PCSK9 inhibition and cholesterol homeostasis in insulin producing β-cells

Abstract

Low-density lipoprotein cholesterol (LDL-C) plays a central role in the pathology of atherosclerotic cardiovascular disease. For decades, the gold standard for LDL-C lowering have been statins, although these drugs carry a moderate risk for the development of new-onset diabetes. The inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged in the last years as potential alternatives to statins due to their high efficiency and safety without indications for a diabetes risk so far. Both approaches finally eliminate LDL-C from bloodstream by upregulation of LDL receptor surface expression. Due to their low antioxidant capacity, insulin producing pancreatic β-cells are sensitive to increased lipid oxidation and related generation of reactive oxygen species. Thus, PCSK9 inhibition has been argued to promote diabetes like statins. Potentially, the remaining patients at risk will be identified in the future. Otherwise, there is increasing evidence that loss of circulating PCSK9 does not worsen glycaemia since it is compensated by local PCSK9 expression in β-cells and other islet cells. This review explores the situation in β-cells. We evaluated the relevant biology of PCSK9 and the effects of its functional loss in rodent knockout models, carriers of LDL-lowering gene variants and PCSK9 inhibitor-treated patients.

Association between serum PCSK9 and coronary heart disease in patients with type 2 diabetes mellitus

“…Soluble PCSK9 binds to the epidermal growth factor homologous domain of LDLR, which is mainly located on the surface of liver cells, thereby preventing it from adhering to LDL-C particles [ 28 ]. In addition, it promotes LDLR degradation by enhancing endocytosis and preventing recycling [ 29 ]. In addition to the classical pathway, PCSK9 regulates lipid metabolism via the intracellular endogenous PCSK9 regulation of ApoB expression and Lp(a) metabolism [ 30 ].…”

PCSK9 and the nervous system: a no-brainer?

“…These studies were however performed in young and otherwise healthy animals which do not recapitulate the pathophysiological conditions of ischemic strokes (aging population, diabetes, and hypertension). In that respect, aging PCSK9 KO mice accumulate cholesterol in pancreatic islets and display impaired glucose-stimulated insulin secretion irrespective of gender and diet as well as signs of glucose intolerance ( 78 ). Given that hyperglycemia and diabetes alone worsen ischemic strokes outcome in terms of prevalence, severity, and complications, and negatively impact on the integrity of the BBB, the initial hypothesis has been revisited: under acute hyperglycemic conditions, PCSK9 KO mice exhibit more intracerebral hemorrhages than wild-type mice following an MCAO procedure ( 79 ).…”

Proteomics and Lipidomics to unveil the contribution of PCSK9 beyond cholesterol lowering: a narrative review

“…This suggests the importance of local PCSK9 expression in pancreatic islets to maintain a β-cell function. Similarly, impairment of glucose metabolism is also variable in human subjects carrying PCSK9 LOF variants, an effect depending on the genetic background of the studied population, in which the risk to develop diabetes is also associated to the individual degree of functional loss ( 77 ).…”