Studies on PCSK9 in the regulation of cholesterol metabolism
Author: Persson, Lena
Date: 2011-06-17
Location: M63 Karolinska Universitetssjukhuset Huddinge
Time: 09.00
Department: Inst för medicin, Huddinge / Dept of Medicine, Huddinge
Abstract
Elevated levels of plasma cholesterol, mainly in low density lipoproteins (LDL), are a major risk factor for coronary heart disease. The level of plasma LDL cholesterol (LDL-C) is largely dependent on the number of hepatic LDL receptors (LDLRs). Increased numbers of LDLRs lead to higher uptake of LDL particles and lower concentration of plasma LDL-C. Proprotein convertase subtilisin Kexin Type 9 (PCSK9) is a novel key regulator in cholesterol metabolism. PCSK9 reduces the number of available hepatic LDLRs leading to increased plasma levels of LDL-C. Inhibition of PCSK9 has a great potential as a cholesterol-lowering agent. However, the physiological role of PCSK9 is largely unknown.
In this study we investigated the regulation of PCSK9 in rats and humans, by hormones and diets and during the diurnal phases. We can show that:
I) Reduced bile acid synthesis, but not changes in PCSK9, likely contributes to the age-dependent hypercholesterolemia in rats. Treatment with growth hormone (GH) restores bile acid synthesis to juvenile levels and upregulates the gene transcription of PCSK9.
II) Hormonal and dietary regulation of hepatic LDLRs in the rat is frequently mediated by PCSK9. Treatment with estrogen, glucagon and a cholesterol-enriched diet reduces PCSK9 expression, while it is increased by insulin. The transcription factor SREBP-2 is partly involved in the hormonal and dietary regulation of PCSK9, although our results suggest that the glucagon-mediated suppression of PCSK9 may involve other mechanisms.
III) Circulating PCSK9 has a pronounced diurnal variation and is strongly reduced during fasting in humans. These changes are presumably related to oscillations in hepatic intracellular cholesterol levels mediated by SREBP-2. GH treatment reduces circulating PCSK9 in men, whereas a ketogenic diet does not alter circulating PCSK9 levels.
IV) Endogenous estrogen exerts rapid and distinct effects on cholesterol metabolism in females, with reduced levels of circulating PCSK9, plasma total and LDL-C, whereas the levels of HDL- and LDL-triglycerides (TGs) and apoAI increase. Some of the effects of estrogen on cholesterol metabolism may be mediated by a rapid induction of GH secretion.
The hormonal regulation of PCSK9 can partly explain the cholesterol-lowering effects of GH, estrogen, glucagon and thyroid hormone. Our results further indicate that such hormonal regulation may involve SREBP-2 independent mechanisms. The regulation of PCSK9 during the diurnal phases and fasting may explain why plasma LDL-C levels remain stable during these situations. We have also shown that PCSK9 can be dietary regulated, partly explaining the pronounced resistance to development of hypercholesterolemia following a cholesterol-enriched diet in the rat. Neither a ketogenic nor a vegan diet alters circulating PCSK9 in humans. Hormonal, dietary and diurnal regulation of PCSK9 may influence serum LDL-C levels, a fact that should be considered in the use of anti-PCSK9 agents.
In this study we investigated the regulation of PCSK9 in rats and humans, by hormones and diets and during the diurnal phases. We can show that:
I) Reduced bile acid synthesis, but not changes in PCSK9, likely contributes to the age-dependent hypercholesterolemia in rats. Treatment with growth hormone (GH) restores bile acid synthesis to juvenile levels and upregulates the gene transcription of PCSK9.
II) Hormonal and dietary regulation of hepatic LDLRs in the rat is frequently mediated by PCSK9. Treatment with estrogen, glucagon and a cholesterol-enriched diet reduces PCSK9 expression, while it is increased by insulin. The transcription factor SREBP-2 is partly involved in the hormonal and dietary regulation of PCSK9, although our results suggest that the glucagon-mediated suppression of PCSK9 may involve other mechanisms.
III) Circulating PCSK9 has a pronounced diurnal variation and is strongly reduced during fasting in humans. These changes are presumably related to oscillations in hepatic intracellular cholesterol levels mediated by SREBP-2. GH treatment reduces circulating PCSK9 in men, whereas a ketogenic diet does not alter circulating PCSK9 levels.
IV) Endogenous estrogen exerts rapid and distinct effects on cholesterol metabolism in females, with reduced levels of circulating PCSK9, plasma total and LDL-C, whereas the levels of HDL- and LDL-triglycerides (TGs) and apoAI increase. Some of the effects of estrogen on cholesterol metabolism may be mediated by a rapid induction of GH secretion.
The hormonal regulation of PCSK9 can partly explain the cholesterol-lowering effects of GH, estrogen, glucagon and thyroid hormone. Our results further indicate that such hormonal regulation may involve SREBP-2 independent mechanisms. The regulation of PCSK9 during the diurnal phases and fasting may explain why plasma LDL-C levels remain stable during these situations. We have also shown that PCSK9 can be dietary regulated, partly explaining the pronounced resistance to development of hypercholesterolemia following a cholesterol-enriched diet in the rat. Neither a ketogenic nor a vegan diet alters circulating PCSK9 in humans. Hormonal, dietary and diurnal regulation of PCSK9 may influence serum LDL-C levels, a fact that should be considered in the use of anti-PCSK9 agents.
List of papers:
I. Age-induced hypercholesterolemia in the rat relates to reduced elimination but not increased intestinal absorption of cholesterol. Gälman C, Matasconi M, Persson L, Parini P, Angelin B, Rudling M. Am J Physiol Endocrinol Metab. 2007 Sep;293(3):E737-42.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Importance of Proprotein Convertase Subtilisin/Kexin Type 9 in the Hormonal and Dietary Regulation of Rat Liver Low-Density Lipoprotein Receptors. Persson L, Gälman C, Angelin B, Rudling M. Endocrinology. 2009 Mar;150(3):1140-6.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Circulating Proprotein Convertase Subtilisin Kexin Type 9 Has a Diurnal Rhythm Synchronous With Cholesterol Synthesis and Is Reduced by Fasting in Humans. Persson L, Cao G, Ståhle L, Sjöberg BG, Troutt JS, Konrad RJ, Gälman C, Wallén H, Eriksson M, Hafström I, Lind S, Dahlin M, Amark P, Angelin B, Rudling M. Arterioscler Thromb Vasc Biol. 2010 Dec;30(12):2666-72.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Stimulation of endogenous estrogen production in females reduces circulating PCSK9 and LDL cholesterol. Persson L, Henriksson P, Westerlund E, Hovatta O, Angelin B, Rudling M. [Manuscript]
I. Age-induced hypercholesterolemia in the rat relates to reduced elimination but not increased intestinal absorption of cholesterol. Gälman C, Matasconi M, Persson L, Parini P, Angelin B, Rudling M. Am J Physiol Endocrinol Metab. 2007 Sep;293(3):E737-42.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Importance of Proprotein Convertase Subtilisin/Kexin Type 9 in the Hormonal and Dietary Regulation of Rat Liver Low-Density Lipoprotein Receptors. Persson L, Gälman C, Angelin B, Rudling M. Endocrinology. 2009 Mar;150(3):1140-6.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Circulating Proprotein Convertase Subtilisin Kexin Type 9 Has a Diurnal Rhythm Synchronous With Cholesterol Synthesis and Is Reduced by Fasting in Humans. Persson L, Cao G, Ståhle L, Sjöberg BG, Troutt JS, Konrad RJ, Gälman C, Wallén H, Eriksson M, Hafström I, Lind S, Dahlin M, Amark P, Angelin B, Rudling M. Arterioscler Thromb Vasc Biol. 2010 Dec;30(12):2666-72.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Stimulation of endogenous estrogen production in females reduces circulating PCSK9 and LDL cholesterol. Persson L, Henriksson P, Westerlund E, Hovatta O, Angelin B, Rudling M. [Manuscript]
Institution: Karolinska Institutet
Issue date: 2011-05-26
Rights:
Publication year: 2011
ISBN: 978-91-7457-348-0
Statistics
Total Visits
Views | |
---|---|
Studies ...(legacy) | 1230 |
Studies ... | 343 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Studies ... | 0 | 3 | 1 | 2 | 3 | 0 | 0 |
File Visits
Views | |
---|---|
Thesis_Persson.pdf(legacy) | 2676 |
Spikblad_Persson.pdf(legacy) | 478 |
Thesis_Persson.pdf | 246 |
Spikblad_Persson.pdf | 51 |
Thesis_Persson.pdf.txt(legacy) | 2 |
Spikblad_Persson.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 531 |
Sweden | 150 |
China | 123 |
Germany | 75 |
South Korea | 71 |
Russia | 45 |
Denmark | 39 |
France | 24 |
Japan | 18 |
United Kingdom | 17 |
Top cities views
Views | |
---|---|
Sunnyvale | 68 |
Seoul | 61 |
Ashburn | 54 |
Romeo | 41 |
Ballerup | 35 |
Beijing | 27 |
Kiez | 25 |
Stockholm | 25 |
Moscow | 16 |
Berlin | 14 |