Neuropeptide Y inhibits hepatocarcinogenesis in overnutrition in mice Neuropeptide Yは過栄養マウスにおいて肝発癌を抑制する

Background: The incidence of hepatocellular carcinoma (HCC) with fatty liver disease has been increasing, and the sympathetic nervous system may be involved in hepatocarcinogenesis in such cases. Here we analyzed the impact of neuropeptide Y (Npy), which is released from sympathetic nerve endings, on hepatocarcinogenesis in different nutritional settings. Methods: Hepatocellular carcinoma was induced by an intraperitoneal injection of diethylnitrosamine (DEN) in male C57BL6/J mice null for Npy gene (Npy?/?) and their haplotype (Npy+/?) as a control (Ctrl). The mice were subjected to one of three dietary regimens: ad libitum feeding with a standard diet (AL) or a high-fat diet (HFD), or 30% dietary-restricted feeding (DR). Results: The occurrence and growth of HCC were accelerated in the Npy?/? mice, particularly in the AL and HFD conditions. Steatosis was promoted at 28 wks in the Npy?/? mice; steatohepatitis was not exacerbated in the Npy?/? mice at 28 or 48 wks. The alterations in the TNFα- and IL-6-mRNA expression levels and phosphorylated NF-κB and ERK1/2 levels in the liver at 28 wks did not support the current paradigm of a steatohepatitis-HCC sequence. By contrast, the DR inhibited steatohepatitis and then hepatocarcinogenesis even in the Npy?/? mice, although the Npy?/?-DR mice displayed peculiar findings, i.e., the activation of TNFα-NF-κB signaling, a possible protective mechanism against the elevated cell proliferation and genotoxic stresses. Conclusions: Npy exerts an inhibitory effect on the occurrence and growth of HCC, particularly in overnutrition. Npy is also dispensable for the tumor-inhibiting effect of DR. The activation of Npy could be a promising target for the prevention of HCC.

長崎大学学位論文 学位記番号:博(医歯薬)甲第1176号 学位授与年月日:令和元年9月4日

Author: Ayaka Kinoshita, Hiroko Hayashi, Natsuho Kusano, Shun Inoue, Toshimitsu Komatsu, Ryoichi Mori, Seongjoon Park, Mitsuhisa Takatsuki, Susumu Eguchi, Isao Shimokawa

Citation: Acta medica Nagasakiensia, 63(1), pp.11-25; 2019

Nagasaki University (長崎大学), 博士(医学) (2019-09-04)

http://hdl.handle.net/10069/39475

長崎大学学位論文 [学位記番号]博（医歯薬）甲第1176号 [学位授与年月日]令和元年9月4日

(2019-09-04)