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 CEBPß 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.
Subject(s)
Autophagy , Carcinoma, Hepatocellular/metabolism , Lipoproteins, LDL/metabolism , Liver Neoplasms/metabolism , Nogo Proteins/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Animals , Carcinoma, Hepatocellular/complications , Carcinoma, Hepatocellular/genetics , Cell Line, Tumor , Diet, High-Fat/adverse effects , Endoplasmic Reticulum/metabolism , Female , Gene Expression Profiling/methods , Hep G2 Cells , Humans , Kaplan-Meier Estimate , Liver Neoplasms/complications , Liver Neoplasms/genetics , Metabolic Syndrome/etiology , Metabolic Syndrome/genetics , Metabolic Syndrome/metabolism , Mice, Inbred C57BL , Mice, Nude , Nogo Proteins/genetics , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/genetics , Signal Transduction/genetics , Transplantation, HeterologousABSTRACT
Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD) and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose, and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management.
