Physicians' Academy for Cardiovascular Education

Reciprocal regulation PCSK9 and LDL-receptor may explain efficacy of PCSK9-inhibition

Literature - Tavori H et al., Atherosclerosis 2015

On the function and homeostasis of PCSK9: Reciprocal interaction with LDLR and additional lipid effects

Tavori H, Rashid S, Fazio S.
Atherosclerosis 2015 Feb;238(2):264-270. doi: 10.1016/j.atherosclerosis.2014.12.017
Proprotein convertase subtilisin kexin type 9 (PCSK9) binds the LDL-receptor (LDLR) and targets the receptor for intracellular degradation, thereby increasing plasma LDL-c levels. Gain-of-function mutations in PCSK9 cause autosomal dominant hypercholesterolaemia, while people with loss-of-function mutations have low LDL-c levels and low cardiovascular (CV) risk. Efforts are directed at inhibiting PCSK9 as a means to lower LDL-c. This paper summarises recent insights into PCSK9 regulation and function, and its reciprocal interaction with LDLR, and LDLR-independent effects on plasma lipid metabolism.

The unexpected complexity of the PCSK9-LDLR axis

PCSK9 and LDLR are both regulated by sterol regulatory element binding protein (SREBPs). SREBPs are overexpressed in case of cellular cholesterol deficiency, which may be caused by statin treatment. Thus, the statin-induced LDL-c lowering via increased LDLR expression may be partly counteracted by the concomitant increase in PCSK9. In parallel, PCSK9 and LDLR share a clearance pathway; binding of the ligand PCSK9 to LDLR terminates the lifecycle of both proteins.

Several mouse models have been developed to study the physiology of PCSK9. Although the overall impact of PCSK9 on LDLR and cholesterol metabolism is similar in mice and humans, the extreme conditions in many mouse models, such as total absence or overexpression of PCSK9 limits their application. A transgenic model has now been developed in which mice express human PCSK9, at physiological plasma levels. This model allows study of murine and human PCSK9 plasma levels and the interaction with LDLR. These studies suggest a homeostatic pathway, in which primary absence of LDLR leads to accumulation of PCSK9 in plasma. If LDLR is depleted by expression of PCSK9, murine PCSK9 accumulates.
Overexpression of the inducible degrader of LDLR (IDOL) in normal mice reduced the levels of surface LDLR, both via a direct degrading effect and through increased PCSK9 accumulation in plasma as a consequence of the primary loss of LDLR. The opposite scenario is also true; low levels of functional PCSK9 lead to increased surface LDLR, which further removes plasma PCSK9, thereby creating conditions for chronic low cholesterol levels.

Human data also provide support for reciprocal regulation, where PCSK9 induces LDLR degradation and LDLR is the receptor through which ligand PCSK9 leaves the circulation.
Subjects with familial hypercholesterolaemia (FH) have elevated PCSK9 levels, when compared with normocholesterolaemic controls. Loss of the receptor-LDL binding function may impair clearance of PCSK9 from the circulation. Indeed, a common polymorphism in LDLR is known to cause low LDLR and impaired response to PCSK9-antibody therapy.
Differences between species appear to exist in the extent to which LDLR simultaneously regulates plasma levels of PCSK9 and LDL. In mice, the effect of LDLR is stronger on PCSK9 than on LDL, while humans show the opposite, possibly because most FH patients have some residual LDLR function, and PCSK9-binding may not be impaired.
Considering the reciprocal regulation between PCSK9 and LDLR, it can be assumed that PCSK9-inhibition not only prevents degradation of LDLR by PCSK9, but also favourably affects the homeostatic balance towards a new situation with high LDLR and low PCSK9 levels.


PCSK9 and friends

PCKS9 interacts with several protein partners, such as Annexin A2, amyloid precursor like protein 2 and intracellular apoB. These interacting partners can modulate PCSK9 function in a variety of ways. Plasma lipoproteins are important extracellular partners of PCSK9. In plasma, PCSK9 associates with LDL into a complex, and 20-40% of PCSK9 appears LDL-bound. On the other hand, stoichiometry analyses suggest that only 1 in 500-1000 LDL particles carries a PCSK9-molecule. These observations suggest that primary, non LDLR-dependent LDL-c changes modulate plasma PCSK9 levels and, in addition to the interaction between PCSK9 and LDLR to modulate LDL-c levels, maintain a low cholesterol state.

The clinical implication of the binding of PCSK9 to LDL became clear in FH patients undergoing lipoprotein apheresis (LA) with a dextran-sulphate cellulose beads column, which removes apoB containing lipoproteins from plasma. In one LA session, over 50% of plasma PCSK9 is removed, mostly LDL-bound PCSK9. This PCSK9 removal by LA may act synergistically with LDL-c removal to keep LDL-c levels low. Moreover, the PCSK9 bound to LDL is particularly the more active , full length 62 kDa protein. Another common molecular form in plasma is the Furin-cleavage 55 kDa product, considered to be less active than intact PCSK9, and mostly found in the apoB-free fraction. The clinical significance of PCSK9-association to LDL needs further elucidation.

PCSK9 does not associate with other apoB-containing lipoproteins, like VLDL and chylomicrons. The nature of the association with LDL remains unknown. PCSK9 may have other interacting partners, which may also modulate its activity. Resistin is a protein that attracts attention in this regard. Resistin levels are high in obesity and are associated with atherosclerotic CV disease. Plasma of obese individuals was shown to induce LDLR degradation in hepatic cell lines via PCSK9 upregulation. An interaction between PCSK9 and resistin remains, however, to be demonstrated.

PCSK9 effects on triglyceride metabolism

PCKS9 may also affect triglyceride-rich lipoproteins (TRL), which are highly involved in the pathogenesis of atherosclerosis. Clinical and mouse studies suggest links between PCSK9 and TRL metabolism and their levels seem correlated. TRL are to a large extent produced in the intestine, in the form of postprandial chylomicrons with apoB48. Knockdown of PCSK9 lowered apoB48 secretion and prevented postprandial hypertriglyceridaemia in mice. Thus, PCSK9 inhibition may also reduce intestinal TRL production, postprandial hypertriglyceridaemia and plasma triglyceride levels.
Many mechanisms via which PCSK9 influences apoB-TRL metabolism remain to be elucidated, but may include posttranscriptional effects and modulation of de novo triglyceride biosynthesis.


The discovery of PCSK9 has greatly advanced our understanding of body cholesterol metabolism and the development of therapies to modulate cholesterol levels. Anti-PCSK9 therapies are remarkably effective at lowering LDL-c. New insights on the reciprocal regulation that leads to a large increase of LDLR upon lowering of PCSK9, and vice versa, may explain the efficacy of this therapeutic strategy. In addition, LDL particles contribute by carrying an active form of PCSK9, and also additional metabolic effects like the impact of PCSK9 on TRL production rate may play a role.
The full physiological role of PCSK9, including possible additional targets, will require further study.
Find this article online at Atherosclerosis

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