title: Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans.
abstract: Reduced plasma LDL-cholesterol is a hallmark of hyperthyroidism and is caused by transcriptional stimulation of LDL receptors in the liver. Here, we investigated whether thyroid hormone (TH) actions involve other mechanisms that may also account for the reduction in LDL-cholesterol, including effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) and bile acid synthesis. Twenty hyperthyroid patients were studied before and after clinical normalization, and the responses to hyperthyroidism were compared with those in 14 healthy individuals after 14 days of treatment with the liver-selective TH analog eprotirome. Both hyperthyroidism and eprotirome treatment reduced circulating PCSK9, lipoprotein cholesterol, apoB and AI, and lipoprotein(a), while cholesterol synthesis was stable. Hyperthyroidism, but not eprotirome treatment, markedly increased bile acid synthesis and reduced fibroblast growth factor (FGF) 19 and dietary cholesterol absorption. Eprotirome treatment, but not hyperthyroidism, reduced plasma triglycerides. Neither hyperthyroidism nor eprotirome treatment altered insulin, glucose, or FGF21 levels. TH reduces circulating PSCK9, thereby likely contributing to lower plasma LDL-cholesterol in hyperthyroidism. TH also stimulates bile acid synthesis, although this response is not critical for its LDL-lowering effect.
authors.affiliation: Metabolism Unit, Department of Endocrinology, Metabolism, and Diabetes, and KI/AZ Integrated CardioMetabolic Center, Department of Medicine Molecular Nutrition Unit, Center for Innovative Medicine, Department of Biosciences and Nutrition.
authors.forename: Ylva
authors.initials: Y
authors.lastname: Bonde
authors.affiliation: Karolinska Institute at Karolinska University Hospital Huddinge, S-14186 Stockholm, Sweden; Karo Bio AB, Novum, S-14186 Stockholm, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Breuer
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Clinics Bonn, D-53105 Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Metabolism Unit, Department of Endocrinology, Metabolism, and Diabetes, and KI/AZ Integrated CardioMetabolic Center, Department of Medicine.
authors.forename: Stefan
authors.initials: S
authors.lastname: Sjöberg
authors.affiliation: Metabolism Unit, Department of Endocrinology, Metabolism, and Diabetes, and KI/AZ Integrated CardioMetabolic Center, Department of Medicine Molecular Nutrition Unit, Center for Innovative Medicine, Department of Biosciences and Nutrition.
authors.forename: Bo
authors.initials: B
authors.lastname: Angelin
authors.affiliation: Metabolism Unit, Department of Endocrinology, Metabolism, and Diabetes, and KI/AZ Integrated CardioMetabolic Center, Department of Medicine Molecular Nutrition Unit, Center for Innovative Medicine, Department of Biosciences and Nutrition.
authors.forename: Mats
authors.initials: M
authors.lastname: Rudling
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000813:Anilides / Q000494:pharmacology; D001055:Apolipoproteins B / Q000097:blood; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000097:blood / Q000737:chemistry; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000097:blood; D005346:Fibroblast Growth Factors / Q000097:blood; D006801:Humans; D006980:Hyperthyroidism / Q000097:blood / Q000201:enzymology / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007408:Intestinal Absorption / Q000187:drug effects; D017270:Lipoprotein(a) / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood*; D011988:Receptors, Thyroid Hormone / Q000819:agonists; D012697:Serine Endopeptidases / Q000097:blood*; D013963:Thyroid Hormones / Q000378:metabolism*; D055815:Young Adult
chemical_list: C526273:3-((3,5-dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid; D000813:Anilides; D001055:Apolipoproteins B; D001647:Bile Acids and Salts; D001786:Blood Glucose; C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; D007328:Insulin; D017270:Lipoprotein(a); D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: bile acids and salts/biosynthesis; cholesterol 7alpha-hydroxylase; cholesterol/absorption; drug therapy/hypolipidemic drugs; eprotirome; fibroblast growth factor; fibroblast growth factor 19; fibroblast growth factor 21; lipoproteins/metabolism; proprotein convertase subtilisin/kexin type 9