Abstract 407: The Role Of Peroxisomes And Bile Acid-initiated Signaling In Vascular Smooth Muscle Cell Phenotype

Background: Atherosclerosis is a chronic inflammatory process characterized by the accumulation of foam cells (lipid-laden macrophage-like cells). Vascular smooth muscle cells (VSMCs) are not terminally differentiated, and their phenotype is modulated in response to various stimuli, such as cholesterol (CHO), which increase susceptibility to vascular diseases. Modulated SMCs contribute to foam cell formation within atherosclerotic plaques. The intracellular metabolism of CHO via peroxisomes in hepatocytes produces bile acids like chenodeoxycholic acid (CDCA), which agonizes farnesoid X nuclear receptor (FXR) and liver X receptor (LXR). FXR regulates bile acid, glucose, and lipid homeostasis. LXR facilitates the first step of reverse CHO transport. It is unknown if VSMCs synthesize bile acids and whether peroxisomes and the bile acids they produce play a role in VSMC-derived foam cell formation. Results: Using human aortic VSMC (HASMCs), we found that CHO treatment decreased expression of several peroxisomal proteins. Peroxisomal loss-of-function experiments demonstrated increased intracellular lipid accumulation, as visualized with Oil Red O (ORO) staining. Peroxisomal biogenesis associated with fenofibrate treatment completely eradicated intracellular ORO. We have shown that HASMCs synthesize bile acids after exposure to CHO, which led us to hypothesize that bile acid-initiated signaling participates in the phenotypic modulation initiated by CHO in VSMCs. Treatment of HASMCs with LXR agonists increased expression of the efflux CHO transporter ABCA1 and differentiation markers SMA and CNN1, and decreased expression of macrophage marker LGALS3. Conclusions: These data show that VSMCs have the metabolic capacity to synthesize bile acids, which is impaired if peroxisomes are non-functional or absent. Our data indicates that activation of bile acid receptors upregulates ABCA1, favoring a differentiated VSMC phenotype. Together, these data suggest that bile acid-mediated activation of FXR and LXR have differential roles in CHO-induced VSMC to foam cell transition and that LXR activation may represent a novel atheroprotective target which increases cellular efflux of CHO, promoting VSMC differentiation.