Mechanism for HIF-1 activation by cholesterol under normoxia: A redox signaling pathway for liver damage

Sarit Anavi, Michal Hahn-Obercyger, Zecharia Madar, Oren Tirosh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


Cholesterol and chronic activation of hypoxia-inducible factor-1 (HIF-1) have been separately implicated in the pathogenesis and progression of liver diseases. In AML12 hepatocytes increased HIF-1α protein accumulation was evident after 2 h of incubation with cholesterol, whereas enhanced HIF-1 transcriptional activity was observed after 6 h. Investigations into the molecular mechanism have shown that cholesterol inhibited HIF-1α degradation. Mitochondrial dysfunction and enhanced mitochondrial reactive oxygen species (ROS) generation were observed in 2-h cholesterol-treated cells along with augmented nitric oxide (NO) levels. Further analysis indicated that HIF-1α stabilization at later time (6 h), but not after 2 h, of incubation with cholesterol was dependent on NO production. To elucidate the role of mitochondrial dysfunction in HIF-1α stabilization, mitochondrial DNA-depleted hepatocytes were prepared. In these cells the ability of cholesterol to activate the HIF-1 pathway was abolished. Similarly, catalase overexpression also attenuated cholesterol-induced HIF-1α accumulation. These results demonstrate that cholesterol promotes HIF-1 activation in a ROS- and NO-dependent manner. Chronic liver activation of HIF-1 by cholesterol may mediate its deleterious effects in the liver.

Original languageAmerican English
Pages (from-to)61-69
Number of pages9
JournalFree Radical Biology and Medicine
StatePublished - Jun 2014

Bibliographical note

Funding Information:
This study was supported by Grant 371/12 from the Israel Science Foundation to O.T. and Z.M.


  • Free radicals
  • Inflammation
  • Lipids
  • Nonalcoholic steatohepatitis
  • Oxidative stress
  • Redox signaling


Dive into the research topics of 'Mechanism for HIF-1 activation by cholesterol under normoxia: A redox signaling pathway for liver damage'. Together they form a unique fingerprint.

Cite this