Cell reports · 2022
Hypothalamic orexin prevents non-alcoholic steatohepatitis and hepatocellular carcinoma in obesity.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Tsuneki Hiroshi, Maeda Takahiro, Takata Shinjiro, Sugiyama Masanori, Otsuka Koyuki, Ishizuka Hinako, Onogi Yasuhiro, Tokai Emi, Koshida Chiaki, Kon Kanta, Takasaki Ichiro, Hamashima Takeru, Sasahara Masakiyo, Rudich Assaf, Koya Daisuke, Sakurai Takeshi, Yanagisawa Masashi, Yamanaka Akihiro, Wada Tsutomu, Sasaoka Toshiyasu
Аннотация
Non-alcoholic steatohepatitis (NASH) occasionally occurs under obesity; however, factors modulating the natural history of fatty liver disease remain unknown. Since hypothalamic orexin that regulates physical activity and autonomic balance prevents obesity, we investigate its role in NASH development. Male orexin-deficient mice fed a high-fat diet (HFD) show severe obesity and progression of NASH with fibrosis in the liver. Hepatic fibrosis also develops in ovariectomized orexin-deficient females fed an HFD but not ovariectomized wild-type controls. Moreover, long-term HFD feeding causes hepatocellular carcinoma (HCC) in orexin-deficient mice. Intracerebroventricular injection of orexin A or pharmacogenetic activation of orexin neurons acutely activates hepatic mTOR-sXbp1 pathway to prevent endoplasmic reticulum (ER) stress, a NASH-causing factor. Daily supplementation of orexin A attenuates hepatic ER stress and inflammation in orexin-deficient mice fed an HFD, and autonomic ganglionic blocker suppresses the orexin actions. These results suggest that hypothalamic orexin is an essential factor for preventing NASH and associated HCC under obesity.