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Abstract
BACKGROUND/AIMS:
Non-alcoholic fatty liver disease (NAFLD) is an emerging metabolic disease. Although it leads to severe hepatic diseases including steatohepatitis, cirrhosis, and hepatic cancer, little is known about therapy to prevent and cure hepatic steatosis, the first step of NAFLD. We conducted this investigation to unveil the mechanism of hepatic steatosis.

METHODS:
We established a novel chronic NAFLD mouse model through whole body irradiation and verified the model through histological and biochemical analysis. To find molecular mechanism for hepatic steatosis, we analyzed hepatic transcriptomic profiles in this model and selected target molecule. To induce the expression of lactotransferrin (Ltf) and regulate the NAFLD, growth hormone (GH) and coumestrol was introduced to hepatocyte and mice. The universal effect of coumestrol was confirmed by administration of coumestrol to NAFLD mouse model induced by high-fructose, high-fat, and MCD diet.

RESULTS:
It was observed that decreased hepatic Ltf expression led to excessive hepatic lipid accumulation in NAFLD mouse. Furthermore, we found that GH was decreased in irradiated mice and functioned as an upstream regulator of Ltf expression. It was observed that GH could stimulate Ltf expression and prevent uptake of dietary lipids in hepatocytes, leading to rescue of NAFLD. Finally, we suggested that coumestrol, a kind of isoflavonoid, could be used as an inducer of hepatic Ltf expression through cooperation with the GH signaling pathway both in vitro and in vivo.

CONCLUSIONS:
Hepatic Ltf prevents hepatic steatosis through inhibition of dietary lipid uptake in radiation-induced NAFLD mouse model. We also suggest coumestrol as a drug candidate for prevention of NAFLD.

Author information

Lee S1, Son B1, Jeon J1,2, Park G1, Kim H1, Kang H3, Youn H4, Jo S2, Song JY5, Youn B1,3.
1
Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea.
2
Department of Radiation Oncology, Haeundae Paik Hospital, Inje University School of Medicine, Busan, Republic of Korea.
3
Department of Biological Sciences, Pusan National University, Busan, Republic of Korea.
4
Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.
5
Division of Applied Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.