Context-Dependent Effects of Apolipoprotein A2 on Lipid Metabolism and Atherogenesis

Apolipoprotein A2 (APOA2) is a component of several plasma lipoproteins, yet its physiological and pathological functions remain unclear. Conflicting data regarding its effects on plasma lipid levels and cardiovascular risk indicate that APOA2 activity may be context dependent. Here, we employed adenovirus-mediated gene transfer of human APOA2 into male C57BL/6, ldlr^-/-, and apoe^-/- mice fed a western-type diet for 2 weeks to investigate in parallel its impact on lipoprotein metabolism and atherogenesis under different conditions of dyslipidemia and atherosclerotic burden. In normolipidemic C57BL/6 mice, APOA2 expression raised plasma VLDL/LDL cholesterol and triglycerides, consistent with inhibition of lipoprotein lipase activity. In HDL density fractions, cholesterol was unaffected while triglycerides increased. In contrast, APOA2 expression in ldlr^-/- mice reduced cholesterol and triglyceride levels across all major lipoprotein fractions, including HDL density fractions. Similarly, in apoe^-/- mice, APOA2 expression markedly lowered VLDL cholesterol and triglycerides, though cholesterol and triglycerides in LDL and HDL density fractions were increased. Interestingly, following oral administration of olive oil containing [¹⁴C]-cholesterol and [³H]-triolein to ldlr^-/- mice, APOA2 expression enhanced tracer deposition in the aorta and aortic root. Corroborating this finding, immunohistochemical analysis of aortic root cryosections from both ldlr^-/- and apoe^-/- mice revealed increased staining for APOA2 and APOB in APOA2-expressing animals, suggesting augmented accumulation of APOB-containing lipoproteins in the arterial wall. Collectively, these findings support a pro-atherogenic role for APOA2. Although under dyslipidemic conditions APOA2 may superficially appear protective by lowering circulating APOB-containing lipoproteins, mechanistic evidence indicates that it promotes vascular retention of APOB-containing particles, thereby accelerating atherogenesis.