The transmissible respiratory disease COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions of people worldwide since its first reported outbreak in December of 2019 in Wuhan, China. Since then, multiple studies have shown an inverse correlation between the levels of high-density lipoprotein (HDL) particles and the severity of COVID-19, with low HDL levels being associated with an increased risk of severe outcomes. Some studies revealed that HDL binds to SARS-CoV-2 particles via the virus’s spike protein and, under certain conditions, such as low HDL particle concentrations, it facilitates SARS-CoV-2 binding to angiotensin-converting enzyme 2 (ACE2) and infection of host cells. Other studies, however, reported that HDL suppressed SARS-CoV-2 infection. In both cases, the ability of HDL to enhance or suppress virus infection appears to be dependent on the expression of the HDL receptor, namely, the Scavenger Receptor Class B type 1 (SR-B1), in the target cells. SR-B1 and HDL represent crucial mediators of cholesterol metabolism. Herein, we review the complex role of HDL and SR-B1 in SARS-CoV-2-induced disease. We also review recent advances in our understanding of HDL structure, properties, and function during SARS-CoV-2 infection and the resulting COVID-19 disease.

Background: Atherosclerosis is a chronic disease affecting artery wall and a major contributor to cardiovascular diseases. Large necrotic cores increase risk of plaque rupture leading to thrombus formation. Necrotic cores are rich in debris from dead macrophages. Programmed necrosis (necroptosis) contributes to necrotic core formation. HDL (high-density lipoprotein) exerts direct atheroprotective effects on different cells within atherosclerotic plaques. Some of these depend on the SR-B1 (scavenger receptor class B type I) and the adapter protein PDZK1 (postsynaptic density protein/Drosophila disc-large protein/Zonula occludens protein containing 1). However, a role for HDL in protecting against necroptosis and necrotic core formation in atherosclerosis is not completely understood. Methods: Low-density lipoprotein receptor–deficient mice engineered to express different amounts of ApoA1 (apolipoprotein A1), or to lack PDZK1 were fed a high fat diet for 10 weeks. Atherosclerotic plaque areas, necrotic cores, and key necroptosis mediators, RIPK3 (receptor interacting protein kinase 3), and MLKL (mixed lineage kinase domain-like protein) were characterized. Cultured macrophages were treated with HDL to determine its effects, as well as the roles of SR-B1, PDZK1, and the PI3K (phosphoinositide 3-kinase) signaling pathway on necroptotic cell death. Results: Genetic overexpression reduced, and ApoA1 knockout increased necrotic core formation and RIPK3 and MLKL within atherosclerotic plaques. Macrophages were protected against necroptosis by HDL and this protection required SR-B1, PDZK1, and PI3K/Akt pathway. PDZK1 knockout increased atherosclerosis in LDLR ^KO mice, increasing necrotic cores and phospho-MLKL; both of which were reversed by restoring PDZK1 in BM-derived cells. Conclusions: Our findings demonstrate that HDL in vitro and ApoA1, in vivo, protect against necroptosis in macrophages and necrotic core formation in atherosclerosis, suggesting a pathway that could be a target for the treatment of atherosclerosis.

Glyphosate-based herbicides (GBHs) are widely used in agriculture, raising concerns about neuroendocrine and metabolic disruption, particularly during critical developmental windows. This study evaluated the effects of pubertal GBH exposure on biometric, metabolic, hepatic, and endocrine parameters in adult female and male mice. From postnatal weeks 4 to 8, C57Bl/6 mice received daily oral gavage with distilled water [control (CTL)] or 50 mg/kg body weight (BW) of GBH. At 21 weeks, biometric, biochemical, and hormonal parameters were analyzed. BW, Lee index, and abdominal fat were not affected by GBH exposure in either sex. Similarly, glycemia, lipidemia, insulinemia, glucose tolerance, and insulin sensitivity did not differ between groups. However, GBH exposure induced sex-specific changes in hepatic cholesterol: GBH females exhibited reduced esterified cholesterol (e-CHOL), whereas males showed increased e-CHOL and free CHOL. No significant hormonal changes were observed in GBH-exposed females. In contrast, males exhibited decreased follicle-stimulating hormone levels and increased testosterone and thyroid-stimulating hormone concentrations in adulthood. These results suggest that pubertal exposure to GBH, even at a dose considered safe by regulatory agencies, can induce long-lasting, sex-specific alterations in hepatic lipid metabolism and endocrine function, reinforcing concerns about GBHs as potential endocrine and metabolic disruptors.