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Editorial |
Medical University of South Carolina (P.W.F.), Charleston, South Carolina 29425; Molecular Endocrinology (S.R.S.), Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808
Address all correspondence and requests for reprints to: Peter W. Wilson, Professor, Medical University of South Carolina, Department of Medicine, Charleston, South Carolina 29425. E-mail: wilsonpw{at}musc.edu.
In this issue of the journal, Pilz et al. (1) provide compelling new data that nonesterified free fatty acids (FFA) contribute to overall mortality and specifically cardiovascular death in older men. This prospective study in men undergoing angiography adds teeth to the existing literature supporting the notion that FFA are highly predictive of cardiovascular death (2), even after adjustment for all of the classic cardiovascular disease (CVD) risk factors. Furthermore, the data from Pilz et al. (1) support the growing body of literature that FFA have deleterious effects and foster the development of the metabolic syndrome, type 2 diabetes, and CVD.
Before we rush to our freezers to measure FFA in archived samples, to our clinics to measure FFA in our patients, or to intervene to reduce FFA and potentially prevent CVD and death, we should scrutinize what FFA are, their origins, and how to measure FFA accurately. Understanding the myriad of pathways that fatty acids take to reach the plasma and understanding how FFA are cleared from the plasma will enable us to answer the most important question—are FFA themselves disease-causing molecules or do they simply accompany the other bad actors of the metabolic syndrome? Furthermore, we need to ask if there are plausible links between FFA and atherosclerosis, sudden death, or other causes of death that compel us to believe that they are indeed bad actors.
First, where do these high levels of FFA come from? The majority of FFA are bound to albumin and are not "free" in the sense that we consider "free" testosterone to be unbound. The term nonesterified fatty acids is more accurate and to some is the preferred terminology. Most of our knowledge of FFA comes from the study of adipose tissue in obesity and diabetes. In fact, most FFA in plasma are derived from hydrolysis of adipose tissue triglyceride stores by the recently discovered key enzyme ATGL (3) and the commonly known hormone-sensitive lipase. Several signaling systems converge at adipocyte lipid droplets (4) to regulate lipolysis. First and foremost, insulin, acting as a lipogenic hormone (5), suppresses lipolysis after a meal, reduces lipid supply to peripheral tissues such as skeletal muscle and the heart, and supports glucose uptake and oxidation. The ß-adrenergic receptor–cAMP-PKA signaling system, once thought to be the primary lipolytic system, works together with a novel signaling system—the natriuretic peptides. Recent work by Lafontan and colleagues (6, 7) implicates the natriuretic peptides as potent activators of lipolysis in primate adipocytes and suggests that these pathways may be the predominate lipolytic stimuli during exercise. This discovery is germane to the paper of Pilz et al. (1), because natriuretic peptides potentially play an important role in heart failure when natriuretic peptide concentrations are very high. Other sources of FFA are possible, as there are several other enzymes that hydrolyze triglycerides. Lipoprotein lipase (LPL) is present in the capillary endothelium of essentially all tissues and liberates FFA for transport into cells, and LPL is also a potential contributor to circulating FFA levels. This is an important factor in the technical aspects of the measurement of FFA and will be discussed in more detail below.
Many control points affect the generation of FFA from adipose tissue, and it is apparent that many different scenarios could lead to increased FFA. Metabolic dysregulation at only a few of these control points is probably responsible for elevated FFA. One of the most likely scenarios is unrestrained lipolytic release of FFA. This occurs when adipocytes hypertrophy in response to energy excess. At some point, lipolysis becomes uncontrolled and tissues become resistant to the antilipolytic effects of insulin. So why do adipocytes hypertrophy? The answer to this question is unclear. Adipose tissue, once thought to be a static organ, is constantly undergoing the creation of new and apoptosis of old fat cells (8, 9). In other words, adipocytes "turn over" like bone. One compelling hypothesis for adipocyte hypertrophy is that there is a failure of the adipose organ to recruit new adipocyte precursors (10) to differentiate and complete the turnover cycle, which then leads to hypertrophic adipocytes. Regardless of the cause, large fat cells in the abdominal region have high lipolytic rates and are the major contributor to increased fasting FFA flux seen in obesity (11).
Stress-induced increases in adrenergic tone, with or without increased cortisol (12), can also contribute to increased fasting FFA under circumstances such as unstable angina and other states of stress or pain. Another source of unrestrained lipolysis might be the recently recognized inflammatory state in the adipose tissue of obese and diabetic patients. As adipocytes hypertrophy, and for other reasons that are not yet not entirely clear, adipocytes recruit macrophages into adipose tissue by the secretion of chemokines and other factors (13, 14). These resident macrophages are thought to secrete a myriad of inflammatory cytokines and other factors that activate lipolysis. The inflammatory cytokines secreted by macrophages may also alter the balance between "good" adipokines such as adiponectin and "bad" adipokines such as TNF
and IL-8 (15). There is growing appreciation that adipocyte-derived adipokines and cytokines originating from macrophages contribute to a dysfunctional adipose tissue milieu. These factors serve as a source of potentially atherogenic and disease-promoting agents in obesity.
In contrast to the dysfunctional, hypertrophic adipocyte, an increase in adipose tissue mass alone may also increase whole-body FFA production. Whether visceral adipose tissue is a unique source of FFA has recently come under intense scrutiny (16). It is likely that increased body fat is sufficient to increase FFA without invoking a special role for visceral adipose tissue (17).
Reduced fatty acid oxidation might also lead to increased plasma levels of FFA. A growing body of evidence suggests that defects in fatty acid oxidation might precede the obese-diabetic state (18, 19), adding another level of complexity to the regulation of fasting FFA. Postprandial declines in FFA are primarily mediated by increases in insulin and exhibit a large degree of interindividual variability (20). Whether FFA kinetics (suppression by insulin) are as important as postprandial glucose and lipoprotein kinetics is unknown, but Kelley et al. (21) demonstrated that insulin-suppressed FFA concentrations were the best predictors of insulin-stimulated glucose uptake, suggesting that the dynamics of FFA might be as important as fasting FFA. Consistent with this, Bajaj and colleagues demonstrated that decreasing FFA with acipimox improves insulin action (22) and increasing FFA with lipid infusion heparin impairs insulin action (23).
An interesting and special case is adiponectin. Adiponectin is an adipokine that is decreased in obesity and diabetes. Because obesity increases fasting FFA and decreases adiponectin levels, the role of decreased adiponectin should be considered in future studies that also investigate the role of FFA. Decreased adiponectin is part of the dysfunctional adipose organ mentioned above. Adiponectin activates fatty acid oxidation by turning on the fuel sensor AMP kinase, which raises the intriguing possibility that both unrestrained lipolysis and low adiponectin might contribute to increased fasting FFA in obesity. Low adiponectin itself has been found to predict cardiovascular events (24) and has antiatherogenic properties (25, 26).
How might FFA cause disease? There are several plausible mechanisms by which FFA might cause CVD and death. First, FFA may be proarrhythmic (27). Pilz et al. (1) do not differentiate between types of CVD (arrhythmia vs. myocardial infarction), so the connection between FFA and arrhythmia cannot be tested in the current work. Potentially more interesting is the observation that FFA might directly activate the immune system, promoting a proinflammatory, proatherogenic state. There is good evidence that this occurs in vivo in humans (28). The signaling mechanisms by which this occurs are unknown, although the discovery of the Toll-like receptor 4 as a fatty acid receptor by Hwang et al. (29) suggests that FFA activation of nuclear factor-
B might play a role. Several other FFA receptors have been identified including the previously "orphan" G protein-coupled receptors GPCR 40 and GPCR 120, suggesting multiple pathways by which FFA might activate inflammatory signaling pathways (30, 31, 32).
A few cautionary notes in the measurement of FFA are warranted. Accurate and precise measurement of FFA is not a trivial matter (33, 34). Residual LPL in the sample can generate FFA from triglycerides, especially in samples with high total triglycerides. Samples should be processed immediately and kept on ice for the entire processing cycle. If not handled properly, FFA values can be artificially elevated, which introduces imprecision or bias in the case of subjects with high triglycerides. Prior freeze-thaw cycles or improper collection procedures could produce misleading results.
Although the results of Pilz et al. (1) suggest that fasting FFA are important in the pathogenesis of CVD and might serve as a practical risk factor, there is still much work to be done to understand the mechanisms by which FFA might increase CVD risk. Difficulties in the precise measurement of fasting FFA hamper the use of FFA in the clinic. It is not clear whether fasting or dynamic changes in FFA, similar to the utility of the oral glucose tolerance test, are most important in risk prediction. Nonetheless, the solid prospective data presented by Pilz et al. (1) strongly suggest that fasting FFA bear further examination in our efforts to reduce CVD risk.
Footnotes
Abbreviations: CVD, Cardiovascular disease; FFA, free fatty acids; LPL, lipoprotein lipase.
Received May 10, 2006.
Accepted May 23, 2006.
References
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