Influence of age on the metabolism of plasma low density lipoproteins in healthy males.

Ericsson, S.; Eriksson, Mats; Vitols, Sigurd; Einarsson, Kurt; Berglund, Lars; Angelin, Bo

doi:10.1172/jci115034

Cited by 151 publications

(114 citation statements)

References 41 publications

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“…Based on their reported menses, these subjects were further divided into three groups ( 23 ): follicular phase (days 1-11), ovulation phase (days [12][13][14][15][16][17][18], and luteal phase (days [19][20][21][22][23][24][25][26][27][28][29][30][31][32]. As expected, the E2 level was highest at ovulation ( Fig.…”

Section: Serum Lipoproteins and Pcsk9 Levels Change During The Menstrmentioning

confidence: 99%

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

Ghosh

Gälman

Rudling

et al. 2015

Journal of Lipid Research

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Section: Serum Lipoproteins and Pcsk9 Levels Change During The Menstrmentioning

confidence: 99%

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

Ghosh

Gälman

Rudling

et al. 2015

Journal of Lipid Research

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“…A progressive relative lack of GH may also underlie the known reduction in LDL clearance that occurs with ageing. 38 The present studies provide novel information on the regulation of circulating PCSK9 during basal physiological conditions. From our data, the hypothesis emerges that during the diurnal phases and after fasting, dynamic changes of the level of hepatic cholesterol regulate the expression of HMGCoA reductase, PCSK9, and LDLRs.…”

Section: Discussionmentioning

confidence: 79%

Circulating Proprotein Convertase Subtilisin Kexin Type 9 Has a Diurnal Rhythm Synchronous With Cholesterol Synthesis and Is Reduced by Fasting in Humans

Persson

Cao

Ståhle

et al. 2010

ATVB

154

119

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Objective-To gain insight into the function of proprotein convertase subtilisin kexin type 9 (PCSK9) in humans by establishing whether circulating levels are influenced by diurnal, dietary, and hormonal changes. Methods and Results-We monitored circulating PCSK9 in a set of dynamic human experiments and could show that serum PCSK9 levels display a diurnal rhythm that closely parallels that of cholesterol synthesis, measured as serum lathosterol. In contrast to these marked diurnal changes in cholesterol metabolism, serum low-density lipoprotein (LDL) cholesterol levels remained stable during the diurnal cycle. Depletion of liver cholesterol by treatment with the bile acid-binding resin, cholestyramine, abolished the diurnal rhythms of both PCSK9 and lathosterol. Fasting (Ͼ18 hours) strongly reduced circulating PCSK9 and lathosterol levels, whereas serum LDL levels remained unchanged. Growth hormone, known to be increased during fasting in humans, reduced circulating PCSK9 in parallel to LDL cholesterol levels. Conclusion-Throughout the day, and in response to fasting and cholesterol depletion, circulating PCSK9 displays marked variation, presumably related to oscillations in hepatic cholesterol that modify its activity in parallel with cholesterol synthesis. In addition to this sterol-mediated regulation, additional effects on LDL receptors may be mediated by hormones directly influencing PCSK9. Key Words: circulating PCSK9 Ⅲ cholesterol synthesis Ⅲ LDL cholesterol Ⅲ diurnal rhythm Ⅲ growth hormone Ⅲ cholesterol-lowering drugs Ⅲ lipoproteins G enetic variants of proprotein convertase subtilisin kexin type 9 (PCSK9) influence plasma low-density lipoprotein (LDL) cholesterol in humans, accounting for both hypercholesterolemia and hypocholesterolemia and altered coronary risk. 1,2 PCSK9 modulates the number of LDL receptors (LDLRs) by triggering the degradation of LDLRs. 3 Gain-offunction mutations in the PCSK9 gene produce a phenotype of familial hypercholesterolemia, 1 whereas loss-of-function mutations reduce plasma LDL cholesterol levels. 2 Circulating PCSK9 is largely derived from the liver, 4,5 and plasma levels relate to the hepatic expression of PCSK9. 6 -9 It is still unclear to what extent PCSK9 is physiologically regulated and if such regulation may influence plasma LDL cholesterol levels in humans. Novel therapies aiming at lowering serum LDL cholesterol by interfering with PCSK9 activity are under development. 10 Fasting plasma levels of PCSK9 correlate positively with LDL cholesterol levels in healthy and diabetic patients 7,[11][12][13][14] ; however, in the most extensive study, 7 with Ͼ3000 subjects, PCSK9 levels only predicted 7% of the variation in LDL cholesterol. In animals, the hepatic gene expression of PCSK9 is partly under hormonal control: treatment with glucagon or high-dose estrogen reduces PCSK9 mRNA and increases the number of LDLRs, 15 whereas insulin 15,16 and growth hormone (GH) 17 both increase PCSK9 mRNA levels in rat liver.The gene expressions of PCSK9, the LDLR and 3-hydroxy-3-...

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“…Furthermore, LDL-cholesterol increased with age, from 3·37 in the young, to 3·76 in the middle aged and to 4·05 mM/l in the old aged. Additionally, VLDLcholesterol has been observed to either remain steady or increase with age, while HDL-cholesterol appears to be unaffected by the ageing process (58,59) . Abbott et al also found sex influences the lipoprotein profile.…”

Section: Intrinsic Ageingmentioning

confidence: 99%

Investigating cholesterol metabolism and ageing using a systems biology approach

et al. 2016

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CVD accounted for 27 % of all deaths in the UK in 2014, and was responsible for 1·7 million hospital admissions in 2013/2014. This condition becomes increasingly prevalent with age, affecting 34·1 and 29·8 % of males and females over 75 years of age respectively in 2011. The dysregulation of cholesterol metabolism with age, often observed as a rise in LDL-cholesterol, has been associated with the pathogenesis of CVD. To compound this problem, it is estimated by 2050, 22 % of the world's population will be over 60 years of age, in culmination with a growing resistance and intolerance to pre-existing cholesterol regulating drugs such as statins. Therefore, it is apparent research into additional therapies for hypercholesterolaemia and CVD prevention is a growing necessity. However, it is also imperative to recognise this complex biological system cannot be studied using a reductionist approach; rather its biological uniqueness necessitates a more integrated methodology, such as that offered by systems biology. In this review, we firstly discuss cholesterol metabolism and how it is affected by diet and the ageing process. Next, we describe therapeutic strategies for hypercholesterolaemia, and finally how the systems biology paradigm can be utilised to investigate how ageing interacts with complex systems such as cholesterol metabolism. We conclude by emphasising the need for nutritionists to work in parallel with the systems biology community, to develop novel approaches to studying cholesterol metabolism and its interaction with ageing.

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Influence of age on the metabolism of plasma low density lipoproteins in healthy males.

Cited by 151 publications

References 41 publications

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

Circulating Proprotein Convertase Subtilisin Kexin Type 9 Has a Diurnal Rhythm Synchronous With Cholesterol Synthesis and Is Reduced by Fasting in Humans

Investigating cholesterol metabolism and ageing using a systems biology approach

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