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

• Published in: Nature communications 2019-07, Vol.10 (1), p.3391-16, Article 3391
• Main Authors: Tian, Yuan, Yang, Bin, Qiu, Weinan, Hao, Yajing, Zhang, Zhenxing, Yang, Bo, Li, Nan, Cheng, Shuqun, Lin, Zhangjun, Rui, Yao-cheng, Cheung, Otto K. W., Yang, Weiqin, Wu, William K. K., Cheung, Yue-Sun, Lai, Paul B. S., Luo, Jianjun, Sung, Joseph J. Y., Chen, Runsheng, Wang, Hong-Yang, Cheng, Alfred S. L., Yang, Pengyuan
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/51; 13/89; 13/95; 14/19; 14/35; 14/63; 38/15; 38/22; 38/88; 38/89; 38/90; 42/44; 631/67/2327; 631/67/395; 64/60; Animals; Autophagy; Cancer; Carbohydrates; Carcinogens; Carcinoma, Hepatocellular - complications; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; CD36 antigen; Cell Line, Tumor; Deregulation; Diet, High-Fat - adverse effects; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Fatty liver; Female; Gene Expression Profiling - methods; Hep G2 Cells; Hepatocellular carcinoma; High carbohydrate diet; High fat diet; Humanities and Social Sciences; Humans; Kaplan-Meier Estimate; Lipid metabolism; Lipids; Lipoproteins, LDL - metabolism; Liver cancer; Liver diseases; Liver Neoplasms - complications; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Lysophosphatidic acid; Metabolic disorders; Metabolic syndrome; Metabolic Syndrome - etiology; Metabolic Syndrome - genetics; Metabolic Syndrome - metabolism; Mice, Inbred C57BL; Mice, Nude; multidisciplinary; Nogo protein; Nogo Proteins - genetics; Nogo Proteins - metabolism; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Science; Science (multidisciplinary); Signal Transduction - genetics; Transplantation, Heterologous; Tumorigenicity; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11274-x

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. Non alcoholic fatty liver disease (NAFLD) associates with an elevated risk of developing hepatocellular carcinoma (HCC). Here, the authors find that Nogo-B, an endoplasmic reticulum resident protein, is upregulated by lipid uptake and acts as an oncogene in NAFLD-associated HCC by promoting lipid droplet breakdown by lipophagy and triggering Hippo pathway dysregulation