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

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 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 under-standing 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.

Multichannel model of cholesterol homeostasis in the hepatocyte

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.

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.

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 compartment [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).

Effects of Statin and PCSK9 inhibitor on apoB kinetics

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].

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].

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 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.

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

PlaceboStatinPCSK9Statin + PCSK9
LDL C baseline 107 111 111 106 
LDL C 8 weeks 107 72 42 15 
LDL apoB baseline 72 72 76 71 
LDL apoB 8 weeks 72 40 31 12 
LDL apoB FCR baseline 0.43 0.44 0.45 0.41 
LDL apoB FCR 8 weeks 0.39 0.74 0.79 1.48 
LDL apoB PR baseline 9.00 8.61 9.01 8.40 
LDL apoB PR 8 weeks 8.21 6.61 4.66 
LDL C/apoB baseline 1.52 1.53 1.45 1.49 
LDL C/apoB 8 weeks 1.48 1.38 1.35 1.22 
LDL C TR baseline 13.68 13.17 13.06 12.52 
LDL C TR baseline 12.2 9.66 8.90 5.69 
Change in LDL C TR (%) −11 −27 −32 −54 
PlaceboStatinPCSK9Statin + PCSK9
LDL C baseline 107 111 111 106 
LDL C 8 weeks 107 72 42 15 
LDL apoB baseline 72 72 76 71 
LDL apoB 8 weeks 72 40 31 12 
LDL apoB FCR baseline 0.43 0.44 0.45 0.41 
LDL apoB FCR 8 weeks 0.39 0.74 0.79 1.48 
LDL apoB PR baseline 9.00 8.61 9.01 8.40 
LDL apoB PR 8 weeks 8.21 6.61 4.66 
LDL C/apoB baseline 1.52 1.53 1.45 1.49 
LDL C/apoB 8 weeks 1.48 1.38 1.35 1.22 
LDL C TR baseline 13.68 13.17 13.06 12.52 
LDL C TR baseline 12.2 9.66 8.90 5.69 
Change in LDL C TR (%) −11 −27 −32 −54 

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 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 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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