Abstract 3621: sLr11, An Enhancer Of Intimal Smooth Muscle Cell Migration, Inhibits Fat Accumulation In Mice As A Novel Adipogenesis Regulator
Circulating level of soluble form of LR11 (sLR11), an LDL receptor family member, is tightly associated with the degree of intima-media thickness (IMT) of human carotid arteries. sLR11 is highly expressed in intimal smooth muscle cells (SMCs), and activates an urokinase type plasminogen activator receptor (uPAR)/integrin/focal adhesion kinase (FAK)-mediated intracellular signaling toward the migration acceleration for SMCs and macrophages. Deficiency of sLR11 showed that drastic decrease in intimal thickening after endothelial injury of femoral arteries in normal chow-fed mice, and macrophage infiltration in the intima in high fat-fed mice. Here, we show that sLR11 is a novel adipogenesis regulator through the inhibition of C/EBP and PPARγ activation through the uPAR/integrin/FAK pathway in adipocytes. The sLR11 gene is specifically expressed in cultured preadipocytes, and the expression level is drastically decreased in mature adipocytes. The addition of recombinant sLR11 almost inhibited the differentiation of 3T3-L1 preadipocytes to the fat-accumulating mature adipocytes. Subcutaneous and epididymal fat tissues weights were significantly increased in Lr11−/− mice in comparison to those in Lr11+/+ mice at 5 weeks old. The cell size and the gene expressions of PPARγ and C/EBPα of adipocytes were significantly increased in Lr11−/− mice in comparison to those in Lr11+/+ mice. Cultured Lr11−/− adipocytes showed the enhanced ability for triglyceride accumulation, and the increase was abolished by the incubation with recombinant LR11. The Lr11−/− adipocytes showed that the significantly decreased MAK kinase activity through the integrin/FAK signaling in comparison to that in Lr11+/+ adipocytes. The addition of a MEK inhibitor PD98059 or a neutralizing antibody against integrin αv recovered the fat accumulation disturbed in the 3T3-L1 adipocytes incubated with sLR11. Thus, sLR11 is abundantly expressed in preadipocytes, and may play an important role in the regulation of adipogenesis as an potent inhibitor of adipocyte differentiation, in addition to as an enhancer of intimal smooth muscle cell migration.