Abstract
Elevated Golgi phosphoprotein 2 (GP73, also known as GOLPH2 or GOLM1) expression in serum and liver, which can be induced by viral infection and cytokine treatments, is intimately connected with liver disease, including acute hepatitis, cirrhosis and hepatocellular carcinoma (HCC). However, its pathogenic roles in hepatic diseases have never been clarified in detail. Here, we showed that the upregulated GP73 is indispensable for SREBPs activation and lipogenesis. Notably, GP73 overexpression enhanced SCAP-SREBPs binding and its Golgi trafficking even under cholesterol sufficiency. Consistent with these functional findings, GP73 blockage could alleviate tunicamycin-induced liver steatosis by reducing SREBPs activation. A significant positive correlation of GP73 with genes in lipid metabolism pathway was also identified in liver cancer based on data from The Cancer Genome Atlas (TCGA) dataset. Our findings revealed previously unrecognized role of GP73 in lipid metabolism.
Highlights
GP73, which is named Golgi membrane protein (GOLM1) or Golgi phosphoprotein 2 (GOLPH2), is a type II transmembrane protein located on cis and medial-Golgi
Our unpublished data indicated that cholesterol pathway were ranked as the one of top 8 upregulated signaling pathways in GP73 overexpressed HepG2 cells, which propelled us to study the effect of GP73 expression on SREBPs activation
To further elucidate SREBPs activation in HepG2 cells and 293T cells, we used Quantitative real-time RT-PCR (QRT-PCR) to determine the effect of GP73 overexpression on the mRNA levels of HMGR, HMGSC1, HMGSC2, FASN2, ACSS2 and ACC1, five genes involved in cholesterol biosynthesis motivated by SREBP-2, SREBP-1a or both
Summary
GP73, which is named Golgi membrane protein (GOLM1) or Golgi phosphoprotein 2 (GOLPH2), is a type II transmembrane protein located on cis and medial-Golgi. Cytokines are confirmed to play an important role in GP73 expression regulation, with interferon gamma (IFN-γ) upregulating, while tumor necrosis factor alpha (TNF-α) downregulates[5]. Both intracellular and secreted GP73 exist as coiled-coil dimers[2]. In the cholesterol and triglyceride biosynthesis pathways, the active SREBP transcription factors trigger the expression of genes that encode cholesterogenic or lipogenic enzymes, promoting lipid synthesis. The involvement of GP73 in promoting SCAP stabilization, SCAP Golgi localization and the increased formation of SCAP-SREBP complex regardless of cholesterol content implicates its pathological roles in hepatic steatosis and HCC progression
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