Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and related clinical significance

• Published in: Journal of physiology and biochemistry Vol. 77; no. 2; pp. 249 - 260
• Main Authors: Ezzeddini, Rana, Taghikhani, Mohammad, Salek Farrokhi, Amir, Somi, Mohammad Hossein, Samadi, Nasser, Esfahani, Ali, Rasaee, Mohammad Javad
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01-05-2021; Springer Nature B.V
• Subjects: Adenocarcinoma; Animal Physiology; Biomedical and Life Sciences; Biomedicine; Carnitine; Catabolism; Cell culture; Clinical significance; Enzyme-linked immunosorbent assay; Fatty acids; Gene expression; Genes; Human Physiology; Hypoxia; Hypoxia-inducible factor 1a; Immunohistochemistry; Lipid metabolism; Lipids; Original Article; Oxidation; Pathogenesis; Patients; Proteins; Real time; Rewiring; Therapeutic targets; Hypoxia; Gastric adenocarcinoma; LCAD; CPT1A; MCAD; PPARγ
• ISSN: 1138-7548; 1877-8755
• DOI: 10.1007/s13105-021-00791-3

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-1α (HIF-1α) 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-1α, carnitine palmitoyl transferase 1 (CPT1A) and peroxisome proliferator-activated receptor γ (PPARγ) was evaluated by immunohistochemistry. In addition, gene expression of
PPARγ
,
CPT1A
,
LCAD
, and
MCAD
was assessed by real-time-PCR. In vitro findings indicate HIF-1α 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-1α and downregulated CPT1A and PPARγ were observed in GA tissues versus controls. Gene expression of
CPT1A
,
PPARγ
,
LCAD
, and
MCAD
were repressed in GA tissues compared to controls. Moreover, reduced expression of CPT1A, PPARγ, and MCAD were correlated with HIF-1α upregulation in GA. Poor patient outcome was associated with lower PPARγ and LCAD expression in GA.
HIF-1α
upregulation in human GA patients and AGS cells was paralleled by downregulation of lipid catabolism genes potentially via reduced
PPARγ
-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.