OBJECTIVE: Atherosclerosis is a chronic and progressive inflammatory disease of the arteries that is characterized by subendothelial accumulation of lipid-rich macrophages, called foam cells. We sought to identify the molecular details of cross-talk between liver X receptor α (LXRα) and hypoxia-inducible factor 1α (HIF-1α) for the formation of triglyceride-rich foam cells under hypoxic conditions. METHODS AND RESULTS: We first observed that expression of LXRα and its target lipogenic genes was time-dependently induced in human primary macrophages and RAW 264.7 cells under hypoxia. Similarly, TO901317, an activator of LXRα, enhanced the expression level and the transcriptional activity of HIF-1α. Second, we demonstrated that LXRα increased HIF-1α protein stability through a physical interaction between the ligand binding domain of LXRα and the oxygen-dependent degradation domain of HIF-1α. Third, we found that the activation of HIF-1α or LXRα synergistically induced triglyceride accumulation in macrophages. Finally, we showed that LXRα and HIF-1α were codistributed in the macrophages of atherosclerotic lesions of patients. CONCLUSIONS: These results suggest that the positive feed-forward regulation of transcriptional activity and protein stability of LXRα and HIF-1α has an important impact in foam cell formation.
OBJECTIVE: Atherosclerosis is a chronic and progressive inflammatory disease of the arteries that is characterized by subendothelial accumulation of lipid-rich macrophages, called foam cells. We sought to identify the molecular details of cross-talk between liver X receptor α (LXRα) and hypoxia-inducible factor 1α (HIF-1α) for the formation of triglyceride-rich foam cells under hypoxic conditions. METHODS AND RESULTS: We first observed that expression of LXRα and its target lipogenic genes was time-dependently induced in human primary macrophages and RAW 264.7 cells under hypoxia. Similarly, TO901317, an activator of LXRα, enhanced the expression level and the transcriptional activity of HIF-1α. Second, we demonstrated that LXRα increased HIF-1α protein stability through a physical interaction between the ligand binding domain of LXRα and the oxygen-dependent degradation domain of HIF-1α. Third, we found that the activation of HIF-1α or LXRα synergistically induced triglyceride accumulation in macrophages. Finally, we showed that LXRα and HIF-1α were codistributed in the macrophages of atherosclerotic lesions of patients. CONCLUSIONS: These results suggest that the positive feed-forward regulation of transcriptional activity and protein stability of LXRα and HIF-1α has an important impact in foam cell formation.
Authors: Hannes M Findeisen; Vivienne C Voges; Laura C Braun; Jannik Sonnenberg; Dennis Schwarz; Helena Körner; Holger Reinecke; Yahya Sohrabi Journal: Int J Mol Sci Date: 2022-05-31 Impact factor: 6.208
Authors: Lu Li; Bo Liu; Liliana Håversen; Emma Lu; Lisa U Magnusson; Marcus Ståhlman; Jan Borén; Göran Bergström; Malin C Levin; Lillemor Mattsson Hultén Journal: PLoS One Date: 2012-08-02 Impact factor: 3.240
Authors: Hyun Jik Lee; Young Hyun Jung; Gee Euhn Choi; So Hee Ko; Sei-Jung Lee; Sang Hun Lee; Ho Jae Han Journal: Redox Biol Date: 2017-07-04 Impact factor: 11.799