ER-residential Nogo-B accelerates NAFLD-associated HCC mediated by metabolic reprogramming of oxLDL lipophagy

Yuan Tian, Bin Yang, Weinan Qiu, Yajing Hao, Zhenxing Zhang, Bo Yang, Nan Li, Shuqun Cheng, Zhangjun Lin, Yao-cheng Rui, Otto K. W. Cheung, Weiqin Yang, William K. K. Wu, Yue-Sun Cheung, Paul B. S. Lai, Jianjun Luo, Joseph J. Y. Sung, Runsheng Chen, Hong-Yang Wang, Alfred S. L. Cheng () and Pengyuan Yang ()
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Yuan Tian: Chinese Academy of Sciences
Bin Yang: Chinese Academy of Sciences
Weinan Qiu: Chinese Academy of Sciences
Yajing Hao: University of Chinese Academy of Sciences
Zhenxing Zhang: Chinese Academy of Sciences
Bo Yang: Chinese Academy of Sciences
Nan Li: Second Military Medical University
Shuqun Cheng: Second Military Medical University
Zhangjun Lin: Chinese Academy of Sciences
Yao-cheng Rui: Second Military Medical University
Otto K. W. Cheung: The Chinese University of Hong Kong
Weiqin Yang: The Chinese University of Hong Kong
William K. K. Wu: The Chinese University of Hong Kong
Yue-Sun Cheung: The Chinese University of Hong Kong
Paul B. S. Lai: The Chinese University of Hong Kong
Jianjun Luo: Chinese Academy of Sciences
Joseph J. Y. Sung: The Chinese University of Hong Kong
Runsheng Chen: Chinese Academy of Sciences
Hong-Yang Wang: Second Military Medical University
Alfred S. L. Cheng: The Chinese University of Hong Kong
Pengyuan Yang: Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome that elevates the risk of hepatocellular carcinoma (HCC). Although alteration of lipid metabolism has been increasingly recognized as a hallmark of cancer cells, the deregulated metabolic modulation of HCC cells in the NAFLD progression remains obscure. Here, we discovers an endoplasmic reticulum-residential protein, Nogo-B, as a highly expressed metabolic modulator in both murine and human NAFLD-associated HCCs, which accelerates high-fat, high-carbohydrate diet-induced metabolic dysfunction and tumorigenicity. Mechanistically, CD36-mediated oxLDL uptake triggers CEBPβ expression to directly upregulate Nogo-B, which interacts with ATG5 to promote lipophagy leading to lysophosphatidic acid-enhanced YAP oncogenic activity. This CD36-Nogo-B-YAP pathway consequently reprograms oxLDL metabolism and induces carcinogenetic signaling for NAFLD-associated HCCs. Targeting the Nogo-B pathway may represent a therapeutic strategy for HCC arising from the metabolic syndrome.

Date: 2019
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DOI: 10.1038/s41467-019-11274-x

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