Diet and C-Reactive Protein Peter M. Clifton, PhD, FRACP Address CSIRO Health Sciences and Nutrition, PO Box 10041 BC, Adelaide, SA 5000, Australia. E-mail: peter.clifton@csiro.au Current Atherosclerosis Reports 2003, 5:431–436 Current Science Inc. ISSN 1523–3804 Copyright © 2003 by Current Science Inc. Introduction The acute phase reactant C-reactive protein (CRP) has gained increasing strength as a predictor of cardiovascular and cerebrovascular events both in healthy subjects and in those with known coronary disease [1]. There is also a growing body of evidence that CRP itself may contribute to the disease process and that some of the risk factors for cardiovascular disease may be mediated partially by increased concentrations of CRP. Thus, environmental factors that contribute to increased concentrations of CRP will be important to identify. C-Reactive Protein and Promotion of Disease As noted in a previous review by Hielbronn and Clifton [2], there are several potential mechanisms by which CRP may enhance atherosclerosis. Since that review, the evidence has increased considerably. C-reactive protein in vitro has been found to upregu- late the angiotensin-1 receptor on vascular smooth muscle cells and promote migration and proliferation of these cells, as well as enhance reactive oxygen species formation [3], albeit at much higher levels than seen in vivo with atherosclerosis alone (up to 100 mg/L). CRP has been shown to stimulate the production of plasminogen- activator inhibitor-1 (PAI-1) antigen and activity in aortic endothelial cells in culture [4]. Verma et al. [5] showed that CRP at a relatively high level (25 mg/L) caused a marked and sustained increase in native low-density lipoprotein (LDL) uptake by macrophages. These proatherosclerotic effects of CRP were mediated, in part, via increased secre- tion of endothelin-1 (ET-1) and interleukin-6 (IL-6) (P<0.01), and were attenuated by both bosentan (an ET-1 receptor antagonist) and IL-6 antagonism with anti–IL-6 antibodies. CRP also caused a marked increase in the expression of vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) in human saphenous vein endothelial cells. Pasceri et al. [6] showed that normal levels of CRP (5 mg/L) induce MCP-1 in human umbilical vein endothelial cells, and that this was blocked by sim- vastatin and fenofibrate. Thus, it appears to be fairly clear that CRP may promote atherosclerotic disease and endo- thelial dysfunction via many mechanisms, and that strate- gies to lower CRP itself via diet, drugs, and exercise may be important in disease prevention. C-reactive protein, interleukin-6, and obesity There is a substantial body of evidence that CRP levels are increased in obesity and that this may be partially medi- ated by increased production of IL-6 from the increased mass of adipose tissue [2]. Connelly et al. [7] found that body mass index (BMI) and IL-6 levels predicted CRP levels in Cree women, whereas waist circumference and IL- 6 levels were predictive in Cree men. The proportion of subjects with high levels (>3.8 mg/L) was higher in women than in men (51% vs 32%). Fernandez-Real et al. [8] found that IL-6 and CRP were correlated in 288 healthy men and women ( r =0.39 overall), but the association was not present in smokers (r=0.16) or in women (r=0.11). The former observation occurs probably because smoking per se elevates IL-6 [9]. The levels of CRP (3 mg/L) and IL-6 (5.8 to 6.4 pg/mL) were similar in these normal-weight men and women. If IL-6 from adipose issue is a major inducer of CRP, then weight loss should lower both IL-6 and CRP in parallel, but the evidence is not entirely consis- tent, although weight loss invariably lowers CRP [10]. Ziccardi et al. [11] found that IL-6 fell in obese women with weight loss. However, Laimer et al. [12] found that CRP fell markedly from 13 mg/L to 4 mg/L in morbidly obese patients after gastric banding, which induced a fat loss of C-reactive protein (CRP) is an independent predictor of cardiovascular events in healthy individuals and those with pre-existing disease. It also probably contributes to the disease process. CRP levels are higher in obese subjects and this link is almost certainly because of increased insulin resistance. Interventions that alter insulin resistance, such as weight loss, exercise, and conjugated linoleic acid, also alter CRP. Glycemic load is associated with CRP, but there have been no interventions with altered macronutrient composition. In the context of weight loss, macronutrient composition is probably not important. Alcohol lowers CRP, but the mechanism is unknown. The interaction between gender and obesity needs further work, but it appears that obesity has a greater effect on CRP levels in women.