The Association of SAA With Apolipoprotein B Affects Cardiovascular Risk

Clinical burden of CVD: CVD is the leading cause of death in developed nations and the VA population is no exception. Despite decades of research, technical, and pharmacological advances, CVD remains a major public health problem. This is partly due to our impaired ability to identify subjects at greatest risk for CVD events and thus the best candidates for pharmacological risk reducing therapies, and partly due to incomplete use or efficacy of currently available therapies. Epidemiological studies have identified major risk factors for CVD including elevated LDL cholesterol, low HDL cholesterol, hypertension, smoking and diabetes. However, despite targeting individuals with these risk factors with aggressive pharmacological interventions, CVD remains a major public health problem. Furthermore, even in individuals with risk factors who are treated with pharmacological or lifestyle interventions the CVD event rates are higher than in those who never had the risk factors. Recent epidemiologic data evaluating the American Heart Association-identified cardiovascular health metrics reported that the prevalence of having CVD risk factors at ideal levels is < 2%10; implying that >98% of the population are candidates for risk reduction. Clearly, health systems cannot cope with pharmacological interventions for such enormous target populations. Thus, additional risk stratifying markers are needed to identify those at highest risk for events and thus at greatest likelihood of benefit. Several biomarkers, including the acute phase reactants C reactive protein (CRP) and serum amyloid A (SAA) have been studied for their role in predicting CVD events. Both CRP and SAA are chronically elevated in individuals with obesity, metabolic syndrome (MetS), diabetes, rheumatoid arthritis, lupus and other chronic inflammatory conditions associated with increased CVD rates, raising the question of whether these biomarkers merely reflect underlying risk or play a causative role in CVD. Although emerging evidence has cast doubt on the role of CRP as a causative factor the investigators and others recently demonstrated that SAA is directly atherogenic in animal models. Thus, in addition to its role as a biomarker for CVD, SAA may play a causal role in CVD.

SAA: SAA is a family of acute phase proteins synthesized primarily in the liver. In healthy individuals SAA concentrations are < 5 mg/L but during an acute phase response SAA can increase up to 1000 mg/L for a few days, then it rapidly returns to baseline levels. However, chronic inflammatory states such as obesity, MetS, diabetes, rheumatoid arthritis etc, are associated with persistently and significantly elevated SAA concentrations of 30-100 mg/L. Acute elevations in SAA are proposed to play a major role in response to injury and inflammation, participating in cholesterol delivery to injured tissues, recruitment of inflammatory cells, and induction of tissue repair cytokines. However, the chronic elevations of SAA now prevalent in modern society likely reflect a maladaptive response and numerous studies are now examining potential roles of SAA in disease pathology. Using murine models in which acute phase SAA is over-expressed, the investigators and others demonstrated direct increases in atherosclerosis development.

SAA and apolipoprotein B (apoB) containing lipoproteins: SAA is a lipid binding apolipoprotein and lipid-free SAA has not been found in vivo. The dogma is that SAA is exclusively an HDL associated lipoprotein; however, the investigators and others have reported SAA on apoB-containing lipoproteins in both mice and humans. Several studies have reported on a complex termed SAA-LDL associated with components of MetS, remnant like particle cholesterol, smoking status, lifestyle interventions, and statin treatment. These studies suggest that SAA-LDL is a risk factor for CVD. In new preliminary studies the investigators demonstrate that SAA has a differential lipoprotein association in diabetes, and in post-prandial lipoprotein metabolism, and the investigators demonstrate that the presence of SAA on apoB-lipoproteins augments their proteoglycan binding, a key step in atherosclerosis development. Thus, emerging evidence suggests that the presence of SAA on apoB-lipoproteins may be a novel CVD risk factor, play a causal role in atherosclerosis, and thus be a therapeutic target.

Post-prandial apoB-lipoprotein metabolism: The various lipoproteins are defined based on size and density criteria, as well as by their protein constituents. However, even within each lipoprotein class there is considerable heterogeneity, as the particles undergo continuous remodeling. Briefly, lipids consumed in the diet associate with apoB-48 to form chylomicrons, which are transported in intestinal lymphatics before entering the bloodstream. Various enzymes act on newly formed chylomicrons shifting lipids and proteins between chylomicrons and HDLs before the chylomicron remnants are taken up by the liver. The liver re-packages the lipids into VLDL particles containing apoB-100. The hydrolysis of VLDL results in smaller apoB-100 particles called VLDL remnants or intermediate density lipoproteins (IDLs). Collectively, these particles are termed triglyceride rich lipoproteins (TGRLs).

Ongoing remodeling of TGRLs by various lipases leads to the formation of LDL. LDL can be taken up by peripheral tissues, including the vasculature, or by the liver. The sub-endothelial retention of apoB-containing particles initiates atherosclerosis.