Hepatocyte-specific IKKβ expression aggravates atherosclerosis development in APOE*3-Leiden mice

Area of Science:

• Cardiovascular Research
• Hepatology
• Immunology

Background:

• The liver plays a crucial role in systemic inflammation, but its direct link to atherosclerosis development is not fully understood.
• Nuclear factor-κB (NF-κB) is a key regulator of inflammatory responses, making it a potential mediator between liver inflammation and cardiovascular disease.

Purpose of the Study:

• To investigate the impact of chronically enhanced hepatic NF-κB activation on atherosclerosis progression.
• To determine if hepatocyte-specific expression of IκB kinase-β (IKKβ) aggravates atherosclerosis in APOE*3-Leiden (E3L) mice.

Main Methods:

• APOE*3-Leiden mice with hepatocyte-specific IKKβ expression (E3L.LIKK) and control littermates (E3L) were fed a Western-type diet for 24 weeks.
• Atherosclerotic lesion area and severity were quantified in the aortic root.
• Plasma cytokine levels and cholesterol profiles were analyzed, particularly after lipopolysaccharide (LPS) challenge.

Main Results:

• E3L.LIKK mice exhibited a 2.3-fold increase in atherosclerotic lesion area compared to controls.
• Atherosclerosis was more advanced in E3L.LIKK mice, with a higher proportion of severe lesions.
• While basal inflammatory markers were unaffected, E3L.LIKK mice showed transiently elevated plasma cholesterol, primarily in (V)LDL, and tended towards higher cytokine levels post-LPS.

Conclusions:

• Selective activation of NF-κB in hepatocytes significantly promotes atherosclerosis development.
• This promotion is partly attributed to heightened sensitivity to pro-inflammatory stimuli.
• Transiently increased plasma cholesterol levels also contribute to the aggravated atherosclerosis observed.