Although studies in vitro and in hypothyroid animals show that thyroid hormone can, under some circumstances, modulate the actions of low-density lipoprotein (LDL) receptors, the mechanisms responsible for thyroid hormone's lipid-lowering effects are not completely understood. We tested whether LDL receptor (LDLR) expression was required for cholesterol reduction by treating control and LDLR-knockout mice with two forms of thyroid hormone T3 and 3,5-diiodo-L-thyronine. High doses of both 3,5-diiodo-L-thyronine and T 3 dramatically reduced circulating total and very low-density lipoprotein/LDL cholesterol (∼70%) and were associated with reduced plasma T4 level. The cholesterol reduction was especially evident in the LDLR-knockout mice. Circulating levels of both apolipoprotein B (apo)B48 and apoB100 were decreased. Surprisingly, this reduction was not associated with increased protein or mRNA expression of the hepatic lipoprotein receptors LDLR-related protein 1 or scavenger receptor-B1. Liver production of apoB was markedly reduced, whereas triglyceride production was increased. Thus, thyroid hormones reduce apoB lipoproteins via anon-LDLR pathway that leads to decreased liver apoB production. This suggests that drugs that operate in a similar manner could be a new therapy for patients with genetic defects in the LDLR.
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