GPD1L supports glycerol-3-phosphate and triacylglycerol synthesis and promotes tumor progression in hepatocellular carcinoma

Background & Aims: Research on metabolic reprogramming in hepatocellular carcinoma (HCC) has increased; however, studies on the metabolism of glycerolipids or interactions between different pathways remain scarce. Enzymes of glycerol phosphate dehydrogenase (GPD) family, which regulate glycerol-3-phosphate shuttle, link the metabolic processes of glycolysis and glycerolipids. Therefore, we aimed to understand the role and regulation of GPDs in HCC. Approach & Results: We performed transcriptomic analysis on clinical HCC samples from in-house and public cohorts and detected upregulation of glycerol-3-phosphate dehydrogenase 1 like (GPD1L) among GPD family genes in HCC. Further analysis showed that high GPD1L expression was associated with more frequent venous invasion and shorter overall survival. Consistent with these clinical findings, GPD1L knockdown suppressed invasiveness of HCC cells, reduced colony- and sphere-forming abilities, and inhibited stemness gene expression in vitro, while also inhibiting tumor growth and metastasis in vivo . On the other hand, we used mass-spectrometry-based metabolomics to confirm that GPD1L facilitated the biogenesis of the glycerolipid precursor glycerol-3-phosphate (G3P) from dihydroxyacetone phosphate (DHAP). Further untargeted lipidomic analysis revealed that GPD1L supported triacylglycerol synthesis. Additionally, our study identified E74 like E-Twenty-Six transcription factor 1 (ELF1) as a direct activator of GPD1L transcription, binding to the GPD1L promoter to boost its transcription while reducing GPD1L expression when ELF1 levels were lowered. Conclusions: GPD1L is overexpressed in human HCCs and associated with worse clinical outcomes. Aberrant GPD1L expression, driven by ELF1, facilitates conversion of DHAP to G3P conversion to support triacylglycerol synthesis in HCC, promoting tumor growth and metastasis.