The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis

安非雷古林 内科学 肝损伤 内分泌学 法尼甾体X受体 小异二聚体伴侣 胆汁淤积 胆固醇7α羟化酶 肝再生 消胆胺 表皮生长因子受体 医学 生物 化学 胆汁酸 受体 胆固醇 再生(生物学) 细胞生物学 转录因子 核受体 生物化学 基因
作者
Eva Santamaría,Carlos M. Rodríguez‐Ortigosa,Iker Uriarte,M. Ujúe Latasa,Raquel Urtasun,Gloria Álvarez‐Sola,Marina Bárcena‐Varela,Leticia Colyn,Sara Arcelus,Maddalen Jiménez,Kathleen Deutschmann,Ana Peleteiro‐Vigil,Julián Gómez-Cambronero,Małgorzata Milkiewicz,Piotr Milkiewicz,Bruno Sangro,Verena Keitel,María J. Monte,José J.G. Marı́n,Maite G. Fernández‐Barrena,Matías A. Ávila,Carmen Berasain
出处
期刊:Hepatology [Wiley]
卷期号:69 (4): 1632-1647 被引量:51
标识
DOI:10.1002/hep.30348
摘要

Intrahepatic accumulation of bile acids (BAs) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ’s function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand, amphiregulin (AREG), during cholestatic liver injury and regulation of AREG expression by BAs. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha‐naphthyl‐isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly up‐regulated. Importantly, Areg–/– mice showed aggravated liver injury after BDL and ANIT administration compared to Areg+/+ mice. Recombinant AREG protected from ANIT and BDL‐induced liver injury and reduced BA‐triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic Areg expression, and, interestingly, cholestyramine feeding reduced postprandial Areg up‐regulation in both tissues. Most interestingly, Areg–/– mice displayed high hepatic cholesterol 7 α‐hydroxylase (CYP7A1) expression, reduced serum cholesterol, and high BA levels. Postprandial repression of Cyp7a1 was impaired in Areg–/– mice, and recombinant AREG down‐regulated Cyp7a1 mRNA in hepatocytes. On the other hand, BAs promoted AREG gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in Fxr–/– mice, and involved EGFR transactivation. Finally, we show that hepatic EGFR expression is indirectly induced by BA‐FXR through activation of suppressor of cytokine signaling‐3 (SOC3). Conclusion: AREG‐EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
找文献呢发布了新的文献求助10
1秒前
小草莓完成签到,获得积分10
2秒前
2秒前
席凡桃发布了新的文献求助10
3秒前
起昵称好困难完成签到 ,获得积分10
4秒前
Owen应助痴情的雪萍采纳,获得30
4秒前
田様应助芝麻小粉采纳,获得10
5秒前
ding应助小孙采纳,获得10
6秒前
科研通AI2S应助旻主采纳,获得10
6秒前
研友_VZG7GZ应助兴兴采纳,获得10
6秒前
8秒前
黎夏发布了新的文献求助10
14秒前
16秒前
16秒前
啊哈哈完成签到,获得积分10
16秒前
16秒前
快哒哒哒完成签到,获得积分10
17秒前
白芷苏完成签到,获得积分10
17秒前
BB发布了新的文献求助10
18秒前
稳重元菱完成签到,获得积分10
20秒前
20秒前
芝麻小粉发布了新的文献求助10
21秒前
小孙发布了新的文献求助10
23秒前
852应助黎夏采纳,获得10
23秒前
文艺的芹菜完成签到,获得积分10
24秒前
25秒前
找文献呢发布了新的文献求助10
26秒前
26秒前
27秒前
李爱国应助青岩采纳,获得10
27秒前
evak发布了新的文献求助10
31秒前
loyalll发布了新的文献求助10
31秒前
35秒前
董丽君完成签到 ,获得积分0
37秒前
leilan发布了新的文献求助30
37秒前
40秒前
41秒前
loyalll完成签到,获得积分10
44秒前
44秒前
可爱的函函应助悦耳蜡烛采纳,获得10
46秒前
高分求助中
The late Devonian Standard Conodont Zonation 2000
Nickel superalloy market size, share, growth, trends, and forecast 2023-2030 2000
The Lali Section: An Excellent Reference Section for Upper - Devonian in South China 1500
Very-high-order BVD Schemes Using β-variable THINC Method 870
Mantiden: Faszinierende Lauerjäger Faszinierende Lauerjäger 800
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 800
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3256323
求助须知:如何正确求助?哪些是违规求助? 2898596
关于积分的说明 8301615
捐赠科研通 2567759
什么是DOI,文献DOI怎么找? 1394681
科研通“疑难数据库(出版商)”最低求助积分说明 652913
邀请新用户注册赠送积分活动 630557