Lack of fibroblast growth factor 21 accelerates metabolic liver injury characterized by steatohepatities in mice.
Fibroblast growth factor 21 (FGF21) concentrations are increased in human subjects who either have type 2 diabetes or nonalcoholic fatty liver disease (NAFLD). While excessive fat in the liver promotes the release of pro-inflammatory cytokines, NAFLD progresses from steatosis to non alcoholic steatohepatitis (NASH), a more aggressive form of hepatic damage, and lastly toward cirrhosis and HCC. In our previous study, loss of FGF21 is associated with hyper-proliferation, aberrant p53, and HCC development in diabetes mice. In this study, we proposed to investigate the liver metabolic disorders by diabetes and the potential roles of FGF21 played in NASH and potential carcinogenetic transformation of HCC. NASH was induced in FGF21 knockout (FGF21KO) mice by streptozotocin administration or fed with high fat diet (HFD). The pathological transformation of steatohepatities as well as parameters of inflammation, lipid metabolism, cellular events, mesenchymal-epithelial transition (MET) and Wnt/β-catenin signaling was determined in the FGF21 KO diabetic mice and HFD fed mice. We found that mice lacking the FGF21 gene are more prone to develop NASH. A compromised microenvironment of NASH, which could facilitate the HCC carcinogenetic transformation, was found in FGF21 KO mice under metabolic disorders by diabetes and HFD feeding. This study provided further evidence that lack of FGF21 worsened the metabolic disorders in NASH and could render a tumor microenvironment for HCC initiation and progression in the liver of diabetes mice.
Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University Changchun 130021, China.
Xingkai
X
Liu
Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University Changchun 130021, China.
Ping
P
Zhang
Department of Surgery, School of Medicine, University of Louisville Louisville, KY 40202, USA.
Robert C
RC
Martin
Department of Hepatology, Cancer Center, The First Hospital of Jilin University Changchun 130021, China.
Guozhen
G
Cui
Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University Changchun 130021, China.
Guangyi
G
Wang
Kosair Children's Hospital Research Institute, The Department of Pediatrics of The University of Louisville Louisville, KY 40202, USA.
Yi
Y
Tan
Kosair Children's Hospital Research Institute, The Department of Pediatrics of The University of Louisville Louisville, KY 40202, USA.
Lu
L
Cai
Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University Changchun 130021, China.
Guoyue
G
Lv
Department of Surgery, School of Medicine, University of Louisville Louisville, KY 40202, USA.
Yan
Y
Li
Fibroblast growth factor 21; diabetes; hepatocellular carcinoma; steatohepatities