Cholesterol-mediated suppression of alpha 1-inhibitor III, a plasma alpha-macroglobulin family protein

Using differential hybridization techniques we have isolated a hamster cDNA encoding a cholesterol-regulated protein. By sequence homology we concluded that the isolated cDNA encodes alpha 1-inhibitor III (alpha 1 I3), a protein of the alpha-macroglobulin (alpha M) family. When hamsters were fed diets rich in cholesterol, cholic acid, or chenodeoxycholic acid, the amount of alpha 1I3 RNA was reduced between 5- and 10-fold. Drugs that lower plasma cholesterol levels, such as colestipol and mevinolin, increased alpha 1I3 RNA between 2- and 3-fold. Additionally, plasma alpha 1I3 protein levels, as measured by immunoblotting techniques using an anti-human alpha 2M antibody, correlate well with alpha 1I3 RNA levels in those hamsters. Plasma alpha 1I3 protein was inversely proportional to plasma cholesterol levels in those hamsters. The observed suppression of alpha 1I3 expression by cholesterol mimics the cholesterol-mediated regulation of other genes that maintain cholesterol homeostasis, such as 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and low density lipoprotein receptor. We hypothesize that alpha 1I3 may play a role in the onset of atherosclerosis and may provide a link between cholesterol and the clotting system. Furthermore, the availability of another sterol-regulated gene, like alpha 1I3, should help elucidate the molecular mechanisms of cholesterol-mediated regulation of gene transcription.