Regulation of lipid metabolism by APOE4 in intrahepatic cholangiocarcinoma via the enhancement of ABCA1 membrane expression

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a malignancy with a dismal prognosis, thus the discovery of promising diagnostic markers and treatment targets is still required. In this study, 1,852 differentially expressed genes (DEGs) were identified in the GSE45001 dataset for weighted gene co-expression network analysis (WGCNA), and the turquoise module was confirmed as the key module. Next, the subnetworks of the 1,009 genes in the turquoise module analyzed by MCODE, MCC, and BottleNeck algorithms identified nine overlapping genes (CAT, APOA1, APOC2, HSD17B4, EHHADH, APOA2, APOE4, ACOX1, AGXT), significantly associated with lipid metabolism pathways, such as peroxisome and cholesterol metabolism. Among them, APOE4 exhibited a potential tumor-suppressive role in ICC and high diagnostic value for ICC in both GSE45001 and GSE32879 datasets. In vitro experiments demonstrated Apolipoprotein E4 (APOE4) overexpression suppressed ICC cell proliferation, migration, and invasion, knockdown was the opposite trend. And in ICC modulated lipid metabolism, notably decreasing levels of TG, LDL-C, and HDL-C, while concurrently increasing the expressions of TC. Further, APOE4 also downregulated lipid metabolism-related genes, suggesting a key regulatory role in maintaining cellular homeostasis, and regulating the expression of the membrane protein ATP-binding cassette transporter A1 (ABCA1). These findings highlighted the coordinated regulation of lipid metabolism by APOE4 and ABCA1 in ICC progression, providing new insights into ICC mechanisms and potential therapeutic strategies.

Elucidating the Role of Lipid-Metabolism-Related Signal Transduction and Inhibitors in Skin Cancer

“…In 2011, Hanahan and Weinberg recognized the deregulation of cellular metabolism as a fundamental hallmark of cancer cells, characterized by disruptions in multiple bioenergetic pathways, including those for glucose, amino acids, and lipids [ 1 ]. Among these metabolic agents, lipids are multifunctional molecules that significantly influence various cellular processes, including the regulation of membrane glycoprotein function, control of membrane trafficking, apoptotic pathways, and drug transport [ 2 , 3 , 4 , 5 , 6 , 7 ]. In addition, research has shown that lipid metabolites can influence the surrounding microenvironment in ways that may promote tumor progression [ 8 , 9 , 10 ].…”