The SAA3 gene is a member of the Serum Amyloid A (SAA) family of genes, which produce proteins involved in the body’s inflammatory responses. These proteins are a component of the innate immune system, the body’s first line of defense against infection and injury. The function and activity of genes within this family, particularly SAA3, can vary significantly between different animal species. This distinction is important for understanding its relevance to human health, as its role in humans is different from that observed in many animal models.
The Serum Amyloid A Protein Family
Serum Amyloid A (SAA) proteins are apolipoproteins that bind to lipids like cholesterol to transport them through the bloodstream. They are considered “acute-phase reactants,” as their plasma concentrations can increase by as much as 1,000-fold during inflammation. This increase is triggered by infection or tissue damage, making them reliable markers for acute inflammatory states.
Their primary role during this acute phase is to associate with high-density lipoproteins (HDL), or “good cholesterol.” This association helps redistribute cholesterol and other lipids toward the liver for processing, which mobilizes energy for tissue repair. Beyond lipid transport, SAA proteins also act as signaling molecules that recruit immune cells to sites of injury. The main proteins in humans performing this function are SAA1 and SAA2.
SAA3 Gene Activation and Location
Unlike SAA1 and SAA2, which are primarily produced in the liver, the SAA3 gene shows a different pattern of expression. In animal models where the gene is functional, SAA3 is considered an “extrahepatic” SAA, meaning it is expressed in tissues outside the liver. The primary locations of SAA3 activation are adipose (fat) tissue and within immune cells known as macrophages. This localized production suggests a more specialized role in tissue-specific inflammation.
The activation of the SAA3 gene is triggered by inflammatory signals known as cytokines. These are molecules used for cell-to-cell communication in the immune system. Activators include tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which are released by macrophages. When macrophages infiltrate fat tissue, a common occurrence in obesity, they release these cytokines, which in turn signal fat cells (adipocytes) to activate the SAA3 gene.
Role in Metabolic Inflammation and Disease
The activation of SAA3 in fat tissue is connected to chronic, low-grade inflammation. In obesity, fat tissue is an active endocrine organ that can become a source of inflammatory signals. The persistent activation of SAA3 in adipocytes and resident macrophages contributes to “metabolic inflammation,” a factor in the development of several metabolic disorders.
Studies in animal models link SAA3 expression to insulin resistance, where cells do not respond effectively to insulin. SAA3 is thought to interfere with insulin signaling pathways, contributing to the impaired glucose uptake that precedes type 2 diabetes. SAA3 has also been implicated in the progression of atherosclerosis, the hardening of the arteries, by attracting immune cells to artery walls and contributing to plaque formation.
The protein produced by the SAA3 gene can also influence lipid metabolism within the artery wall, potentially worsening the buildup of cholesterol in plaques. Research using mouse models has shown that the presence of SAA3 is associated with larger atherosclerotic lesions.
The Human SAA3 Pseudogene
A significant distinction in SAA3 research is its status in humans. The human SAA3 gene is a pseudogene, a non-functional remnant of a gene that has lost its protein-coding ability. This inactivation is the result of a single nucleotide insertion that causes a “frameshift,” leading to a premature stop codon in the gene’s sequence. Consequently, human cells cannot produce a full-length, functional SAA3 protein.
This genetic fact has important implications for research. Most knowledge regarding SAA3’s role in metabolic diseases comes from studies in animal models, such as mice, where the SAA3 gene is fully functional. While these animal studies provide valuable insights, its direct contribution to human disease is different from that of SAA1 and SAA2, which are functional in humans. The SAA3 protein itself is not considered a direct actor in human metabolic inflammation.