Over the last two and a half decades, statins have been effective in reducing the risk and prevalence of cardiovascular diseases (CVDs), the leading cause of morbidity and mortality in western industrialized nations and globally Citation[1]. The mechanism of action of statins is that they inhibit the cellular enzyme, HMG-CoA reductase, which then reduces the cholesterol content of cells, particularly cells in the liver (hepatocytes), and this causes a reactionary increase in hepatocyte LDL receptor levels Citation[2]. Hepatocyte LDL receptors are the main vehicle by which circulating LDL particles are cleared. Statins achieve their reduction in CVD by enhancing LDL clearance from the circulation to the liver via LDL receptors, thereby lowering serum LDL cholesterol levels Citation[2]. This then lowers LDL accumulation in arteries and slows the progression of atherosclerosis Citation[2].
Regardless of these beneficial actions, statin therapy is not sufficiently effective in 30–50% of patients taking statins Citation[1,3,4]. This is due to these patients being unable to achieve their target LDL cholesterol levels with statin therapy despite using the highest tolerable dose. There is also a large residual CVD risk left in patients on statins Citation[1,3,4]. A not insignificant number of individuals on statin therapy also develop muscle myopathies and other complications, requiring them to discontinue statin use Citation[5].
Despite the large number of individuals in whom statin therapy may not be optimal, there is currently no method of screening individuals to predict their response to statin therapy. In our recent publication in the Journal of the American College of Cardiology Citation[6], we identified a novel effect of the serum protein, resistin. in reducing LDL receptor protein levels in human hepatocytes. LDL receptor protein levels were reduced substantially by 40% in response to resistin treatment of human hepatocytes. While statins work by upregulating the number of LDL receptors at the surface of hepatocytes, the addition of resistin to statin treatment completely reversed hepatocyte LDL upregulation by statins Citation[6].
This finding is novel and has important implications for the therapeutic potential of inhibitors of resistin to lower serum LDL levels, help patients achieve their target LDL cholesterol levels and lower their CVD risk, particularly in individuals in whom statins are ineffective or only partially effective. It also brings about the interesting proposition that elevated serum resistin concentrations may be a culprit in statin ineffectiveness in patients in the first place. In this article, we explore the potential role of elevated serum resistin levels in patients on statin therapy.
Elevated resistin as a reflection of statin resistance in obesity
Resistin is a small 12.5-kD signaling protein secreted from fat tissue in humans Citation[7]. Resistin secretion from fat tissue is increased with fat mass expansion as in overweight and obese individuals, and, thus, circulating resistin levels are increased in overweight and obese subjects Citation[8–10]. The quantity of resistin secreted is dependent on the type of fat tissue being considered; it is highest from abdominal visceral fat tissue, the most active and metabolically adverse type of fat Citation[8–11]. Therefore, obese individuals, in whom fat mass expansion is primarily in the visceral abdominal compartment, tend to have higher serum resistin concentrations Citation[8–11]. Fat mass expansion in obesity has a propensity towards enhanced inflammation via macrophage infiltration and in those obese individuals with greater macrophage infiltration and inflammation of their fat tissue, serum resistin levels are higher Citation[8–11].
LDL metabolism in most obese individuals is also impaired. More precisely, the majority of overweight and obese individuals have an increase in LDL particles in their circulation, which elevates their risk of developing atherosclerotic CVD Citation[12]. There is further evidence that overweight and obese individuals have a lesser response to the LDL-lowering effect of statin therapy than lean healthy subjects Citation[13,14].
Our recent findings directly implicate elevated serum resistin levels, for the first time, in the impairments in LDL metabolism and statin responsiveness in obesity. We found that incubation of hepatocytes with serum obtained from obese individuals with elevated resistin levels had the same effect as treatment of the cells with purified resistin. The obese human serum significantly reduced hepatocyte LDL receptor levels and raised LDL production, compared with both untreated cells and with cells incubated with lean human serum with lower resistin concentrations Citation[6,15]. Prior to these studies, serum resistin levels were shown to be significantly correlated with serum LDL levels Citation[16,17]. Our findings showed that elevated serum resistin levels are causal in reducing the effectiveness of obese patients LDL response to statin therapy as they counteract statin-mediated LDL lowering both at the LDL clearance and LDL production ends Citation[6,15].
How quantitatively important are the effects of elevated resistin levels in obese serum on the statin response? Our results showed that when resistin was removed from obese human serum through antibody-immunoprecipitation elimination prior to hepatocyte incubation, the obese–serum-mediated reduction on hepatocyte LDL receptor levels and stimulation of LDL production was reversed by up to 80% Citation[6,15]. This indicates the potential of strong pathophysiological effects of patient serum resistin levels on statin-mediated LDL-lowering responses.
Also, we found resistin concentrations at the range typical of overweight and obese individuals (25–75 µg/ml) Citation[10] to affect hepatocyte LDL metabolism in a dose–response fashion, such that the higher the dose of resistin within the physiological range, the greater the reduction in cellular LDL receptor protein and the greater the overproduction of LDL particles Citation[6,15]. There is a wide variation in serum resistin levels in overweight and obese individuals, probably related to overall quantity of fat, amount of visceral fat and extent of inflammation within fat depots Citation[8–11,18]. This variation in serum resistin levels may be a major reason for why there is a wide variability in the magnitude of the response of individuals to statin therapy, which is particularly evident in overweight and obese individuals Citation[18]. Our findings indicate that the higher the extent of the elevation in a patient’s serum resistin level, the less effective the statin response to LDL lowering may be since higher doses resulted in greater reductions in LDL receptor levels and greater increases in LDL production Citation[6,15].
Elevated resistin as a predictor of the response to statins
These findings on resistin are the first time, to our knowledge, that a circulating protein originating outside the liver in humans alters liver LDL receptor protein levels and LDL production. This opens up an avenue whereby patients can be screened for their circulating resistin levels to predict their LDL-lowering response to statin therapy. To add strength to the prognostic value of serum resistin levels as a predictor of the response to statin therapy, clinical studies with sufficient power are needed in which serum resistin levels are measured in primary and secondary CVD prevention patients prior to receiving statin therapy to see if there are correlations in their baseline serum resistin levels with the magnitude of their LDL-lowering response to the statin.
Statins, of course, not only impart LDL lowering but also mitigate CVD in responsive patients Citation[1,4]. Interestingly, and highlighting its clinical relevance, elevated levels of resistin in humans have been found to consistently inversely correlate with coronary heart disease and atherosclerosis progression Citation[19]. Prospective studies examining associations between serum resistin levels in patients on statins with surrogate markers of atherosclerotic CVD and with CVD events would demonstrate if elevated resistin levels affect statin-mediated declines in CVD.
To make the story more complex, statins actually decrease the synthesis of resistin, and thereby decrease resistin serum levels Citation[18]. Resistance to statin therapy may therefore be due to an inability of the statin to downregulate resistin in the first place, which is possibly a phenomenon more prominent in obese individuals Citation[18]. Thus, dynamic changes in serum resistin levels poststatin therapy from pretherapy levels may be another, possibly better, determinant of the LDL-lowering response to statin therapy in patients than their static baseline resistin concentrations.
An additional aspect to resistin quantification is that resistin is present in multiple forms. Resistin exists as a monomer and also as oligomers, more specifically, as trimers and hexamers Citation[20]. The low-molecular weight form of resistin is the most active, and the form used in our cellular studies on the resistin-mediated effects of hepatocyte LDL metabolism Citation[6,15,20]. Thus, validation of serum resistin levels as a useful prognostic marker of statin effectiveness would require testing of the various forms of resistin in serum to determine their specificity, sensitivity and utility as a marker.
Finally, serum resistin levels are increased in severe inflammatory states such as rheumatoid arthritis and inflammatory bowel disease and also during acute infections Citation[7,19]. Thus, the interpretation of serum resistin levels and their associations with statin effectiveness may be confounded in patients with these conditions and would need to be interpreted with caution.
Conclusion
We have established that elevated serum resistin levels in overweight and obese humans imparts quantitatively important effects in opposing statin LDL-lowering actions at the liver. At the levels typical of obesity, resistin mediates degradation of hepatocyte LDL receptors and stimulates LDL overproduction in a dose–response manner. The variation in serum resistin levels observed in obesity may thus reflect the variability in statin LDL responses observed in obesity.
Currently, the most effective, safe way of reducing serum resistin levels is via lifestyle changes such as weight loss, exercise and diet Citation[6]. More potent means of lowering serum resistin await the development of specific resistin inhibitors through siRNA, antibodies, antisense or small-molecule inhibitors.
At present, there is no clinically recognized prognostic serum biomarker of statin responsiveness in patients. Clinical studies are needed to determine the strength of elevated serum resistin levels in predicting statin LDL-lowering responses and, furthermore, statin-mediated reductions in atherosclerotic CVD progression and events. The future looks bright in the potential of resistin as a tool to predict statin responsiveness, and for inhibitors of resistin to enhance statin effectiveness, and possibly act as statin replacements in statin nonresponsive patients.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Baigent C, Keech A, Kearney PM et al.; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366(9493), 1267–1278 (2005).
- Brown MS, Goldstein JL. Biomedicine. Lowering LDL–not only how low, but how long? Science 311(5768), 1721–1723 (2006).
- Josan K, Majumdar SR, McAlister FA. The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. CMAJ 178(5), 576–584 (2008).
- Mihaylova B, Emberson J, Blackwell L et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380(9841), 581–590 (2012).
- Jacobson TA. Myopathy with statin-fibrate combination therapy: clinical considerations. Nat. Rev. Endocrinol. 5(9), 507–518 (2009).
- Melone M, Wilsie L, Palyha O, Strack A, Rashid S. Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. J. Am. Coll. Cardiol. 59(19), 1697–1705 (2012).
- Steppan CM, Bailey ST, Bhat S et al. The hormone resistin links obesity to diabetes. Nature 409(6818), 307–312 (2001).
- Degawa-Yamauchi M, Bovenkerk JE, Juliar BE et al. Serum resistin (FIZZ3) protein is increased in obese humans. J. Clin. Endocrinol. Metab. 88(11), 5452–5455 (2003).
- Azuma K, Katsukawa F, Oguchi S et al. Correlation between serum resistin level and adiposity in obese individuals. Obes. Res. 11(8), 997–1001 (2003).
- Piestrzeniewicz K, Luczak K, Komorowski J, Maciejewski M, Jankiewicz Wika J, Goch JH. Resistin increases with obesity and atherosclerotic risk factors in patients with myocardial infarction. Metab. Clin. Exp. 57(4), 488–493 (2008).
- Curat CA, Wegner V, Sengenès C et al. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 49(4), 744–747 (2006).
- Rosenson RS. Low high-density lipoprotein cholesterol disorders and cardiovascular risk: contribution of associated low-density lipoprotein subclass abnormalities. Curr. Opin. Cardiol. 20(4), 313–317 (2005).
- Quilliam BJ, Perez HE, Andros V, Jones P. Quantifying the effect of applying the NCEP ATP III criteria in a managed care population treated with statin therapy. J. Manag. Care Pharm. 10(3), 244–250 (2004).
- Vega GL, Grundy SM. Effect of statins on metabolism of apoB-containing lipoproteins in hypertriglyceridemic men. Am. J. Cardiol. 81(4A), 36B–42B (1998).
- Costandi J, Melone M, Zhao A, Rashid S. Human resistin stimulates hepatic overproduction of atherogenic ApoB-containing lipoprotein particles by enhancing ApoB stability and impairing intracellular insulin signaling. Circ. Res. 108(6), 727–742 (2011).
- Owecki M, Nikisch E, Miczke A, Pupek-Musialik D, Sowinski J. Serum resistin is related to plasma HDL cholesterol and inversely correlated with LDL cholesterol in diabetic and obese humans. Neuro. Endocrinol. Lett. 31(5), 673–678 (2010).
- de Luis DA, Sagrado MG, Conde R et al. Relation of resistin levels with cardiovascular risk factors, insulin resistance and inflammation in naïve diabetes obese patients. Diabetes Res. Clin. Pract. 89(2), 110–114 (2010).
- Fazio S, Linton MF. Proprotein convertase subtilisin/kexin type 9 as transducer of physiologic influences on cellular cholesterol: a case for resistin. J. Am. Coll. Cardiol. 59(19), 1706–1708 (2012).
- Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation 111(7), 932–939 (2005).
- Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L. Disulfide-dependent multimeric assembly of resistin family hormones. Science 304(5674), 1154–1158 (2004).