The Opposite Effect of c-Jun Transcription Factor on Apolipoprotein E Gene Regulation in Hepatocytes and Macrophages

Area of Science:

• Molecular Biology
• Cardiovascular Research
• Cell Biology

Background:

• Apolipoprotein E (apoE) is crucial for lipoprotein metabolism and is produced by both hepatocytes and macrophages.
• Atherosclerosis development involves cholesterol accumulation in macrophages and regulation of apoE expression by cell-specific enhancers.
• The AP-1 family member c-Jun is known to influence the transcription of genes involved in inflammation and lipid metabolism.

Purpose of the Study:

• To investigate the differential effects of c-Jun on apoE gene expression in macrophages versus hepatocytes.
• To elucidate the molecular mechanisms underlying c-Jun's cell-specific regulation of apoE.
• To understand how c-Jun's dual action on apoE contributes to atherogenesis.

Main Methods:

• Transient transfections with deletion mutants of apoE regulatory elements (ME.2, HCRs).
• DNA pull-down (DNAP) assays to identify c-Jun binding sites.
• Chromatin immunoprecipitation (ChIP) assays to confirm in vivo binding.
• Assessment of apoE expression levels and cholesterol efflux.

Main Results:

• c-Jun downregulated apoE expression in macrophages via binding to a site on ME.2 (301/311).
• c-Jun upregulated apoE expression in hepatocytes through binding to the proximal promoter site (-94/-84).
• The opposing effects of c-Jun on apoE in macrophages and hepatocytes influence cholesterol homeostasis and systemic apoE levels.

Conclusions:

• c-Jun exhibits cell-specific, opposing regulation of apoE expression in macrophages and hepatocytes.
• This dual regulation contributes to decreased cholesterol efflux in macrophages and increased systemic apoE from the liver.
• The findings suggest that c-Jun's modulation of apoE plays a significant role in the pathogenesis of atherosclerosis.