title: 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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea; Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Wonbaek
authors.initials: W
authors.lastname: Yoo
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Noh
authors.forename: Jae Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Yu
authors.forename: Ji A
authors.initials: JA
authors.lastname: Seo
authors.forename: Sin Gon
authors.initials: SG
authors.lastname: Kim
authors.forename: Kyung Mook
authors.initials: KM
authors.lastname: Choi
authors.forename: Sei Hyun
authors.initials: SH
authors.lastname: Baik
authors.forename: Dong Seop
authors.initials: DS
authors.lastname: Choi
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.forename: Hyo Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Nan Hee
authors.initials: NH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002796:Choline Deficiency; D004032:Diet; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008715:Methionine / Q000172:deficiency; D008810:Mice, Inbred C57BL; D019308:Palmitic Acid / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D065840:Protective Factors; D011485:Protein Binding; D034622:RNA Interference; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C497442:HIF1A protein, human; D006360:Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051742:Transcription Factor CHOP; D019308:Palmitic Acid; D008715:Methionine; D053148:Caspase 3
keywords: CHOP; ER STRESS; HEPATIC STEATOSIS; HIF-1α; LIPOAPOPTOSIS; NON-ALCOHOLIC FATTY LIVER DISEASE