GP73 regulates Hepatic Steatosis by enhancing SCAP-SREBPs interaction

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.

Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice

“…Existing evidence indicates that ER stress can also be induced upon viral infection or cytokine treatment . In addition, both UPR activation and GP73 up‐regulation lead to transcriptional activation of sterol regulatory element‐binding proteins . We thus hypothesized that expression of GP73 might be regulated by ER stress UPR.…”

“…F), and cholesterol (Supporting Fig. G) was detected in mice livers challenging with Tm, indicating a prominent HS phenotype . We then performed qRT‐PCR analyses with liver tissue sections.…”

“…Previous studies have shown that GP73 is up-or down-regulated in hepatocytes in response to liver diseases, viral infection, and cytokine treatments. (14,24) ER stress UPR has been implicated in the pathogenesis of several different types of liver diseases, including nonalcoholic fatty liver disease (NAFLD), chronic viral hepatitis, and alcoholinduced liver injury. (25) Existing evidence indicates that ER stress can also be induced upon viral infection or cytokine treatment.…”

“…(26,27) In addition, both UPR activation and GP73 up-regulation lead to transcriptional activation of sterol regulatory element-binding proteins. (24,28) We thus hypothesized that expression of GP73 might be regulated by ER stress UPR. To investigate the potential link between ER stress and GP73 expression, we treated HepG2 cells with two classical ER stressors: Tg and Tm.…”

“…S1G) was detected in mice livers challenging with Tm, indicating a prominent HS phenotype. (24,31) We then performed qRT-PCR analyses with liver tissue sections. Increased mRNA expression of GP73 was found in liver 8, 12, and 24 hours after Tm challenge, along with up-regulated mRNA expression of CHOP ( Fig.…”