Abstract 13617: Bone Morphogenetic Protein Signaling is a Regulator of Hepatic Cholesterol Biosynthesis in vitro and in vivo
Introduction: We have previously found that Inhibition of bone morphogenetic protein (BMP) signaling reduces atherosclerosis and vascular calcification in mouse models, but the mechanisms by which BMP signaling contributes to atherogenesis are incompletely understood.
Hypothesis: BMP signaling contributes to atherogenesis by altering cholesterol biosynthesis and/or metabolism.
Methods: Levels of LDL and HDL serum cholesterol were measured in LDL receptor-deficient (LDLR-/-) mice fed a Western diet for 20 weeks, treated with vehicle or LDN-193189 (a small molecule BMP type I receptor kinase inhibitor). Hepatic tissue sections were stained with H+E to detect lipid accumulation (steatosis). Apolipoprotein B100 (ApoB) production by HepG2 cells was measured (using ELISA) in the presence and absence of BMP2, LDN-193189, recombinant noggin (an endogenous BMP inhibitor), and atorvastatin (an HMG-CoA reductase inhibitor). The impact of LDN-193189 or noggin on HMG-CoA reductase enzyme activity was measured using an in vitro HMG-CoA reductase assay. Data are reported as mean ± SEM.
Results: LDL cholesterol levels in LDLR-/- mice treated with LDN-193189 (n = 8) were less than those in mice treated with vehicle (n = 9, 1166±91 vs 1797±102 mg/dl, p<0.05), whereas HDL levels did not differ (74±9 vs 90±10 mg/dl, respectively, p=ns). The reduction in serum LDL was paralleled by markedly reduced steatosis in animals treated with LDN-193189 versus vehicle. In HepG2 cells, ApoB production was upregulated by treatment with BMP2 versus control (220±10 vs 173±14 ng/ml, p<0.05). BMP2-mediated induction of ApoB production was abolished by pretreatment with LDN-193189 or noggin (168±8 and 177±9 ng/ml, respectively, p<0.05 for both vs BMP2 treatment alone). In contrast, atorvastatin reduced basal ApoB secretion but had no impact on the ability of BMP2 to stimulate ApoB secretion. Moreover, LDN-193189 or noggin did not inhibit HMG-CoA reductase activity in vitro.
Conclusion: These results demonstrate that BMP signaling appears to contribute to atherogenesis by inducing LDL biosynthesis, suggesting a novel target for the treatment of hyperlipidemia and atherosclerosis.
- © 2011 by American Heart Association, Inc.