1. C-Reactive Protein: What Is It?  Marker of inflammation made in liver 1  Acute-phase response  Illness or injury 2  Adipocyte release of cytokines may trigger release 3  Measure of general inflammation = non- specific  Further investigation required to determine actual source 2

2. High-Sensitivity C-Reactive Protein: Difference?  Sensitive measure of chronic inflammation seen in patients with atherosclerosis and other chronic diseases 1  hs-CRP assay test that is more sensitive than the standard test 4  Stable and easy to measure 5

3. CRP Levels for Risk and Testing  Blood test  Low Risk: <1mg/L  Average Risk: 2-3mg/L  High Risk: >3mg/L  Average of 2 measurements taken  At least 2 week apart  Normal individual w/o inflammation or infection: <0.6mg/L 2

4. What is inflammation? An attempt for the body to restore homeostasis after an injury. (3) Acute inflammation is our bodies initial response to harmful stimuli- it is a positive response that initiates healing (2) Chronic inflammation is characterized by the simultaneous healing and destruction of tissue from the inflammatory process

5. Mechanism of Acute Inflammation(5) 1.Vasodilatation and increased permeability of blood vessels (5)

6. Mechanism of Acute Inflammation 2. Emigration of phagocytes from the blood into interstitial fluid (5)

7. Mechanism of Acute Inflammation

8. Mechanisms of Acute Inflammation 3. Repair

9. CRP Acute Phase Response InfectionsBacterial, Systemic/ Severe Fungal Mycobacterial, viral Allergic Complications of infectionRheumatic fever Erythema nodosum Inflammatory DiseaseRheumatoid arthritis Juvenile chronic arthritis Psoriatic arthritis Crohn disease Familial Mediterranean fever NecrosisMyocardial infarction Tumor embolization Acute pancreatitis TraumaSugery, burns, fractures MalignancyLymphoma, Carcinoma, Sarcoma

10. C-Reaction Protein’s Role in Chronic Inflammation Strong association between base line CRP and BMI. (3) CRP values also associated with many features of insulin resistance, metabolic syndrome, and diabetes. (3) Not just a marker for inflammation, but also a participant! (3)

12. Atherosclerosis (1) Verma S et al. Circulation 2004;109:1914-1917 Copyright © American Heart Association

13. Overview of Metabolic Syndrome Pathways

14. Let’s draw this process step by step! What is the role of CRP in this process? Because is a calcium dependent ligand-binding protein, is involved in the acute-phase immune system response. Plasma CRP is produced by hepatocytes in the liver and regulated by pro inflammatory cytokines, especially IL-6 and TNF alpha. CRP is a predictor of development of type 2 diabetes. Why are we starting this diagram with the picture of lipid droplets? Because this diagram explains how obesity can lead to several health problems where many factors including CRP are involved.

15. Hormones and C-reactive protein

16. Hormones and C-reactive Protein NAMEACTIONPRODUCED FROM EFFECT ON CRP CORTISOLINCREASES GLYCOGENESIS WITHIN LIVER ADRENAL GLANDS OF THE KIDNEYS INCREASE CRP WITHIN 24 HOURS- STIMULATES CRP PRODUCTION DEOXYCORTICOSTERONEACTS AS A PRECURSER TO ALDOSTERONE ADRENAL GLAND INCREASE CRP WITHIN 24 HOURS ADRENALINFIGHT OR FLIGHT RESPONSE – SYMPATHETIC NERVOUS SYSTEM ADRENAL GLANDS OF KIDNEYS INCREASE CRP WITHIN 24 HOURS DEXAMETHASONEACTS AS AN ANTI- INFLAMMATORY AND IMMUNOSUPRESENT ELEVATES CRP LEVELS PROGESTERONEMENSTRUAL HORMONE OVARIES AS WELL AS THE ADRENAL GLANDS INCRESES CRP LEVELS DURING MENSTRATION DEHYDROEPIANDROSTERO NE (DHEA) PRECURSER TO MALE/FEMALE SEX HORMONES ADRENAL GLAND FUNCTIONS TO SUPRESS CERTAIN PRO-INFLAMMATORY IMMUNE CYTOKINES THAT CASUE ELEVATED C-REACTIVE PROTEIN

17. Considering CRP and Estrogen  Many current studies are exploring the connection between hormone replacement therapy and estradiol and the effect it has on increasing CRP levels.  Consider that Fat cells produce estrogen as well as certain cytokines. (if you are obese you thusly have a greater production of these elements)  We know that cytokines trigger an inflammatory response that result in greater levels of blood CRP  Do increased levels of adipocytes produce increased levels of estrogen and therefore result in higher levels of CRP within blood?  It is speculated that sex hormones, in conjunction with obesity affect circulating CRP concentrations w/in women

18. A Closer Look at CRP and Leptin  Leptin is a hormone produced from adipose tissue that signals to the brain when to stop eating. The amount of fat an individual has regulates the amount of leptin produced (weight of the evidence)  current research is trying to determine why when the weight of individual increases their response to leptin decreases  one theory is looking at CRP as the cause based on the similarity of leptin and CRP receptors  -higher fat= greater inflammation = higher production of inflammatory response of CRP from the liver  -greater % fat per body weight= greater % adipose tissue per body weight= greater leptin production. (nature.com)

19. Lifestyles Impacting CRP Levels: Obesity  Increase in adipose tissue  Adipocytes and immune cells that can secrete cytokines 6  One theory: bloated fat cells can leak or break open  Macrophages recruited  release cytokines  More WBC’s move in = increase in inflammation  More cytokines = more inflammation = more CRP 7

20. Lifestyles Impacting CRP Levels: Obesity  Fat tissue swells with increased positive energy balance  Increases inflammatory activity  Spills over into blood stream  systemic chronic, low-grade inflammation  Chronic low-grade inflammation makes brain more resistant to effects of insulin, cortisol, and leptin 7

21. Lifestyles Impacting CRP Levels: Obesity  Metabolic signals sent to hypothalamus  “master switch” for inflammation is chronic overeating  Leads to weight gain and insulin resistance  Weight gain = more adipose tissue = more cytokines = more inflammation = more CRP 8

22. Lifestyles Impacting CRP Levels: Atherogenesis/Atherosclerosis  Atherogenesis: process leading to development of Atherosclerosis  Plaques form when inflammation stimulates WBCs  Monocytes become macrophages that engulf cholesterol  foam cells  fatty streaks that deposit within smooth muscle 9

23. Lifestyles Impacting CRP Levels: Atherogenesis/Atherosclerosis  Protective fibrin layer forms between arterial lining and fatty deposits (Atheroma)  Secretes enzymes that work to enlarge artery to compensate for narrowing  Can rupture forming a Thrombus that attracts platelets and causes clotting  blockage 9  CRP found in arterial atheromas  Considered risk factor and causal agent for atherothrombosis 10

24. Verma S et al. Circulation 2004;109:1914-1917 Copyright © American Heart Association

25. Lifestyles Impacting CRP Levels: Atherogenesis/Atherosclerosis  Atherosclerosis causes angina (chest pain), myocardial infarction, and strokes  CRP has been shown to be elevated (>3mg/L) in these individuals 10

26. CRP and Macronutrients NutrientCRP Level Glucose IntakeIncreases Fructose IntakeIncreases Sucrose IntakeIncreases Fiber IntakeDecreases Branched Chain Amino Acid Intake Decreases Saturated Fat IntakeIncreases Unsaturated Fat IntakeDecreases Trans Fat IntakeIncreases

27. CRP and Sugary Sweetened Beverages CRP levels were shown to increase after the consumption of sugary sweetened beverages. The beverages were sweetened with fructose, glucose and sucrose CRP levels increased with each sugar consumption, but rose the most after high fructose consumption 1

28. CRP increases as fasting and 2 hour postload glucose levels rise. This indicates that people who are pre-diabetic, have elevated CRP levels It is not known whether this is a cause or an effect 2 CRP and Glucose

29. CRP and Fructose As fructose consumption increases, CRP levels increase. There is no mechanism that has shown a connection between CRP levels and increased fructose consumption, but it is widely thought that increased fructose consumption increases inflammation through the release of cytokines 3.

30. CRP and Fiber As fiber intake increases, CRP levels decrease in individuals with one or more of the following conditions: diabetes, hypertension and CVD. As fiber intake increases, CRP levels decrease in individuals without any preexisting conditions. Reduced consumption of fiber showed higher CRP levels regardless of preexisting conditions 4.

31. CRP and Fiber Continued….. Increased fiber intake is associated with lower CRP levels in normal weight individuals. Increased fiber intake does not seem to have an effect on CRP levels in obese or overweight individuals 5.

32. CRP and Protein, Fat Low levels of branched chain amino acids are correlated with higher levels of CRP and illness in dogs 6. Trans fat consumption has been shown to increase CRP levels, especially in overweight individuals and those with heart disease 7.

33. 1.Aeberli, I., et al (2011). Low to moderate sugar-sweetened beverage consumption impairs glucose and lipid metabolism and promotes inflammation in healthy young men: a randomized controlled trial. Am J Clin Nutr, 94, 479-85. 2.Doi, Y., et al (2005). Relationship between c-reactive protein and glucose levels in community-dwelling subject without diabetes. Diabetes Care, 28(5), 1211-3. 3.Pollock, N.K., et al (2012). Greater fructose consumption is associated with cardiometabolic risk markers and visceral adiposity in adolescents. J Nutr, 142, 251-7. 4.King, D.E., Mainous, A.G., Egan, B.M., Woolson, R.F. & Geesey, M.E. (2005). Fiber and c-reactive protein in diabetes, hypertension and obesity. Diabetes Care, 28(6), 1487-9. 5.North, C.J., Venter, C.S. & Jerling, J.C. (2009). The effects of dietary fibre on c- reactive protein, an inflammation marker predicting cardiovascular disease. Euro J Clin Nutr, 63, 921-33. 6.Chan, D.L., Rozanski, E.A. & Freeman, L.M. (2009). Relationship among plasma amino acids, c-reactive protein, illness severity and outcome in critically ill dogs. J Vet Intern Med, 23, 559-63. 7.Mozaffarian, D., Katan, M.B., Ascherio, A., Stampfer, M.J. & Willett, W.C. (2006). Trans fatty acids and cardiovascular disease. N Engl J Med, 354, 1601- 13.