Transforming growth factor beta is sequestered into an inactive pool by lipoproteins

Elevated plasma concentrations of low density lipoprotein (LDL) and very-low density lipoprotein (VLDL) have been correlated with the development of atherosclerosis. These lipoproteins may promote atherogenesis by direct deposition of lipid in the vessel wall. In addition, previous data suggested that there was an inverse correlation between serum LDL-cholesterol concentration and the proportion of transforming growth factor beta (TGF-beta) in an active form (Grainger et al. 1995. Nature Med. 1:74). Here we have investigated whether lipoproteins can affect the activity of TGF-beta1 in plasma and show that TGF-beta can associate with the lipoprotein fraction. In the plasma of healthy males, 16 +/- 5% (mean +/- standard deviation; n = 57) of the total plasma TGF-beta1 was associated with the lipoprotein fraction, with the major proportion (64 +/- 15%) in the HDL-3 subfraction. However, in ten diabetic subjects with moderately poor glucose control (Hb alc > 8.0), the proportion of total plasma TGF-beta in the lipoprotein fraction was 68 +/- 21%. This large increase in TGF-beta1 associated with the lipoprotein fraction was mainly due to association with VLDL, chylomicrons, and LDL. The lipoprotein fraction inhibits TGF-beta1 binding to the type II TGF-beta receptor extracellular domain in an ELISA and inhibits TGF-beta1 activity in the mink lung cell bioassay. We propose that sequestration of TGF-beta into lipoproteins represents a novel mechanism by which TGF-beta activity in circulation may be regulated. Lipoprotein sequestration of TGF-beta may therefore contribute to the severe depression of TGF-beta activity in advanced atherosclerosis.