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Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective, well-tolerated, and safe glucose-lowering compounds for patients with type 2 diabetes mellitus (T2DM). SGLT2i benefit encompasses protection from heart and kidney failure, independently of the presence of diabetes. In addition, SGLT2i consistently reduce the risk of hospitalization for heart failure and, although with some heterogeneity between specific members of the class, favourably affect the risk of cardiovascular outcomes. The molecular mechanisms underlying the cardiovascular favourable effect are not fully clarified. Studies testing the efficacy of SGLT2i in human cohorts and experimental models of atherosclerotic cardiovascular disease (ASCVD) have reported significant differences in circulating levels and composition of lipoprotein classes. In randomized clinical trials, small but significant increases in low-density lipoprotein cholesterol (LDL-C) levels have been observed, with a still undefined clinical significance; on the other hand, favourable (although modest) effects on high-density lipoprotein cholesterol (HDL-C) and triglycerides have been reported. At the molecular level, glycosuria may promote a starving-like state that ultimately leads to a metabolic improvement through the mobilization of fatty acids from the adipose tissue and their oxidation for the production of ketone bodies. This, however, may also fuel hepatic cholesterol synthesis, thus inhibiting atherogenic lipoprotein uptake from the liver. Long-term studies collecting detailed information on lipid-lowering therapies at baseline and during the trials with SGLT2i, as well as regularly monitoring lipid profiles are warranted to disentangle the potential implications of SGLT2i in modulating lipoprotein-mediated atherosclerotic cardiovascular risk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

High density lipoproteins (HDL) are heterogeneous particles composed by a vast array of proteins and lipids, mostly recognized for their cardiovascular (CV) protective effects. However, evidences from basic to clinical research have contributed to depict a role of HDL in the modulation of immune-inflammatory response thus paving the road to investigate their involvement in other diseases beyond those related to the CV system. HDL-C levels and HDL composition are indeed altered in patients with autoimmune diseases and usually associated to disease severity. At molecular levels, HDL have been shown to modulate the anti-inflammatory potential of endothelial cells and, by controlling the amount of cellular cholesterol, to interfere with the signaling through plasma membrane lipid rafts in immune cells. These findings, coupled to observations acquired from subjects carrying mutations in genes related to HDL system, have helped to elucidate the contribution of HDL beyond cholesterol efflux thus posing HDL-based therapies as a compelling interventional approach to limit the inflammatory burden of immune-inflammatory diseases.

Purpose of Review: Cellular cholesterol content influences the structure and function of lipid rafts, plasma membrane microdomains essential for cell signaling and activation. HDL modulate cellular cholesterol efflux, thus limiting cholesterol accumulation and controlling immune cell activation. Aim of this review is to discuss the link between HDL and cellular cholesterol metabolism in immune cells and the therapeutic potential of targeting cholesterol removal from cell membranes., Recent Findings: The inverse relationship between HDL-cholesterol (HDL-C) levels and the risk of cardiovascular disease has been recently challenged by observations linking elevated levels of HDL-C with increased risk of all-cause mortality, infections and autoimmune diseases, paralleled by the failure of clinical trials with HDL-C-raising therapies. These findings suggest that improving HDL function might be more important than merely raising HDL-C levels. New approaches aimed at increasing the ability of HDL to remove cellular cholesterol have been assessed for their effect on immune cells, and the results have suggested that this could be a new effective approach., Summary: Cholesterol removal from plasma membrane by different means affects the activity of immune cells, suggesting that approaches aimed at increasing the ability of HDL to mobilize cholesterol from cells would represent the next step in HDL biology.

Inflammation represents the driving feature of many diseases, including atherosclerosis, cancer, autoimmunity and infections. It is now established that metabolic processes shape a proper immune response and within this context the alteration in cellular cholesterol homeostasis has emerged as a culprit of many metabolic abnormalities observed in chronic inflammatory diseases. Cholesterol accumulation supports the inflammatory response of myeloid cells (i.e. augmentation of toll-like receptor signalling, inflammasome activation, and production of monocytes and neutrophils) which is beneficial in the response to infections, but worsens diseases associated with chronic metabolic inflammation including atherosclerosis. In addition to the innate immune system, cells of adaptive immunity, upon activation, have also been shown to undergo a reprogramming of cellular cholesterol metabolism, which results in the amplification of inflammatory responses. Aim of this review is to discuss (i) the molecular mechanisms linking cellular cholesterol metabolism to specific immune functions; (ii) how cellular cholesterol accumulation sustains chronic inflammatory diseases such as atherosclerosis; (iii) the immunometabolic profile of patients with defects of genes affecting cholesterol metabolism including familial hypercholesterolaemia, cholesteryl ester storage disease, Niemann-Pick type C, and immunoglobulin D syndrome/mevalonate kinase deficiency. Available data indicate that cholesterol immunometabolism plays a key role in directing immune cells function and set the stage for investigating the repurposing of existing 'metabolic' drugs to modulate the immune response., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Pentraxin 3 (PTX3) is an essential component of the humoral arm of innate immunity and belongs, together with the C-reactive protein (CRP) and other acute phase proteins, to the pentraxins' superfamily: soluble, multifunctional, pattern recognition proteins. Pentraxins share a common C-terminal pentraxin domain, which in the case of PTX3 is coupled to an unrelated long N-terminal domain. PTX3 in humans, like CRP, correlates with surrogate markers of atherosclerosis and is independently associated with the risk of developing vascular events. Studies addressing the potential physiopathological role of CRP in the cardiovascular system were so far inconclusive and have been limited by the fact that the sequence and regulation have not been conserved during evolution between mouse and man. On the contrary, the conservation of sequence, gene organization, and regulation of PTX3 supports the translation of animal model findings in humans. While PTX3 deficiency is associated with increased inflammation, cardiac damage, and atherosclerosis, the overexpression limits carotid restenosis after angioplasty. These observations point to a cardiovascular protective effect of PTX3 potentially associated with the ability of tuning inflammation and favor the hypothesis that the increased levels of PTX3 in subjects with cardiovascular diseases may reflect a protective physiological mechanism, which correlates with the immunoinflammatory response observed in several cardiovascular disorders.