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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.
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Details
1 Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
2 Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
3 University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of RNA Biology of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
4 Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
5 Department of Pharmacology and School of Pharmacy, Second Military Medical University, Shanghai, China
6 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
7 State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China; Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
8 Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
9 Key Laboratory of RNA Biology of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
10 State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
11 Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, China
12 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
13 Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, China