Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
University of Chinese Academy of Sciences, 100049, Beijing, China.
Nat Commun. 2019 Jul 29;10(1):3391. 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.
非酒精性脂肪性肝病 (NAFLD) 是代谢综合征的肝脏表现，会增加肝细胞癌 (HCC) 的风险。尽管脂质代谢的改变已被越来越多地认为是癌细胞的一个标志，但在 NAFLD 进展中 HCC 细胞的代谢调节紊乱仍不清楚。在这里，我们发现内质网驻留蛋白 Nogo-B 作为一种在鼠类和人类与 NAFLD 相关的 HCC 中高度表达的代谢调节剂，它加速了高脂肪、高碳水化合物饮食诱导的代谢功能障碍和肿瘤发生。从机制上讲，CD36 介导的氧化型低密度脂蛋白 (oxLDL) 摄取触发 CEBPβ 表达，直接上调 Nogo-B，Nogo-B 与 ATG5 相互作用促进脂自噬，导致溶血磷脂酸增强 YAP 致癌活性。因此，CD36-Nogo-B-YAP 通路重新编程 oxLDL 代谢，并诱导与 NAFLD 相关的 HCC 的致癌信号。靶向 Nogo-B 通路可能是治疗代谢综合征相关 HCC 的一种策略。
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