Strong relationship between cholesterol, low-density lipoprotein receptor, Na+/H+ exchanger, and SARS-COV-2: this association may be the cause of death in the patient with COVID-19

Abstract

Lipids have a wide variety and vital functions. Lipids play roles in energy metabolism, intracellular and extracellular signal traffic, and transport of fat-soluble vitamins. Also, they form the structure of the cell membrane. SARS-CoV-2 interacts with lipids since its genetic material contains lipid-enveloped ribonucleic acid (RNA). Previous studies have shown that total cholesterol, high-density lipoprotein, and low-density lipoprotein (LDL) levels are lower in patients with severe novel coronavirus disease 2019 (COVID-19) compared to patients with non-severe COVID-19.Na+/H+ Exchanger (NHE) is an important antiport that keeps the intracellular pH value within physiological limits. When the intracellular pH falls, NHE is activated and pumps H+ ions outward. However, prolonged NHE activation causes cell damage and atherosclerosis. Prolonged NHE activation may increase susceptibility to SARS-CoV-2 infection and severity of COVID-19.In COVID-19, increased angiotensin II (Ang II) due to angiotensin-converting enzyme-2 (ACE2) dysfunction stimulates NHE. Lipids are in close association with the NHE pump. Prolonged NHE activity increases the influx of H+ ions and free fatty acid (FFA) inward. Ang II also causes increased low-density lipoprotein receptor (LDLR) levels by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Thus, intracellular atheroma plaque formation is accelerated.Besides, SARS-CoV-2 may replicate more rapidly as intracellular cholesterol increases. SARS-CoV-2 swiftly infects the cell whose intracellular pH decreases with NHE activation and FFA movement. Novel treatment regimens based on NHE and lipids should be explored for the treatment of COVID-19.

COVID-19 and Lipid Disorders

“…Since a local increase in Ang II also increases the tendency to thrombosis, patients with COVID-19 may die suddenly from a heart attack even though their blood cholesterol is low [3]. Moreover, an intracellular influx of free fatty acids and prolonged Na + /H + exchanger (NHE) activation may accelerate the atherosclerotic process in patients with COVID-19 [3].…”

“…In this context, Cure et al [3] raised the following question: If low cholesterol levels are associated with increased COVID-19 mortality, should lowering cholesterol levels be an eligible treatment? A recently published review aimed to investigate the association between statin use and outcomes in COVID-19 patients with diabetes [42].…”

“…1 ) 6 7 8 . These patients are already predisposed to atherosclerosis, and excessive Ang II and cytokine levels during COVID-19 may upregulate LDLR and LOX-1, accelerating intimal plaque formation 3 7 .…”

“…2 ). As a consequence, Ang II- and LDLR-related endothelial dysfunction and arterial plaque formation may be excessively accelerated 3 7 .…”

“…Recently, it has been discussed that high cholesterol levels may increase susceptibility to SARS-CoV-2 infection [3]. Countries with higher BMI or cholesterol at aggregate levels had higher ratios of COVID-19 incidence and mortality [11].…”