Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans - PubMed (original) (raw)

Clinical Trial

. 2014 Nov;55(11):2408-15.

doi: 10.1194/jlr.M051664. Epub 2014 Aug 29.

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Clinical Trial

Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans

Ylva Bonde et al. J Lipid Res. 2014 Nov.

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.

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.

Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

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Figures

Fig. 1.

Fig. 1.

Hyperthyroidism reduces lipoprotein cholesterol, apoB, and PCSK9 levels. Serum levels of fT3 and fT4 (A) in 20 patients before start of treatment in the HY and after clinical normalization in the EU. Serum levels of SHBG reflecting the impact of hyperthyroidism on the liver and correlation between SHBG and fT3 levels in the HY (B). Cholesterol content of specific lipoprotein fractions in the HY (red line) and EU (black line); dotted lines represent SD. Serum levels of apoB and apoAI (C). Correlations between plasma total cholesterol, VLDL-cholesterol, and LDL-cholesterol and fT3 levels in the HY (D). Serum levels of circulating PCSK9 (E). Horizontal bars represent mean values.

Fig. 2.

Fig. 2.

Hyperthyroidism stimulates bile acid synthesis and reduces FGF19 and intestinal absorption of dietary cholesterol. Serum levels of C4 (A), FGF19 (B), lathosterol (C), and plant sterols sitosterol and campesterol (D, E) in 20 hyperthyroid patients before start of treatment in HY and after clinical normalization in EU. Horizontal bars represent mean values.

Fig. 3.

Fig. 3.

Stimulation of hepatic TH receptors by eprotirome treatment lowers lipoprotein cholesterol, apoB, and PCSK9 levels. Serum levels of SHBG (A) in 14 healthy subjects off (−E) and on (**+**E) treatment with the liver-selective thyromimetic eprotirome. Cholesterol content of specific lipoprotein fractions off treatment (black line) and on treatment (red line); dotted lines represent SD (B). Serum levels of apoB (C), apoAI (D), and circulating PCSK9 (E). Horizontal bars represent mean values.

Fig. 4.

Fig. 4.

Bile acid synthesis, FGF19, cholesterol synthesis, and intestinal absorption are unaltered by stimulation of hepatic TH receptors by eprotirome treatment. Serum levels of 7α-hydroxycholesterol (A), FGF19 (B), lathosterol (C), and plant sterols sitosterol and campesterol (D, E) in 14 healthy subjects off (−E) and on (+E) treatment with the liver-selective thyromimetic eprotirome. Horizontal bars represent mean values.

Fig. 5.

Fig. 5.

Summary of the effects of hyperthyroidism and eprotirome on serum markers and metabolites in lipid metabolism. 7α-OH-cholesterol, 7α-hydroxycholesterol; BAs, bile acids; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; CM, chylomicron; CMR, chylomicron remnant; HMG-CoAR, HMG-CoA reductase; HSL, hormone sensitive lipase; SRBI, scavenger receptor class B type I.

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