Hepatocyte-specific ABCA1 transfer increases HDL cholesterol but impairs HDL function and accelerates atherosclerosis

Area of Science:

• Cardiovascular Biology
• Lipid Metabolism
• Gene Therapy

Background:

• ATP-binding cassette transporter A1 (ABCA1) facilitates cholesterol efflux to apolipoprotein A-I (apoA-I), a key step in high-density lipoprotein (HDL) biogenesis.
• Dysfunctional HDL is implicated in the progression of atherosclerosis.
• The role of hepatocyte-specific ABCA1 overexpression in modulating HDL function and atherosclerosis remains to be fully elucidated.

Purpose of the Study:

• To investigate the impact of hepatocyte-specific ABCA1 overexpression on HDL function and atherosclerosis progression.
• To compare the effects of ABCA1 gene transfer with apolipoprotein A-I (apoA-I) gene transfer in a mouse model of atherosclerosis.

Main Methods:

• Adenoviral vectors were used for hepatocyte-specific gene transfer of murine ABCA1 (AdABCA1) or human apoA-I (AdA-I) in apoE(-/-) mice.
• Lipoprotein profiles, HDL cholesterol levels, and atherosclerosis progression were assessed.
• In vitro assays evaluated HDL's effects on endothelial progenitor cell (EPC) migration and endothelial cell survival.

Main Results:

• AdA-I transfer significantly increased HDL cholesterol and inhibited atherosclerosis progression.
• AdABCA1 transfer increased HDL cholesterol but exacerbated atherosclerosis, particularly in male mice.
• HDL from AdABCA1 mice failed to enhance EPC migration or protect endothelial cells, and liver SR-BI protein levels were reduced.

Conclusions:

• Hepatocyte-specific ABCA1 overexpression impairs HDL's beneficial functions, including effects on EPCs and endothelial cells.
• Reduced HDL function following ABCA1 transfer may contribute to accelerated atherosclerosis.
• Targeting ABCA1 expression in hepatocytes may have complex effects on cardiovascular health.