HIF‐1α Expression as a Protective Strategy of HepG2 Cells Against Fatty Acid‐Induced Toxicity

Abstract

Free fatty acid-induced lipotoxicity via increased endoplasmic reticulum (ER) stress and hepatocyte apoptosis is a key pathological mechanism of non-alcoholic steatohepatitis. A role of hypoxia-inducible factor 1α (HIF-1α) in this process has been suggested, but direct evidence is lacking. Here, we used HepG2 cells as a model to study whether HIF-1α can reduce palmitic acid-induced lipotoxicity and ER stress. In HepG2 cells treated with 500 µM palmitic acid, HIF-1α expression increased transiently, the decline was associated with increased cleaved caspase-3 expression. Overexpression and knockdown of HIF-1α decreased and exacerbated, respectively, palmitic acid-induced lipoapoptosis. The overexpression also blunted upregulation of the ER stress markers, C/EBP homologous protein (CHOP) and chaperone immunoglobulin heavy chain binding protein (Bip), while the knockdown increased the level of CHOP. In line with this, CHOP promoter activity decreased following HIF-1α binding to the CHOP promoter hypoxia response element. These results indicate that hepatocyte lipotoxicity is associated with decreased HIF-1α expression. It also suggests that upregulation of HIF-1α can be a possible strategy to reduce lipotoxicity in non-alcoholic fatty liver disease.

Palmitic Acid-BSA enhances Amyloid-β production through GPR40-mediated dual pathways in neuronal cells: Involvement of the Akt/mTOR/HIF-1α and Akt/NF-κB pathways

“…Moreover, hypoxia-mediated HIF-1α signaling is involved in the amyloidogenic processing of the amyloid precursor protein, and subsequent downstream events influence the activation of the pro-death gene BNIP3, thus leading to an increased incidence of AD and neurodegeneration after cerebral ischemia and stroke 62, 64 . In agreement with our current findings, HIF-1α activation induced by FAs and HFD has been shown to act as a central mediator of angiogenesis and metabolic process 65, 66 . These results are consistent with the notion that patients who suffer from ischemia are more sensitive to AD development 67, 68 .…”

Macrophage‐Specific Hypoxia‐Inducible Factor‐1α Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis

“…In whole liver tissue, increased HIF‐1α and decreased autophagic flux mediate NASH pathogenesis . In addition, an increase of liver macrophage infiltrate, and its importance for NASH progression, has been reported .…”

“…NASH pathogenesis is linked to hepatocyte steatosis and necroinflammation, and liver macrophages play an important role in both of these processes . Previous studies demonstrated that steatosis is linked to metabolic signals such as FFAs that induce cellular stress responses in hepatocytes including HIF‐1α and autophagy . However, the role of HIF‐1α and autophagy in macrophages is not well understood, despite their crucial involvement in the disease progression of NASH.…”

“…In NASH, free fatty acids (FFAs) are important mediators of lipotoxicity, leading to cell injury and inducing hepatocyte damage via different pathways including endoplasmic reticulum stress. This process is counterbalanced by the upregulation of autophagic pathways that maintain cellular survival and homeostasis . Impaired autophagy is a key element of hepatocyte damage in NASH .…”

“…Cellular stressors such as hypoxia and HIF activation can also interact with autophagy in hepatocytes . In vitro data demonstrate that HIF‐1α protects against fatty acid–induced toxicity in hepatocytes . However, the role of these pathways is undefined in macrophages in NASH.…”