Abstract
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 highāfat diet (HFD) promotes cholangitis and the development of CCC in mice. We used liverāspecific Eācadherin gene (CDH1) knockout mice, CDH1āLiv, which develop spontaneous inflammation in the portal areas along with periductal onion skinālike fibrosis, similar to that of primary sclerosing cholangitis (PSC). An HFD or normal diet (ND) was fed to CDH1āLiv mice for 7 mo. In addition, CDH1āLiv mice were crossed with LSLāKrasG12D 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 NDāadministered CDH1āLiv mice. The numbers of Sox9 and CD44āpositive stem cellālike cells were significantly increased in HFD mice. LSLāKrasG12D /CDH1āLiv HFD mice exhibited increased aggressiveness along with the development of numerous HCC and CCC, whereas LSLāKrasG12D/CDH1āLiv 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.
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