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Editorial
Statins, PCSK9 inhibitors and cholesterol
homeostasis: a view from within the hepatocyte
Allan D. Sniderman1 , Robert Scott Kiss1 , Thomas Reid1 , George Thanassoulis1 and Gerald F. Watts2
1 Royal
Victoria Hospital – McGill University Health Centre 1001, Decarie Boul., Montreal, Quebec, Canada H4A 3J1; 2 Lipid Disorders Clinic, Department of Cardiology, Royal Perth
Hospital, School of Medicine, University of Western Australia, Perth, Australia
Correspondence: Allan D. Sniderman ([email protected])
Statins and PCSK9 inhibitors dramatically lower plasma LDL levels and dramatically increase LDL receptor number within hepatocyte cell membranes. It seems self-evident that
total clearance of LDL particles from plasma and total delivery of cholesterol to the liver must
increase in consequence. However, based on the results of stable isotope tracer studies,
this analysis demonstrates the contrary to be the case. Statins do not change the production rate of LDL particles. Accordingly, at steady state, the clearance rate cannot change.
Because LDL particles contain less cholesterol on statin therapy, the delivery of cholesterol
to the liver must, therefore, be reduced. PCSK9 inhibitors reduce the production of LDL
particles and this further reduces cholesterol delivery to the liver. With both agents, a larger fraction of a smaller pool is removed per unit time. These findings are inconsistent with
the conventional model of cholesterol homeostasis within the liver, but are consistent with a
new model of regulation, the multi-channel model, which postulates that different lipoprotein
particles enter the hepatocyte by different routes and have different metabolic fates within
the hepatocyte. The multi-channel model, but not the conventional model, may explain how
statins and PCSK9 inhibitors can produce sustained increases in LDL receptor number.
Introduction
Received: 13 January 2017
Revised: 21 February 2017
Accepted: 6 March 2017
Version of Record published:
19 April 2017
The metabolic consequences of therapies provide a unique opportunity to understand how critical biological processes are regulated. That statins and proprotein convertase subtilisin/kexin type 9 (PCSK9)
inhibitors markedly reduce the plasma concentration of low-density lipoprotein (LDL) particles because
they substantially increase the number of LDL receptors (LDLR) at the hepatocyte cell surface is undeniable [1,2]. That these effects are associated with substantial increases in the fractional rate – or efficiency – of clearance (FCR) of LDL particles from plasma is also undeniable [1,2]. However, the conclusion
that statins and PCSK9 inhibitors increase the total clearance of LDL particles from plasma and increase
the total delivery of cholesterol to the liver, a belief that is widely held because it seems so self-evident,
may not be correct. Rather, based on the results of stable isotope tracer studies, once the new equilibrium
is reached, statins and PCSK9 inhibitor treatments reduce the total mass of cholesterol delivered to the
liver via the uptake of LDL apolipoprotein B-100 (apoB) particles from plasma [3,4].
This insight is inconsistent with the conventional model, which posits that cholesterol homeostasis in
the liver is self-regulating: reduced uptake of cholesterol leads to increased synthesis of cholesterol and
the receptors for LDL particles (LDLR); increased uptake leads to decreased synthesis of cholesterol and
LDLR. If this is the case, it is not obvious how pharmacological agents that increase LDLR could have the
persistent potent effects they do. This discordance between theory and reality suggests the conventional
model may need to be reconsidered.
So far as our arteries are concerned, all that matters is the striking reduction in the concentration of LDL
particles in their lumens and therefore the striking reduction in the number of LDL particles, which enter
from the lumen and lodge within the subendothelial space. The mechanism by which this decrease occurs
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is not relevant. However, realizing the distinction between the mass of cholesterol transported to the liver within
LDL particles and the fractional rate at which the plasma pool of LDL particles turns over leads to a different understanding of how statins and PCSK9 inhibitors affect hepatic and total body cholesterol homeostasis and illustrates
how much there is yet to learn about how cholesterol traffic within the hepatocyte is regulated and how cholesterol
homeostasis within the body is achieved in both the shorter and longer term.
The liver and cholesterol homeostasis
As illustrated in Figure 1, the liver is the central hub of all the major cholesterol fluxes in the organism. Chylomicron
remnants (CR) deliver the dietary cholesterol, the cholesterol synthesized within the enterocytes, as well as the cholesterol reabsorbed from the bile to the liver. Very low-density lipoprotein (VLDL) particles remove excess triglycerides
and cholesterol from the liver. Whereas most of the triglyceride within the VLDL particles is delivered to adipose
tissue and skeletal muscle, most of the cholesterol is returned to the liver. This occurs because a substantial portion
of VLDL particles are directly taken up by the liver while the rest are converted into LDL particles, the great majority
of which are also subsequently taken up by the liver. The cholesterol within the LDL particles that are cleared by the
liver originated in part from the cholesterol within the VLDL particles that were secreted by the liver as well as the
cholesterol ester transferred from HDL particles to VLDL particles. Thus, while HDL particles deliver cholesterol to
the liver from the periphery, so also do VLDL and LDL particles.
The sterol regulatory element-binding protein (SREBP) pathway is the major determinant of cholesterol fluxes
across the liver [5]. Increased release of SREBP2, due to decreased concentration of cholesterol within the endoplasmic reticulum (ER), results in increased synthesis of cholesterol, the LDLR and PCSK9. SREBP1 results in increased
triglyceride synthesis and increased VLDL secretion [6]. Increased uptake up of LDL particles leads to increased secretion of apoB particles through a shunt pathway without reduction in the activity of the SREBP pathway whereas
uptake of chylomicron particles leads primarily to expansion of cholesterol within the exchangeable pool and regulatory cholesterol pools of the hepatocyte and decreased activity of the SREBP pathway [7,8]. The cholesterol delivered
from HDL particles appears primarily directed to secretion in bile and conversion to bile acids. Thus, the metabolic
consequences of cholesterol, which enters the hepatocyte, are determined in large part by the lipoprotein particle
within which it was taken up.
LDL turnover studies
The most clinically relevant metabolic effect of statins and PCSK9 inhibitors is to reduce LDL particle number in
plasma. With few exceptions, the great majority of cholesterol in plasma is present in LDL particles, which make
up the great majority – 90% of total apoB particles in the circulation. VLDL particles account for only the minority
of apoB particles in plasma. Therefore, we will not review the more complex regulation of VLDL particle number
although the same general arguments apply.
The concentration of any factor in plasma, such as LDL apoB, is a function of the rate at which it is produced and
the rate at which it is removed or cleared from the plasma compartment [5]. The pool size (PS), or the total mass of
a factor, is the concentration of the factor times the volume in which it is distributed. At steady state, the absolute
rate at which LDL particles are removed from plasma must equal the absolute at which they are being produced; this
is a fundamental requirement of the mass balance equation that underpins the mathematical models fitted to the
tracer data in lipoprotein systems [5]. The fractional clearance rate (FCR) is the fraction of the PS of the factor that is
removed per day and the absolute amount removed per day will equal the FCR × PS. For apoB, this is expressed as
mg apoB cleared per kg body weight per day.
LDL particles contain variable amounts of cholesterol and therefore the LDL cholesterol/apoB ratio (LDL C/apoB)
may vary substantially. The LDL C/apoB represents the outcome of the multiple processes that can affect the mass of
cholesterol within an LDL particle. When an LDL particle is removed from plasma by the liver, the cholesterol within
the particle enters the hepatocyte as well. Accordingly, the mass of cholesterol transported by LDL particles through
plasma can be calculated by multiplying the absolute removal rate of LDL particles by the LDL C/apoB. Since the great
majority of LDL particles are removed from plasma by the liver, this will represent the transport rate of cholesterol to
the liver via LDL particles.
The clearance of LDL particles from plasma
Hepatocytes are separated from the plasma compartment by the space of Disse, the major site of the extravascular
pool of LDL particles, which are in rapid, reversible equilibrium with the LDL particles within the plasma compart-
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Figure 1. Multichannel model of cholesterol homeostasis in the hepatocyte
The fate of cholesterol derived from different lipoprotein sources is varied. The cholesterol liberated from each particle is differentially trafficked in the hepatocyte, which we term channels: (1) HDL; (2) LDL; (3) CR. HDL (1) cholesterol is taken up via scavenger receptor class
B member 1 (SR-B1), and later resecreted with bile into the intestines at the apical surface of the hepatocyte via ATP-binding cassette
transporter G5 and G8 (ABCG5/58). ABCA1/G1 are responsible for HDL formation at the basolateral surface of the hepatocyte. Cholesterol
derived from LDL (2) is endocytosed via the LDLR and delivered to the ER. It is then esterified by ACAT2, packaged into VLDL particles and
then resecreted into the circulation. CR-derived cholesterol (3) is endocytosed via apoE receptors such as LRP1 and delivered to the regulatory pool at the ER where it interacts with the sterol cleavage activating protein/sterol regulatory element-binding protein (SCAP/SREBP)
complex where intracellular regulation of cholesterol levels can occur.
ment [9,10]. LDL particles are removed from the space of Disse by a specific clearance pathway – the LDL receptor
pathway – and by multiple non-specific pathways. Both statins and PCSK9 inhibitors, albeit by different mechanisms,
lead to a substantial increase in LDLR at the cell surface and therefore to an increase in the proportion of LDL particles
removed by the specific pathway.
Binding to the LDLR is of higher affinity than to the non-specific pathways, which do not appear to have distinct receptors. However, LDLR binding is saturable whereas the non-specific binding and uptake of LDL particles
is a constant proportion of the plasma concentration. The binding of LDL particles to the LDLR is governed by
Michaelis–Menten kinetics. If the production rate of LDL particles does not change and if the number of LDLR increases, the number of LDL particles relative to the number of LDLR will decrease. This change from the baseline
conditions will lead to greater total binding of LDL particles to LDLR. The result will be more efficient clearance of
LDL particles than prior to the intervention (Figure 2).
Consequently, the plasma concentration of LDL particles will decrease. This decrease in the concentration of LDL
particles due to greater clearance will continue until a new steady state is achieved. At the new steady state, the total
number of particles that are cleared will once more equal the total number of particles that are produced. The fractional clearance will remain higher than baseline but the concentration of LDL particles will be lower. It is the higher
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Figure 2. Effects of Statin and PCSK9 inhibitor on apoB kinetics
Summary of LDL apoB kinetics in four states: (1) basal; (2) post-statin; (3) post-PCSK9 Ab; and (4) post-statin + PCSK9 mAb. The LDL apoB
production rate mg apoB/kg body weight per day is shown for each state. The LDL apoB production rates – PR1 and PR2 – were equivalent
in both the basal state and the post-statin state. These were greater than the PR rate post-PCSK9 (PR3 ), which in turn, was greater than the
LDL PR post-statin + PCSK9. The relative PSs in the different states are a function of the LDL apoB FCR at that state and the LDL apoB
production rates. For fuller details see Watts et al. [3].
fractional clearance rate along with the lower concentration that results in clearance being in balance with production. A larger fraction of a smaller pool is being cleared compared with baseline in which a smaller fraction of a larger
pool was being cleared.
Effects of statins and PCSK9 inhibitors on LDL turnover in
plasma
Using stable isotopes, these parameters of apoB metabolism have been quantitated in normals and in many patients
who have received statins [11]. Studies of the effects of PCSK9 inhibitors are more limited but fortunately a comprehensive study has been recently published that determines the effects of both agents on apoB-100 turnover in
normals [3]. The principal findings of the stable isotope study [3] were that: (1) both statins and PCSK9 inhibitors
markedly reduce the concentrations in plasma of LDL C and LDL apoB but the decrease in LDL C is approximately
25% more than the decrease in LDL apoB; (2) the PR of LDL apoB is not statistically significantly smaller with statin
therapy but is significantly lower with the PCSK9 inhibitor and even lower still with combination therapy; (3) the
FCR is markedly increased by each agent and further increased when both are given in combination. These findings
are noted in Table 1.
In this study, LDL C includes two fractions that were separated by ultracentrifugation for the apoB kinetics: IDL
apoB (d 1.006–1.109 g/ml) and LDL apoB (1.019–1.063 g/ml). Based on the PS of these two fractions, we have calculated the concentration of LDL C in the 1.019–1.063 density range since this fraction contains the bulk of the
cholesterol in LDL and the IDL apoB appears to be largely precursor particles to LDL apoB particles. As listed in
Table 1, the LDL C/LDL apoB ratio in the placebo group is almost the same at baseline and with repeat at 8 weeks.
Moreover, as expected, the LDL C/apoB is almost the same at baseline in all the groups. By contrast, in all the treatment groups, the LDL C/LDL apoB ratio is lower after treatment than before. Based on the composition of the LDL
particles and their removal rate, the LDL cholesterol transport rate (LDL C TR) – i.e. the mass of cholesterol that is
transported in LDL particles in plasma and taken up by the liver – was calculated and is listed in Table 1. The LDL
C TR is similar in all groups at baseline and is similar in placebo at baseline and at 8 weeks ( − 11%). However, the
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Table 1 Effects of Statin and PCSK9 inhibitor on LDL C and LDL apoB kinetics
Baseline value: 8-week value; LDL C: LDL cholesterol (d 1.019–1.063 g/l) in mg/dl; LDL apoB: LDL apoB (d 1.019–1.063 g/l)
in mg/dl; LDL apoB FCR: FCR of apoB – number of pools of apoB cleared per day; Pool of apoB is the concentration of apoB
× the volume of distribution of apoB; LDL apoB PR: production rate of apoB = mg apoB produced per kg body weight per
day; LDL C TR: the transport rate of cholesterol in LDL particles per kg body weight per day; LDL C/apoB of LDL cholesterol
(d 1.019 g/l) to LDL apoB (d 1.019 g/l); Change in LDL PR = per cent change in LDL cholesterol TR at 8 weeks compared
with baseline
Placebo
Statin
PCSK9
Statin + PCSK9
LDL C baseline
107
111
111
106
LDL C 8 weeks
LDL apoB baseline
LDL apoB 8 weeks
107
72
72
72
72
40
42
76
31
15
71
12
LDL apoB FCR baseline
LDL apoB FCR 8 weeks
LDL apoB PR baseline
0.43
0.39
9.00
0.44
0.74
8.61
0.45
0.79
9.01
0.41
1.48
8.40
LDL apoB PR 8 weeks
LDL C/apoB baseline
LDL C/apoB 8 weeks
8.21
1.52
1.48
7
1.53
1.38
6.61
1.45
1.35
4.66
1.49
1.22
LDL C TR baseline
LDL C TR baseline
Change in LDL C TR (%)
13.68
12.2
− 11
13.17
9.66
− 27
13.06
8.90
− 32
12.52
5.69
− 54
LDL C TR is substantially reduced relative to baseline by statin therapy ( − 27%), reduced slightly more by therapy
with the PCSK9 inhibitor ( − 32%), and reduced yet more with combination therapy of a statin and PCSK9 inhibitor
( − 54%).
That statins do not increase the total clearance of LDL particles from plasma notwithstanding that they substantially
increase the number of LDLR at the hepatocyte cell surface and the FCR for LDL particles may seem counterintuitive.
However, this must be the case if the production of LDL particles remains the same as at baseline. The increased
number of LDLR does cause clearance to increase, but only transiently, until a new steady state is reached. If the
production of LDL particles remains constant, the increase in clearance will cause the concentration of LDL particles
to decrease until a new steady state is reached at which point absolute production and removal of LDL particles
are once more in balance, as required by the mass balance equation at that steady state. If this did not occur, the
concentration of LDL particles would continue to decrease indefinitely.
The number of LDLR is greater at the new steady state but the concentration of LDL particles is lower and so is the
PS of LDL particles. Accordingly, to clear the same number of LDL particles as at baseline, the fraction of the total
pool of LDL particles that is cleared per day, the FCR, must increase. The results with PCSK9 inhibitors are different,
more complex, since, in addition to the increase in LDLR number, the production of LDL particles is reduced. Thus,
PCSK9 inhibitors lower LDL particle number in plasma by two mechanisms whereas statins achieve their effect by
one.
Both statins and PCSK9 inhibitors reduce the mass of cholesterol within LDL particles since both produce significant reductions in the LDL C/apoB [3,12]. At the new steady state, statins have not increased the absolute clearance
rate per day of LDL particles above baseline. However, since statins have reduced the mass of cholesterol within LDL
particles, the mass of cholesterol delivered to the liver per day via the uptake of LDL particles at the new steady induced
by statin therapy must be reduced. The impact of PCSK9 inhibitors on reducing cholesterol transport to the liver is
even more profound since PCSK9 inhibitors decrease the endogenous absolute production rate of LDL particles in
plasma whereas statins do not. The mechanism responsible needs to be elucidated.
Implications for cholesterol homeostasis in the liver
The conventional model of cholesterol homeostasis posits that all cholesterol taken up by the hepatocyte enters a
common exchangeable pool. The mass of cholesterol within the exchangeable pool determines the mass of cholesterol
within a regulatory pool, which determines the rate of cholesterol and LDLR synthesis. The increased LDLR number
induced by statins and PCSK9 inhibitors must transiently increase cholesterol delivery to the liver as levels of LDL
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C and LDL particle number decrease in plasma. According to the conventional model, the increased delivery of
cholesterol should result in decreased LDLR synthesis. Were this to occur, the reduction in LDL C induced by statins
and/or PCSK9 inhibitors would be transient. Similarly, at steady state, as this analysis has shown, cholesterol delivery
to the liver would be reduced and LDLR number should increase resulting in a further decrease in LDL C. However,
the sustained reduction in levels of LDL C induced by both statins and PCSK9 inhibitors argues against the validity
of the conventional model of cholesterol homeostasis in the liver. In summary, the conventional model of cholesterol
homeostasis posits that any change in cholesterol balance produces a counter series of changes designed to restore
the original equilibrium. This is not what is observed clinically: statins and PCSK9 inhibitors produce sustained
reductions in LDL C and LDL particle number due to sustained increases in LDLR number. The status quo ante is
not restored. The predictions of the conventional model are not fulfilled.
By contrast, a persistent effect of statins and PCSK9 inhibitors on LDLR number would be predicted by the multichannel model of cholesterol homeostasis outlined in Figure 1. The multichannel model posits that the metabolic
fate of cholesterol that enters the hepatocyte is a function of the route by which it entered and that more than one
site of metabolic control axis. Thus, cholesterol from CR rapidly equilibrates with the exchangeable pool, which is in
dynamic equilibrium with the regulatory pool with the consequence that cholesterol and LDLR are rapidly reduced
[8,13]. Cholesterol from HDL is channeled to bile acids and secretion from the liver within bile acids [14,15]. Most
of the cholesterol internalized within LDL particles does not enter the rapidly exchangeable pool of cholesterol but is
converted into cholesteryl ester by acyl CoA:cholesterol acyltransferase 2 (ACAT2) and then secreted from the hepatocyte within apoB lipoprotein particles [7,8]. The result is that cholesterol returned to the hepatocyte within LDL
particles does not affect the synthesis of cholesterol or the LDLR because it does not enter the exchangeable pool of
cholesterol and therefore cannot affect the mass of cholesterol in the regulatory pool. This would explain why agents
such as statins and PCSK9 inhibitors can have persistent effects on the number of LDLR at the hepatocyte surface
and therefore persistent effects on lowering levels of LDL in plasma. The multichannel of cholesterol homeostasis in
the liver is, therefore, more consistent with the experimental observations than the conventional model.
Funding
This work was funded by an unrestricted grant from the Doggone Foundation – Amgen (to G.T.); IONIS (to G.T.); Amgen (to G.F.W.);
Sanofi (to G.F.W.); Regeneron (to G.F.W.); and Kowa (to G.F.W.).
Competing interests
The authors declare that there are no competing interests associated with the manuscript.
Abbreviations
ACAT2, acyl CoA:cholesterol acyltransferase 2; apoB, apolipoprotein B-100; CR, chylomicron remnants; ER, endoplasmic reticulum; FCR, fractional clearance rate; IDL, intermediate density lipoprotein; LDL, low-density lipoprotein; LDL C/apoB, LDL cholesterol/apoB ratio; LDL C TR, LDL cholesterol transport rate; LDLR, LDL receptors; LRP1, low density lipoprotein receptor-related
protein 1; PCSK9, proprotein convertase subtilisin/kexin type 9; PR1, production rate 1; PR2, production rate 2; PS, pool size;
SREBP, sterol regulatory element-binding protein; TR, transport rate; VLDL, very low-density lipoprotein.
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