using heterozygous MGP knockout (Mgp+/-) mice. The mechanistic role of MGP in transforming growth factor-beta (TGF-β) signaling was examined in the LX-2 stellate cell line by using a loss of function approach. Local cis-acting regulation of MGP was correlated with fibrosis, suggesting a causal role in NASH, and this was validated using loss of function experiments in 2 models of diet-induced NASH. Using single-cell RNA sequencing, Mgp was found to be primarily expressed in hepatic stellate cells and dendritic cells in mice. Knockdown of MGP expression in stellate LX-2 cells led to a blunted response to TGF-β stimulation. This was associated with reduced regulatory SMAD phosphorylation and TGF-β receptor ALK1 expression as well as increased expression of inhibitory SMAD6. Hepatic MGP expression was found to be significantly correlated with the severity of fibrosis in livers of patients with NASH, suggesting relevance to human disease. MGP regulates liver fibrosis and TGF-β signaling in hepatic stellate cells and contributes to NASH pathogenesis.
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WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
DOI：
10.1002/hep.31995
发表时间：
2021-11
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Kozumi K;Kodama T;Murai H;Sakane S;Govaere O;Cockell S;Motooka D;Kakita N;Yamada Y;Kondo Y;Tahata Y;Yamada R;Hikita H;Sakamori R;Kamada Y;Daly AK;Anstee QM;Tatsumi T;Morii E;Takehara T
通讯作者：
Takehara T
DOI：
10.1111/liv.14743
发表时间：
2021-04
期刊：
Liver international : official journal of the International Association for the Study of the Liver
影响因子：
--
作者：
de Mello VD;Sehgal R;Männistö V;Klåvus A;Nilsson E;Perfilyev A;Kaminska D;Miao Z;Pajukanta P;Ling C;Hanhineva K;Pihlajamäki J
通讯作者：
Pihlajamäki J
影响因子：
10.5
作者：
Hata, A;Lagna, G;Hemmati-Brivanlou, A
通讯作者：
Hemmati-Brivanlou, A
影响因子：
4.5
作者：
Bennett BJ;Davis RC;Civelek M;Orozco L;Wu J;Qi H;Pan C;Packard RR;Eskin E;Yan M;Kirchgessner T;Wang Z;Li X;Gregory JC;Hazen SL;Gargalovic PS;Lusis AJ
通讯作者：
Lusis AJ