{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:13:41Z","timestamp":1791915221808,"version":"4.3.4"},"reference-count":82,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hartis Pharma SA"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Membranes"],"abstract":"<jats:p>Cell membrane lipid composition, especially cholesterol, affects many functions of embedded enzymes, transporters and receptors in red blood cells (RBC). High membrane cholesterol content affects the RBCs\u2019 main vital function, O2 and CO2 transport and delivery, with consequences on peripheral tissue physiology and pathology. A high degree of deformability of RBCs is required to accommodate the size of micro-vessels with diameters significantly lower than RBCs. The potential therapeutic role of high-density lipoproteins (HDL) in the removal of cholesterol and its activity regarding maintenance of an optimal concentration of RBC membrane cholesterol have not been well investigated. On the contrary, the focus for HDL research has mainly been on the clearance of cholesterol accumulated in atherosclerotic macrophages and plaques. Since all interventions aiming at decreasing cardiovascular diseases by increasing the plasma level of HDL cholesterol have failed so far in large outcome studies, we reviewed the potential role of HDL to remove excess membrane cholesterol from RBC, especially in sickle cell disease (SCD). Indeed, abundant literature supports a consistent decrease in cholesterol transported by all plasma lipoproteins in SCD, in addition to HDL, low- (LDL) and very low-density lipoproteins (VLDL). Unexpectedly, these decreases in plasma were associated with an increase in RBC membrane cholesterol. The concentration and activity of the main enzyme involved in the removal of cholesterol and generation of large HDL particles\u2014lecithin cholesterol ester transferase (LCAT)\u2014are also significantly decreased in SCD. These observations might partially explain the decrease in RBC deformability, diminished gas exchange and tendency of RBCs to aggregate in SCD. We showed that incubation of RBC from SCD patients with human HDL or the HDL-mimetic peptide Fx5A improves the impaired RBC deformability and decreases intracellular reactive oxygen species levels. We propose that the main physiological role of HDL is to regulate the cholesterol\/phospholipid ratio (C\/PL), which is fundamental to the transport of oxygen and its delivery to peripheral tissues.<\/jats:p>","DOI":"10.3390\/membranes12111134","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T02:26:37Z","timestamp":1668392797000},"page":"1134","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Red Blood Cell Membrane Cholesterol May Be a Key Regulator of Sickle Cell Disease Microvascular Complications"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2923-2027","authenticated-orcid":false,"given":"Eric J.","family":"Niesor","sequence":"first","affiliation":[{"name":"Hartis Pharma SA Nyon, 1260 Nyon, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elie","family":"Nader","sequence":"additional","affiliation":[{"name":"Laboratory LIBM EA7424, Vascular Biology and Red Blood Cell Team, University of Lyon, 69007 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Perez","sequence":"additional","affiliation":[{"name":"Hartis Pharma SA Nyon, 1260 Nyon, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1020-5793","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Lamour","sequence":"additional","affiliation":[{"name":"Hartis Pharma SA Nyon, 1260 Nyon, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9e","family":"Benghozi","sequence":"additional","affiliation":[{"name":"Hartis Pharma SA Nyon, 1260 Nyon, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Remaley","sequence":"additional","affiliation":[{"name":"National Institutes of Health, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swee Lay","family":"Thein","sequence":"additional","affiliation":[{"name":"National Institutes of Health, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9232-0268","authenticated-orcid":false,"given":"Philippe","family":"Connes","sequence":"additional","affiliation":[{"name":"Laboratory LIBM EA7424, Vascular Biology and Red Blood Cell Team, University of Lyon, 69007 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s12013-017-0792-7","article-title":"High Cholesterol\/Low Cholesterol: Effects in Biological Membranes: A Review","volume":"75","author":"Subczynski","year":"2017","journal-title":"Cell Biochem. 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