Silencing HIF-1α aggravates non-alcoholic fatty liver disease in vitro through inhibiting PPAR-α/ANGPTL4 singling pathway.

Abstract

OBJECTIVE:

Non-alcoholic fatty liver disease (NAFLD) is an aberrant lipid metabolism disease. Hypoxia inducible factor-1 (HIF-1α) is a transcription factor which plays an important part in adapting lower oxygen condition. Here, we aimed to clarify the relationship between HIF-1α and NAFLD.

METHODS:

HepG2 cells was stimulated by oleic acid (OA) and palmitic acid (PA) to establish in vitro model of NAFLD. The expression of lipid metabolism-related genes, the binding of PPARα to HIF-1α promoter, the lipid deposition, and oxidative stress were detected by qRT-PCR, western blot, Chip assay, Oil Red O staining and ELISA assays, respectively.

RESULTS:

HIF-1α silence promoted lipid accumulation in NAFLD cells, accompanying by the significantly increased contents of TG (triglyceride) and ApoB (apolipoprotein B). In HepG2 cells treated with OA/PA, the expression of lipid metabolism-related genes and proteins, including APOE, A2m, TNFRSF11B, LDLr, and SREBP2, and the intracellular lipid deposition were up-regulated and further aggravated after silencing HIF-1α. In addition, the loss of HIF-1α could remarkably elevate MDA contents while inhibit the activities of beneficial antioxidant enzymes SOD and GSH-Px to activate oxidative stress, and promote the secretion of pro-inflammatory IL-6 and TNF-α to aggravate inflammation in NDFLD cells. PPARα positively bound to HIF-1α promoter. The silence of PPARα aggravated lipid deposition under normal or hypoxic environment in NAFLD cells. In addition, PPAR-α silence could decrease the expression of HIF-1α and ANGPTL4 in NAFLD cell model; moreover, the expression of APOE, A2m and TNFRSF11B and the production of TG and MDA were increased by PPAR-α suppression.

CONCLUSION:

HIF-1α plays a crucial role in the regulation of lipid metabolism through activating PPAR-α/ANGPTL4 signaling pathway in NAFLD.

• Authors: Yan He, Wenhui Yang, Lulu Gan, Shijie Liu, Qing Ni, Yunxia Bi, Tun Han, Qian Liu, Hongyan Chen, Yang Hu, Yun Long, Li Yang
• Journal: Gastroenterologia y hepatologia (Gastroenterol Hepatol) Vol. 44 Issue 5 Pg. 355-365 (May 2021) ISSN: 0210-5705 [Print] Spain
• PMID: 33272734 (Publication Type: Journal Article)
• Copyright: Copyright © 2020. Publicado por Elsevier España, S.L.U.

Chemical References

• ANGPTL4 protein, human
• Angiopoietin-Like Protein 4
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• PPAR alpha
• PPARA protein, human

Topics

• Angiopoietin-Like Protein 4 (antagonists & inhibitors)
• Cells, Cultured
• Gene Silencing
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, physiology)
• Non-alcoholic Fatty Liver Disease (genetics)
• PPAR alpha (antagonists & inhibitors)
• Signal Transduction