Multifaced Roles of HDL in Sepsis and SARS-CoV-2 Infection: Renal Implications

Abstract

High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies.

Keywords: SARS-CoV-2 infection; acute kidney injury (AKI); dysfunctional HDL; lipid profile changes; sepsis.

Figure 1

Schematic representation of HDL multi-protective mechanisms. The principal function of HDL is the reverse cholesterol transport (RCT). In atherosclerotic lesions, HDL induces cholesterol efflux from macrophages, avoiding foam cells formation. The process starts with premature HDL (Nascent HDL) that interacts with ATP-binding cassette transporter A1 (ABCA1), expressed on macrophages, and acquires phospholipids and free cholesterol. This nascent HDL evolves in mature HDL (HDL3) that further acquires cholesterol, cholesterol ester, and triglycerides via specific enzymes and interacting with other lipid transporters such as scavenger receptor class B type I (SR-BI) and ATP Binding Cassette Subfamily G Member 1 (ABCG1). This large HDL (HDL2) turns to the liver and after binding SR-BI, cholesterol esters are internalized and degraded and excreted into the bile. The second mechanism for cholesterol degradation is mediated by mature low-density lipoproteins (LDLs) that uptake cholesterol from HDL2 mediating cholesterol internalization by hepatocytes via the LDL receptor (LDL-R). Other important functions of HDL include anti-thrombotic activities (increased expression of nitric oxide [NO] and prostacyclin [PG12] in endothelial cells with reduced platelet activation and augmented fibrinolysis), anti-inflammatory effects (reduced monocytes activation), immunomodulatory properties (lymphocytes anergy), and anti-oxidant effects (prevention of LDL oxidation).

Figure 2

Renal HDL catabolism and transport. Senescent circulating HDLs are filtered in the glomerular capillaries. Renal tubular cells bind pre-B HDL particles or lipid poor ApoA-I via the Cubulin-amnioless complex and Megalin. HDL dissociates from tubulin in their endocytic vesicles and HDL is degraded into lysosome.

Figure 3

Role of HDLs in counteracting bacterial sepsis and SARS-CoV2 infection. (A) HDLs exert scavenger effects in bacterial infections. HDLs are able to bind and neutralize Gram-positive and Gram-negative components and promote their clearance via the liver and subsequent bile elimination. In addition, HDL has multiple protective functions. Preclinical studies demonstrated that exogenous HDL injection increased survival rate, reducing systemic inflammatory response. (B) Recent studies support the notion that SARS-CoV-2 has a specific affinity for cholesterol and HDL. However, it is not clear if HDL could interfere with SARS-CoV-2 entry into host cells. Serum lipid profile changes and reduced HDL levels are correlated to severe forms. Therefore, HDL-based therapies or drugs that modulate cholesterol metabolism could increase HDL levels, provide pleiotropic functions that ameliorate clinical outcome.