Thyroid hormone regulation and cholesterol metabolism are connected through Sterol Regulatory Element-Binding Protein-2 (SREBP-2).
High affinity uptake of serum-derived low density lipoprotein (LDL) cholesterol is accomplished through the LDL receptor in the liver. In mammals, thyroid hormone depletion leads to decreased LDL receptor expression and elevated serum cholesterol. The clinical association in humans has been known since the 1920s; however, a molecular explanation has been lacking. LDL receptor levels are subject to negative feedback regulation by cellular cholesterol through sterol regulatory element-binding protein-2 (SREBP-2). Here we demonstrate that the SREBP-2 gene is regulated by thyroid hormone and that increased SREBP-2 nuclear protein levels in hypothyroid animals results in thyroid hormone-independent activation of LDL receptor gene expression and reversal of the associated hypercholesterolemia. This occurs without effects on other thyroid hormone-regulated genes. Thus, we propose that the decreased LDL receptor and increased serum cholesterol associated with hypothyroidism are secondary to the thyroid hormone effects on SREBP-2. These results suggest that hypercholesterolemia associated with hypothyroidism can be reversed by agents that directly increase SREBP-2. Additionally, these results indicate that mutations or drugs that lower nuclear SREBP-2 would cause hypercholesterolemia.
Shin
Dong-Ju
DJ
Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, USA.
Osborne
Timothy F
TF
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D015152:Blotting, Northern; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism; D007037:Hypothyroidism / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D051379:Mice; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2; D013963:Thyroid Hormones / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C497390:SREBF2 protein, human; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D013963:Thyroid Hormones; D014157:Transcription Factors; D002784:Cholesterol; D008148:Lovastatin; D012260:Ribonucleases