Na Li1, Zhang-Sen Zhou2, Yang Shen1, Jie Xu1, Hong-Hua Miao1, Ying Xiong1, Feng Xu3, Bo-Liang Li1, Jie Luo2, Bao-Liang Song2. 1. State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. 2. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan, China. 3. Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
Abstract
Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element-binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78-kDa cell-surface glycoprotein or SREBP cleavage-activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine-induced HCC progression by down-regulating tumor-promoting cytokines, including interleukin (IL)-6, tumor necrosis factor alpha, and IL-1β. CONCLUSION: Inhibition of de novo lipid biosynthesis by suppressing the SREBP pathway prevents HCC. This study identifies a previously underappreciated role of the SREBP pathway in HCC and suggests a novel metabolic strategy to control liver cancer. (Hepatology 2017;65:1936-1947).
Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element-binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78-kDa cell-surface glycoprotein or SREBP cleavage-activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine-induced HCC progression by down-regulating tumor-promoting cytokines, including interleukin (IL)-6, tumor necrosis factor alpha, and IL-1β. CONCLUSION: Inhibition of de novo lipid biosynthesis by suppressing the SREBP pathway prevents HCC. This study identifies a previously underappreciated role of the SREBP pathway in HCC and suggests a novel metabolic strategy to control liver cancer. (Hepatology 2017;65:1936-1947).
Authors: Lisa M Butler; Ylenia Perone; Jonas Dehairs; Leslie E Lupien; Vincent de Laat; Ali Talebi; Massimo Loda; William B Kinlaw; Johannes V Swinnen Journal: Adv Drug Deliv Rev Date: 2020-07-23 Impact factor: 15.470