The complement system in lipid-mediated pathologies

Abstract

The complement system, a coordinator and facilitator of the innate immune response, plays an essential role in maintaining host homeostasis. It promotes clearance of pathogen- and danger-associated molecular patterns, regulates adaptive immunity, and can modify various metabolic processes such as energy expenditure, lipid metabolism, and glucose homeostasis. In this review, we will focus on the intricate interplay between complement components and lipid metabolism. More precisely, we will display how alterations in the activation and regulation of the complement system affect pathological outcome in lipid-associated diseases, such as atherosclerosis, obesity, metabolic syndrome, age-related macular degeneration, and metabolic dysfunction-associated steatotic liver disease. In addition to that, we will present and evaluate underlying complement-mediated physiological mechanisms, observed both in vitro and in vivo. Our manuscript will demonstrate the clinical significance of the complement system as a bridging figure between innate immunity and lipid homeostasis.

Keywords: complement; complement system; innate immunity; lipid metabolism; lipid-mediated pathologies.

Figure 1

Schematic illustration of complement levels alterations (A) and their effects (B) in lipid-mediated pathologies. The components of the classical (CP), lectin (LP), alternative (AP) and terminal (C5b-C9) pathways are labeled in red, green, yellow and black, respectively. IR, Insulin resistance; T2DM, Type 2 diabetes mellitus; MASLD, Metabolic dysfunction-associated steatotic liver disease; AMD, Age-related macular degeneration; IgM, Immunoglobulin M; C1q, Complement Component 1q; C2, Complement Component 2; C4, Complement Component 4; MBL, Mannan binding lectin; MASP1, MBL Associated Serine Protease 1; C3, Complement Component 3; Asp, C3adesArg – acylation stimulating protein; FB, Factor B; FD, Factor D; FH, Factor H; FHR1, Factor H related protein 1; FI, Factor I; C3aR, Complement C3a Receptor; VSIG4, V-Set And Immunoglobulin Domain Containing 4; CR3, Complement Component Receptor 3; C5, Complement Component 5; C5aR1, Complement C5a Receptor 1; C5aR2, Complement C5a Receptor 2; C9, Complement Component 9; del, gene deletion; gene variants are given in the bracket after affected gene.