Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans

Abstract

Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.

PCSK9 inhibitors and foamy monocytes in familial hypercholesterolaemia

“…Importantly, foamy monocytes infiltrate into arterial walls and contribute to the development of atherosclerosis in mice with hypercholesterolaemia 6 . The observations made by Bernelot Moens et al of circulating monocytes with intracellular lipid accumulation (‘foamy monocytes’), increased monocyte expression of chemokine receptors and adhesion molecules, and enhanced monocyte migration in patients with FH 2 or FD 5 also support an important role of these foamy monocytes in the development of ASCVD in humans with hyperlipidaemia — severe hyperlipidaemia in particular. Furthermore, the findings of this study suggest that monocyte lipid accumulation in patients with FH did not rely on the LDL receptor and could be reversed by PCSK9-inhibitor treatment 2 .…”

“…Most previous studies indicated that levels of intermediate and/or nonclassical monocytes were increased in hyperlipidaemia and associated with ASCVD. Bernelot Moens et al reported that the above phenotypic changes occurred mainly in classical monocytes, and that the ratios of each monocyte subset did not change in patients with FH or FD compared with healthy controls 2,5 . By contrast, Christensen et al showed that, compared with healthy controls, children with FH, particularly those with low HDL-cholesterol levels, had higher circulating intermediate and nonclassical monocytes and lower levels of classical monocytes 10 .…”

“…In another publication, the same research group reported that monocytes from patients with familial dysbetalipoproteinaemia (FD) also had increased intracellular lipid accumulation and higher expression of surface β 2 -integrins, including integrin-α M (CD11b), integrin-α X (CD11c), and integrin-β 2 (CD18) 5 . These observations support an important role of intracellular lipid accumulation in monocyte phenotypic changes in patients with FH or FD, and are consistent with previous reports from our laboratory and others showing emergence of monocytes with intracellular lipid droplets, which we termed ‘foamy monocytes’, and monocyte phenotypic changes including increased levels of integrin-α X in the circulation of humans and animals with hyperlipidaemia 6–9 .…”

“…By contrast, Christensen et al showed that, compared with healthy controls, children with FH, particularly those with low HDL-cholesterol levels, had higher circulating intermediate and nonclassical monocytes and lower levels of classical monocytes 10 . From the articles by Bernelot Moens et al , we note that the researchers followed the common gating strategy for flow cytometric analyses of monocytes (with low side scatter pattern) in patients with FH or FD 2,5 . However, from our previous studies, mainly in mouse models of hypercholesterolaemia, we realized that the flow cytometry gating strategy had to be revised in order to examine foamy monocytes, particularly monocytes with abundant lipid droplets, which displayed dramatic elevations in granularity with high side scatter pattern and, therefore, appeared in granulocyte regions 6,7 .…”

Nile Red quantifier: A novel and quantitative tool to study lipid accumulation in patient-derived circulating monocytes using confocal microscopy

“…Previous studies reported the presence of lipid-laden monocytes in a setting of postprandial hyperlipidemia (6), genetically elevated levels of remnant cholesterol (28), and familial hypercholesterolemia (FH) (29). To assess the applicability of the NRQ in disease settings, we included pilot analyses of: a) three heterozygous FH patients (30) currently not receiving therapy due to statin-associated muscle symptoms (31) and compared them to age and gender matched healthy controls and b) three obese subjects who underwent an oral fat load.…”