Abstract
Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common liver disease in developed countries
NAFLD patients often develop nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, which is characterized by inflammation, hepatocyte degeneration-like ballooning, and fibrosis
Representative images of F4/80 and Gr-1 immunostaining of transferase dUTP nick end labeling (TUNEL) staining the livers of CDAHFD-fed mice(H)
Summary
Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common liver disease in developed countries. NAFLD is recognized as a hepatic phenotype of metabolic syndrome and is strongly associated with obesity, insulin resistance, and hyperlipidemia [2,3,4]. NAFLD can exhibit a large spectrum of pathological changes—from simple steatosis to severe liver injury. NAFLD patients often develop nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, which is characterized by inflammation, hepatocyte degeneration-like ballooning, and fibrosis. This may further lead to cirrhosis and hepatocellular carcinoma [5,6]. The pathological mechanism of NAFLD is still not fully
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call