Revolution Health & Wellness

Free Fatty Acids

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Free Fatty Acids

Test Description

Plasma fatty acids can be esterified to form triacylglycerols (triglycerides [TGs]) for storage, or metabolized as a high-energy fuel source of adenosine triphosphate (ATP). Plasma fatty acids that are not esterified to TGs are bound primarily to albumin and are termed “nonesterified fatty acids (NEFAs)” or “free fatty acids (FFAs).”  FFAs are the primary form by which lipid stored in adipose tissue is transported to other sites for utilization.1

The FFAs are released from adipocytes via lipolysis of TGs, mediated by the combined actions of adipose triglyceride ligase (ATGL) and hormone sensitive lipase (HSL).2,3 Release and uptake of FFAs by tissues such as skeletal muscle and liver, is regulated by both insulin and catecholamines. FFA turnover is rapid, with a plasma half-life of ~2-4 min.4

Mitochondrial oxidation of FFAs (fatty acid β-oxidation) provides a significant energy source for organs and body tissues including myocardium, skeletal muscle, liver, and the kidney. Specific FFAs may also directly regulate cellular function, either by interactions with membrane phospholipid fatty acids, or in their role as natural ligands of cytoplasmic nuclear hormone receptors, such as peroxisome proliferator-activated receptors (PPARs).2

Following a meal, most lipids are transported as triglycerides packaged in chylomicrons and taken up primarily by adipose tissue and skeletal muscle.5,6 Both tissues can take up albumin-bound FFAs, but the majority of FFA uptake in adipose tissue is from chylomicrons after a meal. Of the postprandial FFAs taken up into adipocytes for storage, a proportion escapes and joins the plasma FFA pool (they may constitute 40-50% of circulating FFAs), in a process referred to as “spillover.”1,7 Hence, the plasma FFA pool changes in composition after a meal to reflect the fatty acid content of the meal.8

Secretion of insulin, stimulated by glucose in the postprandial state, results in suppression of lipolysis and a rapid drop in circulating FFAs. Circadian profiles of plasma FFA levels therefore show the highest concentrations after an overnight fast (when insulin is lowest and catecholamines high), with suppression after each meal.6,9,10

Typical plasma FFA concentrations range from around 0.3 to 0.6 mmol/L in the overnight fasting state (depending upon methodology and cohort) to 1.3 mmol/L after a 72-hour fast.11 Plasma FFA concentrations are usually found to be higher in women than in men,12-14 and are increased under physiological/psychological stress.15

Risk ranges for the Free Fatty Acids test are as follows:

Free Fatty Acids (mmol/L):

  • High risk > 0.7
  • Intermediate risk 0.6-0.7
  • Optimal < 0.6

Clinical Interpretation

Elevated FFA and metabolic syndrome

Alterations in FFA metabolism are likely a major factor involved in the pathogenesis of hyperglycemia and dyslipidemia associated with the metabolic syndrome (MetS). MetS represents a constellation of metabolic abnormalities that are risk factors for cardiovascular disease [coronary heart disease (CAD), myocardial infarction, and stroke].16

The clinical criteria of Metabolic Syndrome include:

  • abdominal obesity (high body mass index and/or large waist circumference)
  • insulin-resistant glucose metabolism (hyperinsulinemia, impaired fasting glucose, impaired glucose tolerance, type 2 diabetes)
  • dyslipidemia (high serum TG and low serum HDL-C concentrations)
  • increased blood pressure.17

Metabolic Syndrome is also known as the insulin resistance syndrome, as insulin resistance is thought to be an underlying cause of the metabolic derangements.18

Elevated FFA levels are also associated with insulin resistance, leptin resistance, and decreased adiponectin levels. Decreased fatty acid oxidation may cause increased plasma FFA levels and evidence suggests that defects in fatty acid oxidation may precede the obese diabetic state.2,19,20 High plasma FFA levels are commonly observed in type 2 diabetes (T2DM), with an early increase indicating a shift from impaired glucose tolerance (IGT) to T2DM.10,21

Mechanisms underlying FFA-induced insulin resistance

Insulin, which inhibits lipolysis, is the major physiological regulator of basal adipose tissue lipolytic activity.22,23 Lipolysis of adipose tissue TGs is the major source of plasma FFA. Therefore, insulin resistance in adipose tissue stimulates an increase in lipolytic rate and FFA release into the bloodstream. The typical increase in plasma insulin levels associated with obesity does not completely compensate for adipose tissue insulin resistance, so insulin-resistant obese subjects have high basal lipolytic rates and plasma FFA levels.23

Increased plasma FFA levels can impair the ability of insulin to stimulate muscle glucose uptake and oxidation24,25 and suppress hepatic glucose production,26,27 leading to hyperglycemia. Increased delivery of FFAs to the liver can lead to atherogenic dyslipidemia by inducing hepatic very low-density lipoprotein (VLDL)-TG production,28,29 which results in elevated TG and apolipoprotein B (apoB) levels, and a subsequent decrease in HDL-C levels.30-33 This in turn increases the transfer of TG from VLDL to HDL, leading to increased HDL clearance and decreased plasma HDL levels.34

The resulting lipid profile, often observed with both T2DM and Metabolic Syndrome, is associated with significantly increased risk for cardiovascular disease (CVD).35-37 Furthermore, elevated FFA concentrations also impair endothelial function, stimulate vasoconstriction, and increase sodium absorption, possibly leading to increased blood pressure.38,39

Other factors related to intracellular fatty acid metabolism also contribute to insulin resistance. Relative impairments of mitochondrial oxidative phosphorylation in skeletal muscle have been identified in persons who have insulin resistance and are at increased risk for developing T2DM.40 Impaired mitochondrial fatty acid oxidation, in particular, may contribute to impaired insulin action by increasing the intracellular accumulation of fatty acids.

Adverse effects of elevated FFA in the liver and vasculature

Like those in skeletal muscle, cellular events responsible for fatty acid-induced insulin resistance in the liver are fairly complicated. In addition to the impairment of insulin-mediated glucose uptake and utilization by the liver,17,37 the effect of elevated FFAs in the liver may indirectly lead to increased small dense (sd)LDL particle concentration, by stimulating secretion of apoB and raising numbers of apoB-containing lipoprotein particles which eventually become remodeled to sdLDL particles. The presence of such atherogenic particles has been associated with an increased risk for myocardial infarction and worsened severity of coronary artery disease (CAD).34 In insulin resistance, arteries are also exposed to high chronic levels of albumin-FFA complexes and

FFAs are locally released by lipases from the lipids of apoB-lipoproteins entrapped by proteoglycans of the intima.41,42 Therefore, in insulin resistance and diabetes, the main organ responsible for apoB-lipoprotein generation and metabolism, the liver, and the endothelium, where these liver products can initiate atherosclerotic lesions, are both exposed to potentially deleterious effects of excess circulating FFAs.

Seminal experiments by Hennig et al. showed that exposure of endothelial cells to high levels of albumin-bound fatty acids altered the amount and composition of the basement membrane proteoglycans, causing endothelial cell activation, an early step in the atherosclerotic process.43 Fatty acids can increase permeability of the endothelial basement membrane by reduction of heparan proteoglycans,44 while cellular exposure to high FFA levels increases intracellular diacylglycerol (DAG) concentration, activating protein kinase C (PKC) isoforms and resulting in compromised insulin signaling. By this mechanism, FFAs reduce insulin’s control of proteoglycan expression, which may contribute to increase retention of LDL in the intima, a key step in atherogenesis.45,46

FFAs are an important precursor for the synthesis of ceramides (a type of sphingolipid) that exert multiple injurious effects on the vasculature, including induction of reactive oxygen species and induction of proinflammatory nuclear factor kappa B (NFkB)-mediated signaling.47 Multiple studies have implicated the toll-like receptor-4 (TLR4) as a FFA “receptor” that activates NFkB signaling in endothelium and impairs insulin action in other tissues.48 It has been proposed that the chronic inflammatory state induced by FFAs and ceramides not only increases cardiovascular risk but further worsens insulin-glucose homeostasis in a positive feedback manner.49,50

In summary, recent studies support the increasing body of literature demonstrating that high FFA levels have deleterious effects and promote the development of Metabolic Syndrome, Type-2 diabetes, and cardiovascular disease. FFA levels are highly predictive of cardiovascular death even after adjustment for all of the classic cardiovascular risk factors. Clinical studies have shown that high FFA levels are associated with impairment of endothelium-dependent vasodilation, high blood pressure, myocardial infarction, stroke, atrial fibrillation, and sudden death.1-3,38,52-53

Treatment Considerations

Whether FFAs are only an independent risk marker of specific underlying pathophysiology, or also directly impact cardiovascular risk, interventions to reduce FFA levels should target the underlying cardiometabolic stress (e.g., at the level of the adipocyte). Reducing circulating FFA levels should be considered an important target for any therapeutic intervention intended to decrease CVD, especially with concomitant insulin resistance.

A combination of basic lifestyle measures such as

  • smoking cessation
  • greater physical activity
  • modest dietary change (e.g., reduced calories, consumption of whole grains in place of refined carbohydrates, reduced trans fat)
  • modest weight loss
  • drugs that reduce VLDL (i.e., niacin, fenofibrate) and reduce FFA levels
  • drugs that improve insulin sensitivity (e.g., metformin).54
  • PPAR gamma receptor agonist, pioglitazone, may also inhibit FFA release from adipose tissue via enhanced insulin activity, as well as by its ability to promote lipogenesis and lipid storage over fatty acid release.

Although insulin resistance is the sole cause of elevated FFA, women and the elderly have higher levels than men or younger individuals. Therefore, it is important to evaluate the overall cardiometabolic risk profile of each individual with elevated FFA levels.

Lifestyle55-61

  • Limit carbohydrates (especially simple sugars and processed carbohydrates) while maintaining moderate fat intake
  • Regular exercise (150 minutes/week combining cardiovascular activity at a moderate-to-vigorous pace with resistance training)

Medication choices may include:

  • Metformin (e.g., Glucophage®, Glumetza®)
  • Pioglitazone (Actos®)
  • Pioglitazone-metformin combination

 

References

  1. Karpe F, Dickmann JR, Frayn KN. Fatty acids, obesity, and insulin resistance: time for a re-evaluation. Diabetes 2011;60:2441-2449.
  2. Mozaffarian D. Free fatty acids, cardiovascular mortality, and cardiometabolic stress. Eur Heart J 2007;28:2699-2700.
  3. Smith SR, Wilson PWF: Free Fatty Acids and Atherosclerosis—Guilty or Innocent? J Clin Endocrinol Metab 91(7):2506–2508.
  4. Eaton RP, Berman M, Steinberg D. Kinetic studies of plasma free fatty acid and triglyceride metabolism in man. J Clin Invest 1969;48:1560–1579.
  5. Bickerton AS, Roberts R, Fielding BA, Hodson L, Blaak EE, Wagenmakers AJ, Gilbert M, Karpe F, Frayn KN. Preferential uptake of dietary Fatty acids in adipose tissue and muscle in the postprandial period. Diabetes 2007;56(1):168-76.
  6. Ruge T, Hodson L, Cheeseman J, Dennis AL, Fielding BA, et al. Fasted to fed trafficking of fatty acids in human adipose tissue reveals a novel regulatory step for enhanced fat storage. J Clin Endocrinol Metab 2009; 94(5):1781-8.
  7. McQuaid SE, Hodson L, Neville MJ, et al. Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition? Diabetes 2011;60:47–55.
  8. Fielding BA, Callow J, Owen RM, et al. Postprandial lipemia: the origin of an early peak studied by specific dietary fatty acid intake during sequential meals. Am J Clin Nutr 1996;63:36–41.
  9. Singer P, Gödicke W, Voigt S, Hajdu I, Weiss M. Postprandial hyperinsulinemia in patients with mild essential hypertension. Hypertension 1985;7:182–186
  10. Reaven GM, Hollenbeck C, Jeng C-Y, Wu MS, Chen Y-DI. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes 1988;37:1020–1024
  11. Frayn KN, Williams CM, Arner P. Are increased plasma non-esterified fatty acid concentrations a risk marker for coronary heart disease and other chronic diseases? Clin Sci (Lond) 1996;90:243–253.
  12. Bakewell L, Burdge GC, Calder PC. Polyunsaturated fatty acid concentrations in young men and women consuming their habitual diets. Br J Nutr 2006;96:93–99
  13. Shadid S, Kanaley JA, Sheehan MT, Jensen MD. Basal and insulin-regulated free fatty acid and glucose metabolism in humans. Am J Physiol Endocrinol Metab 2007;292:E1770–E1774
  14. Magkos F, Patterson BW, Mohammed BS, Klein S, Mittendorfer B. Women produce fewer but triglyceride-richer very low-density lipoproteins than men. J Clin Endocrinol Metab 2007;92:1311–1318.
  15. Taggart P, Carruthers M. Endogenous hyperlipidaemia induced by emotional stress of racing driving. Lancet 1971;1:363–366.
  16. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24:683–9.
  17. Kirk EP, Klein S. Pathogenesis and pathophysiology of the cardiometabolic syndrome. J Clin Hypertens 2009;11(12):761–765
  18. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595–607.
  19. Colberg SR, Simoneau JA, Thaete FL, Kelley DE. Skeletal muscle utilization of free fatty acids in women with visceral obesity. J Clin Invest 1995;95:1846–1853.
  20. Ukropcova B, McNeil M, Sereda O, et al. Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donor. J Clin Invest 2005;115:1934–1941
  21. Moors CC, van der Zijl NJ, et al. Impaired insulin sensitivity is accompanied by disturbances in skeletal muscle fatty acid handling in subjects with impaired glucose metabolism. Int J Obes (Lond) 2012; 36(5):709-17.
  22. Klein S, Peters EJ, Holland OB, Wolfe RR. Effect of short- and long-term beta-adrenergic blockade on lipolysis during fasting in humans. Am J Physiol Endocrinol Metab 1989;257:E65–73.
  23. Horowitz JF, Klein S. Whole body and abdominal lipolytic sensitivity to epinephrine is suppressed in upper body obese women. Am J Physiol Endocrinol Metab 2000;278:E1144–E52.
  24. Boden G, Chen X, Ruiz J, White JV, Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 1994;93:2438–2446.
  25. Shah PV, Vella A, Basu A, et al. Effects of free fatty acids and glycerol on splanchnic glucose metabolism and insulin extraction in nondiabetic humans. Diabetes 2002;51:301–310.
  26. Roden M, Stingl H, et al. Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. Diabetes 2000;49:701-707.
  27. Staehr P, Hother-Nielosn O, Landau BR, et al. Effects of free fatty acids per se on glucose production, gluconeogenesis, and glycogenolysis. Diabetes 2003;52:260-267.
  28. Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. Interaction between free fatty acids and insulin in the acute control of very lowdensity lipoprotein production in humans. J Clin Invest 1995;95:158–66.
  29. Zhang YL, Hernandez-Ono A, Ko C, et al. Regulation of hepatic apolipoprotein B-lipoprotein assembly and secretion by the availability of fatty acids. I. Differential response to the delivery of fatty acids via albumin or remnant-like emulsion particles. J Biol Chem 2004; 279:19362–74.
  30. Carmena R. Type 2 diabetes, dyslipidemia, and vascular risk: rationale and evidence for correcting the lipid imbalance. Am Heart J 2005;150(5):859-70.
  31. Friedberg SJ, Klein RF, Trout DL, Bogdonoff MD, Estes EHJ Jr. The incorporation of plasma free fatty acids into plasma triglycerides in man. J Clin Invest 1961;40:1846–1855.
  32. Hodson L, Bickerton AS, McQuaid SE, et al. The contribution of splanchnic fat to VLDL triglyceride is greater in insulin-resistant than insulin-sensitive men and women: studies in the postprandial state. Diabetes 2007;56:2433–2441.
  33. Mittendorfer B, Patterson BW, Klein S. Effect of sex and obesity on basal VLDL-triacylglycerol kinetics. Am J Clin Nutr 2003; 77:573–9.
  34. Hopkins GJ, Barter PJ. Role of triglyceride-rich lipoproteins and hepatic lipase in determining the particle size and composition of high density lipoproteins. J Lipid Res 1986;27:1265–77.
  35. Steinmetz A, Fenselau S, Schrezenmeir J. Treatment of dyslipoproteinemia in the metabolic syndrome. Exp Clin Endocrinol Diabetes 2001:109:S548-59.
  36. Brunzell JD, Ayyobi AF. Dyslipidemia in the metabolic syndrome and type 2 diabetes mellitus. Am J Med 2003; 115 Suppl 8A:24S-28S.
  37. Bays H. Atherogenic dyslipidaemia in type 2 diabetes and metabolic syndrome: current and future treatment options. Br J Diabetes Vasc Dis 2003; 3(5):356-60.
  38. Steinberg HO, Paradisi G, Hook G, Crowder K, Cronin J, Baron AD. Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes 2000;49:1231–1238.
  39. Florian JP, Pawelczyk JA. Non-esterified fatty acids increase arterial pressure via central sympathetic activation in humans. Clin Sci (Lond) 2010;118:61–69.
  40. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004;350:664–71.
  41. Khalil MF, Wagner WD, Goldberg IJ. Molecular interactions leading to lipoprotein retention and the initiation of atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:2211–2218.
  42. Mahley RW, Huang Y. Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing. [comment]. J Clin Invest 2007;117:94–98.
  43. Hennig B, Meerani P, Ramadass P, et al. Fatty acid mediated activation of vascular endothelial cells. Metabolism 2000; 49:1006–1013.
  44. Hsueh WA, Quinones MJ. Role of endothelial dysfunction in insulin resistance. Am J Cardiol 2003;92:10J–17J.
  45. Hurt-Camejo E, Olsson U, et al. Cellular consequences of the association of Apo B lipoproteins with proteoglycans: potential contribution to atherogenesis. Arterioscler Thromb Vasc Biol 1997;17:1011–1017.
  46. Gustafsson M, Bore´n J. Mechanisms of lipoprotein retention by the extracellular matrix. Curr Opin Lipidol 2004;15:505–514.
  47. Samad F, Badeanlou L, Shah C, Yang G. Adipose tissue and ceramide biosynthesis in the pathogenesis of obesity. Adv Exp Med Biol 2011;721:67-86.
  48. Fim F, Pham M, et al. Toll-like receptor-4 (TLR 4) mediates vascular inflammation and insulin resistance in diet-induced obesity, Circ Res 2007;100:1589–1596.
  49. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002;51:2005–11.
  50. Kim F, Tysseling KA, et al. Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta, Arterioscler Thromb Vasc Biol 2005;25:989–994.
  51. Pilz S, Scharnagl H, Tiran B, et al. Elevated plasma free fatty acids predict sudden cardiac death: a 6.85-year follow-up of 3315 patients after coronary angiography. Eur Heart J 2007;28:2763–2769.
  52. Pilz S, Scharnagl H, Tiran B, et al. Free fatty acids are independently associated with all-cause and cardiovascular mortality in subjects with coronary artery disease. J Clin Endocrinol Metab 2006;91:2542–2547.
  53. Khawaja O, Bartz TM, Ix JH, et al. Plasma free fatty acids and risk of atrial fibrillation (from the Cardiovascular Health Study). Am J Cardiol 2012;110:212-216.
  54. Cabezas MC, van Wijk JPH, et al. Effects of metformin on the regulation of free fatty acids in insulin resistance: A double-blind, placebocontrolled study. J Nutr Metab 2012;2012:394623.
  55. Mirza NM, Palmer MG, Sinclair KB, McCarter R, He J, Ebbeling CB, Ludwig DS, Yanovski JA. Effects of a low glycemic load or a low-fat dietary intervention on body weight in obese Hispanic American children and adolescents: a randomized controlled trial. Am J Clin Nutr 2013;97:276-285.
  56. Yki-Ja¨rvinen H. Nutritional modulation of nonalcoholic fatty liver disease and insulin resistance: human data. Curr Opin Clin Nutr Metab Care 2010;13(6):709-14.
  57. Bradley U, Spence M, Courtney CH, McKinley MC, Ennis CN, McCance DR, McEneny J, Bell PM, Young IS, Hunter SJ. Low-fat versus low-carbohydrate weight reduction diets: effects on weight loss, insulin resistance, and cardiovascular risk: a randomized control trial. Diabetes 2009;58(12):2741-8.
  58. Ross R, Janssen I, Dawson J, Kungl AM, Kuk JL, Wong SL, Nguyen-Duy TB, et al.. Exercise-induced reduction in obesity and insulin resistance in women: a randomized controlled trial. Obes Res 2004;12(5):789-798.
  59. O’Hagan C, De Vito G, Boreham CA. Exercise prescription in the treatment of type 2 diabetes mellitus : current practices, existing guidelines and future directions. Sports Med 2013;43:39-49.
  60. Davidson LE, Hudson R, Kilpatrick K, Kuk JL, McMillan K, Janiszewski PM, Lee S, Lam M, Ross R. Effects of exercise modality on insulin resistance and functional limitation in older adults: a randomized controlled trial. Arch Intern Med 2009;169(2):122-131.
  61. Williams MA, Haskell WL, et al.; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Nutrition, Physical Activity, and Metabolism. Resistance exercise in individuals with and without cardiovascular disease: 2007 update: a scientific statement from the American Heart Association Council on Clinical Cardiology and Council on Nutrition, Physical Activity, and Metabolism. Circulation 2007;116:572-584.
  62. Aguilar RB. Evaluating treatment algorithms for the management of patients with type 2 diabetes mellitus: a perspective on the definition of treatment success. Clin Ther 2011;33(4):408-24.
  63. Moore EM, Mander AG, Ames A, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 2013;36(10):2981-7.