Serum amyloid A and metabolic disease: evidence for a critical role in chronic inflammatory conditions

Abstract

Serum amyloid A (SAA) subtypes 1–3 are well-described acute phase reactants that are elevated in acute inflammatory conditions such as infection, tissue injury, and trauma, while SAA4 is constitutively expressed. SAA subtypes also have been implicated as playing roles in chronic metabolic diseases including obesity, diabetes, and cardiovascular disease, and possibly in autoimmune diseases such as systemic lupus erythematosis, rheumatoid arthritis, and inflammatory bowel disease. Distinctions between the expression kinetics of SAA in acute inflammatory responses and chronic disease states suggest the potential for differentiating SAA functions. Although circulating SAA levels can rise up to 1,000-fold during an acute inflammatory event, elevations are more modest (∼5-fold) in chronic metabolic conditions. The majority of acute-phase SAA derives from the liver, while in chronic inflammatory conditions SAA also derives from adipose tissue, the intestine, and elsewhere. In this review, roles for SAA subtypes in chronic metabolic disease states are contrasted to current knowledge about acute phase SAA. Investigations show distinct differences between SAA expression and function in human and animal models of metabolic disease, as well as sexual dimorphism of SAA subtype responses.

Structural studies of a serum amyloid A octamer that is primed to scaffold lipid nanodiscs

“…The ab initio model of lipid-free SAA2.1 built using our SAXS data shows important similarities to the structure of lipid-free ApoA-I, having an open structure formed by an approximately 2 nm thick helical assembly. With a strong body of evidence indicating that SAA displaces at least some fraction of the ApoA-I from HDL during the acute phase response, it is likely that this structural similarity has functional implications, potentially priming SAA to make extended helical contacts with lipid membranes (De Beer et al, 2010).…”

“…SAA is also highly upregulated in patients with chronic inflammatory conditions, including autoimmune diseases, diabetes, cardiovascular disease, inflammatory bowel disease and COVID‐19 associated hyper‐inflammatory syndrome. In these instances, both hepatic and non‐hepatic expression of SAA are considered to stimulate pro‐inflammatory pathways and contributes to disease progression (Sorić Hosman et al, 2021 ; den Hartigh et al, 2023 ; Sack, 2018 ; Chen et al, 2023 ; Buck et al, 2016 ).…”

Overlapping Receptor-Based Pathogenic Cascades in Degenerative Disease: Implications Ranging from Tumor Targeting to Aging and Dementia Therapeutics

“…In the meantime, proinflammatory cytokines can reach the brain, inducing glia reactivity, due to the increased BBB permeability brought on by aging and/or malfunction. Similarly, it has been noted that neuroinflammation following traumatic brain injury is a chronic response to an acute injury and is frequently linked to activated microglia and the release of pro-inflammatory cytokines [33,70]. Young adults who suffer moderate to severe head trauma also have a greater-than-two-fold increased risk of developing Alzheimer's disease or a related dementia later in life.…”

Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets

“…The acute-phase protein serum amyloid A (SAA) has been implicated in CKD and its circulating level inversely correlates with renal function [159,160]. It has value as a biomarker for CKD, as shown in murine studies [161]. In mice with renal fibrosis induced via unilateral ureteral obstruction, SAA was expressed at high levels in the obstructed kidney, and its depletion slowed fibrosis progression [162].…”