NAFLD exacerbates cholangitis and promotes cholangiocellular carcinoma in mice.
NAFLD exacerbates cholangitis and promotes cholangiocellular carcinoma in mice.
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DOI：
10.1111/cas.14828
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发表时间：
2021-04
期刊：
影响因子：
5.7
通讯作者：
Chuma M
中科院分区：
文献类型：
--
作者：
Maeda S;Hikiba Y;Fujiwara H;Ikenoue T;Sue S;Sugimori M;Matsubayashi M;Kaneko H;Irie K;Sasaki T;Chuma M
非酒精性脂肪肝（NAFLD）是一种越来越常见的疾病，影响全球高达25%的人口。NAFLD与几种疾病有关，包括肝脏炎症、纤维化和肝细胞癌（HCC），但NAFLD在胆管炎和胆管细胞癌（CCC）发展中的作用仍知之甚少。这项研究调查了高脂饮食（HFD）是否会促进小鼠胆管炎和CCC的发展。我们使用肝脏特异性E-钙粘蛋白基因（CDH 1）敲除小鼠，CDH 1 Liv，其在汇管区发生自发性炎症，伴沿着管周洋葱皮样纤维化，类似于原发性硬化性胆管炎（PSC）。将HFD或正常饮食（ND）喂养给CDH 1 HPLiv小鼠7个月。此外，将CDH 1 α Liv小鼠与LSL-KrasG 12 D小鼠杂交，喂食HFD，并评估肝脏肿瘤发展。与ND-给药的CDH 1 CDHliv小鼠相比，喂食HFD的小鼠的胆管炎程度和胆管数量显著增加。HFD小鼠中Sox 9和CD 44阳性干细胞样细胞的数量显著增加。LSL-KrasG 12 D/CDH 1 α Liv HFD小鼠表现出增加的攻击性，沿着许多HCC和CCC的发展，而LSL-KrasG 12 D/CDH 1 α Liv ND小鼠显示出几种具有HCC和CCC组分的肉眼可见肿瘤。总之，在小鼠中，NAFLD加重胆管炎并促进HCC和CCC的发展。胆管细胞cdh 1缺失可引起自发性胆管炎和胆管反应。NAFLD小鼠的胆管炎和胆管反应程度增加。额外的Kras突变在具有Cdh 1缺失的胆管细胞的小鼠中发展胆管细胞肿瘤，并且NAFLD促进胆管细胞肿瘤的发展。
Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition, affecting up to 25% of the population worldwide. NAFLD has been linked to several conditions, including hepatic inflammation, fibrosis, and hepatocellular carcinoma (HCC), however the role of NAFLD in cholangitis and the development of cholangiocellular carcinoma (CCC) remains poorly understood. This study investigated whether a high‐fat diet (HFD) promotes cholangitis and the development of CCC in mice. We used liver‐specific E‐cadherin gene (CDH1) knockout mice, CDH1∆Liv, which develop spontaneous inflammation in the portal areas along with periductal onion skin‐like fibrosis, similar to that of primary sclerosing cholangitis (PSC). An HFD or normal diet (ND) was fed to CDH1∆Liv mice for 7 mo. In addition, CDH1∆Liv mice were crossed with LSL‐KrasG12D mice, fed an HFD, and assessed in terms of liver tumor development. The extent of cholangitis and number of bile ductules significantly increased in mice fed an HFD compared with ND‐administered CDH1∆Liv mice. The numbers of Sox9 and CD44‐positive stem cell‐like cells were significantly increased in HFD mice. LSL‐KrasG12D /CDH1∆Liv HFD mice exhibited increased aggressiveness along with the development of numerous HCC and CCC, whereas LSL‐KrasG12D/CDH1∆Liv ND mice showed several macroscopic tumors with both HCC and CCC components. In conclusion, NAFLD exacerbates cholangitis and promotes the development of both HCC and CCC in mice. Cdh1 deletion in cholangiocytes develops spontaneous cholangitis and ductular reaction. The extent of cholangitis and ductular reaction is increased in mice with NAFLD. Additional Kras mutation develops cholangiocellular tumors in mice with Cdh1 deleted cholangiocytes and NAFLD promotes development of cholangiocellular tumors.
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影响因子：
11.2
作者：
Gao D;Vahdat LT;Wong S;Chang JC;Mittal V
通讯作者：
Mittal V
影响因子：
5.7
作者：
Maeda S;Hikiba Y;Fujiwara H;Ikenoue T;Sue S;Sugimori M;Matsubayashi M;Kaneko H;Irie K;Sasaki T;Chuma M
通讯作者：
Chuma M
DOI：
10.1002/hep.30150
发表时间：
2019-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Sato K;Marzioni M;Meng F;Francis H;Glaser S;Alpini G
通讯作者：
Alpini G
影响因子：
9.8
作者：
Buzzetti, Elena;Pinzani, Massimo;Tsochatzis, Emmanuel A.
通讯作者：
Tsochatzis, Emmanuel A.
影响因子：
15.9
作者：
Sekiya, Sayaka;Suzuki, Atsushi
通讯作者：
Suzuki, Atsushi