Downregulation Of Fatty Acid Oxidation By Involvement Of Hif-1 Alpha And Ppar Gamma In Human Gastric Adenocarcinoma And Related Clinical Significance

Lipid metabolism rewiring in gastric adenocarcinoma (GA) pathogenesis is still not clearly elucidated. This study aimed to describe the role of lipid catabolism in GA patient outcomes and possible therapeutic targets by analyzing the effect of hypoxia-inducible factor-1 alpha (HIF-1 alpha) on fatty acid oxidation (FAO). AGS cell line was cultured in normoxic and hypoxic conditions, and FAO-related genes were analyzed by real-time-PCR and Western-blot. The study group comprised 108 newly diagnosed GA patients and 152 control cases. Serum concentrations of medium and long-chain acyl-CoA dehydrogenases (MCAD and LCAD) proteins were measured using ELISA, and local expression of HIF-1 alpha, carnitine palmitoyl transferase 1 (CPT1A) and peroxisome proliferator-activated receptor gamma (PPAR gamma) was evaluated by immunohistochemistry. In addition, gene expression of PPAR gamma, CPT1A, LCAD, and MCAD was assessed by real-time-PCR. In vitro findings indicate HIF-1 alpha upregulation and FAO-related genes and proteins reduction in the hypoxic culture of AGS cells. GA patients had significantly lower circulating levels of LCAD compared to controls. Higher protein expression of HIF-1 alpha and downregulated CPT1A and PPAR gamma were observed in GA tissues versus controls. Gene expression of CPT1A, PPAR gamma, LCAD, and MCAD were repressed in GA tissues compared to controls. Moreover, reduced expression of CPT1A, PPAR gamma, and MCAD were correlated with HIF-1 alpha upregulation in GA. Poor patient outcome was associated with lower PPAR gamma and LCAD expression in GA. HIF-1 alpha upregulation in human GA patients and AGS cells was paralleled by downregulation of lipid catabolism genes potentially via reduced PPAR gamma-mediated FAO. This metabolic adaptation to hypoxic condition may play a role in GA pathogenesis and might have clinical and therapeutic value in GA patients.