Thyroid hormone. Basis for its hypocholesterolemic effect.

Abstract

The liver is the key organ involved in cholesterol homeostasis. Thyroid hormone binds to nuclear receptors in the liver and thereby acts to alter the expression of several genes coding for proteins involved in cholesterol homeostasis. The expression of apo B-100, the major protein of LDL, is markedly decreased by thyroid hormone while expression of apo A-I, the major protein of HDL, is profoundly increased by thyroid hormone. The thyroid hormone acts to increase hepatic LDL receptor and cholesterol 7 alpha hydroxylase gene expression. The increase in cholesterol 7 alpha hydroxylase, the enzyme which catalyzes the rate-limiting reaction in the degradation of cholesterol to form bile acids, occurs the most rapidly (within one hour) and requires low physiological doses of hormone. Inspection of the 5' flanking region of the cholesterol 7 alpha hydroxylase gene revealed two possible thyroid responsive elements, suggesting that thyroid hormone may exert a primary effect on this gene. The alterations in gene expression produced by thyroid hormone would be expected to result in decreased LDL levels because of decreased apo B-100 synthesis, increased HDL to assist in reverse cholesterol transport from peripheral tissue to the liver, increased removal of LDL from blood by increased hepatic LDL receptors, and increased elimination of cholesterol as neutral sterols and bile acids due to increased cholesterol 7 alpha hydroxylase. These actions would lead to lower serum cholesterol levels.