Generic placeholder image

Current Vascular Pharmacology


ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Research Article

Association of PAF and its Metabolic Enzymes with GGT and the Fatty Liver Index in Healthy Volunteers

Author(s): Paraskevi Detopoulou, Tzortzis Nomikos, Elizabeth Fragopoulou and Smaragdi Antonopoulou*

Volume 19 , Issue 6 , 2021

Published on: 28 June, 2021

Page: [663 - 672] Pages: 10

DOI: 10.2174/1570161119666210628125239

Price: $65


Background: Platelet-activating-factor (PAF) is a lipid inflammatory mediator implicated in liver disease. Its main biosynthetic enzymes are cytidine diphosphate (CDP)-choline: 1-alkyl-2-acetyl-sn-glycerol-cholinephosphotransferase (PAF-CPT) and acetyl-coenzyme A: lyso-PAF-acetyltransferases (Lyso-PAF-AT). At the same time, PAF acetylhydrolase (PAF-AH) and lipoprotein-associated phospholipase A2 (Lp-PLA2) degrade PAF.

Objective: To explore the relation of PAF metabolism with liver diseases and non-alcoholic fatty liver disease, as reflected by the fatty liver index (FLI).

Methods: In 106 healthy volunteers, PAF concentration, the activity of its metabolic enzymes and gamma-glutamyl transferase (GGT) were measured in whole blood, leukocytes and serum, respectively and the FLI was calculated. Partial correlations and linear regression models were used.

Results: In males, serum GGT activity was positively correlated with abdominal fat (as assessed by analysis of a manually defined region of interest in dual-energy X-ray absorptiometry), triacylglycerols, bound-PAF and Lp-PLA2, while the FLI was positively correlated with Lp-PLA2 activity. In females, serum GGT activity was negatively associated with high-density lipoprotein cholesterol (HDL-C) (age adjusted correlations, all p<0.05). Lp-PLA2 was a significant determinant of serum GGT activity in males after controlling for age, low- density lipoprotein cholesterol (LDL-C) and abdominal fat. The addition of bound-PAF in the model significantly increased the explained variance of serum GGT activity (total variance explanation 30%).

Conclusion: Bound-PAF and Lp-PLA2 activity predicted serum GGT activity while Lp-PLA2 was also related to FLI. Our findings shed light on the metabolic pathways linking Lp-PLA2 to other atherosclerosis and/or oxidative markers, such as HDL-C, LDL-C, GGT and FLI and underline the important role of PAF.

Keywords: Platelet-activating-factor, gamma-glutamyl transferase, fatty liver index, lipoprotein associated phospholipase A2 (Lp-PLA2), lyso-PAF-acetyltransferase, PAF acetylhydrolase.

Graphical Abstract
Demopoulos CA, Karantonis C, Antonopoulou S. Platelet activating factor - a molecular link between atherosclerosis theories. Eur J Lipid Sci Technol 2003; 105(11): 705-16.
Karidis NP, Kouraklis G, Theocharis SE. Platelet-activating factor in liver injury: a relational scope. World J Gastroenterol 2006; 12(23): 3695-706.
[] [PMID: 16773686]
Ashraf MA, Nookala V. Biochemistry, Platelet Activating Factor. In: StatPearls. Treasure Island (FL): StatPearls Publishing 2020. Available from:
Detopoulou P, Nomikos T, Fragopoulou E, et al. Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, platelet-activating factor acetylhydrolase (PAF-AH) in leukocytes and body composition in healthy adults. Lipids Health Dis 2009; 8: 19.
[] [PMID: 19500354]
Nagel G, Rapp K, Wabitsch M, et al. Prevalence and cluster of cardiometabolic biomarkers in overweight and obese schoolchildren: results from a large survey in southwest Germany. Clin Chem 2008; 54(2): 317-25.
[] [PMID: 18089656]
Imhof A, Kratzer W, Boehm B, et al. Prevalence of non-alcoholic fatty liver and characteristics in overweight adolescents in the general population. Eur J Epidemiol 2007; 22(12): 889-97.
[] [PMID: 17896181]
Liu Z, Li H, Zheng Y, et al. Association of lipoprotein-associated phospholipase A2 with the prevalence of nonalcoholic fatty liver disease: A result from the APAC study. Sci Rep 2018; 8(1): 10127.
[] [PMID: 29973631]
Feng L, Zhao Y, Feng G, Chen Y. Clinical application of elevated platelet-activating factor acetylhydrolase in patients with hepatitis B. Lipids Health Dis 2014; 13: 105.
[] [PMID: 24973921]
Lonardo A, Lombardini S, Scaglioni F, et al. Hepatic steatosis and insulin resistance: does etiology make a difference? J Hepatol 2006; 44(1): 190-6.
[] [PMID: 16168516]
Emdin M, Pompella A, Paolicchi A. Gamma-glutamyltransferase, atherosclerosis, and cardiovascular disease: triggering oxidative stress within the plaque. Circulation 2005; 112(14): 2078-80.
[] [PMID: 16203922]
Artur Y, Wellman-Bednawska M, Jacquier A, Siest G. Complexes of serum gamma-glutamyltransferase with apolipoproteins and immunoglobulin A. Clin Chem 1984; 30(5): 631-3.
[] [PMID: 6143627]
Lippi G, Targher G, Montagnana M, Salvagno GL, Guidi GC. Relationship between gamma-glutamyltransferase, lipids and lipoprotein(a) in the general population. Clin Chim Acta 2007; 384(1-2): 163-6.
[] [PMID: 17601521]
Sunto A, Mochizuki K, Miyauchi R, et al. Serum γ-GTP activity is closely associated with serum CRP levels in non-overweight and overweight middle-aged Japanese men. J Nutr Sci Vitaminol (Tokyo) 2013; 59(2): 108-14.
[] [PMID: 23727640]
Lee D-H, Ha M-H, Kim J-H, et al. Gamma-glutamyltransferase and diabetes--a 4 year follow-up study. Diabetologia 2003; 46(3): 359-64.
[] [PMID: 12687334]
Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 2006; 6: 33.
[] [PMID: 17081293]
Kim JH, Moon JS, Byun SJ, et al. Fatty liver index and development of cardiovascular disease in Koreans without pre-existing myocardial infarction and ischemic stroke: a large population-based study. Cardiovasc Diabetol 2020; 19(1): 51.
[] [PMID: 32359355]
Meade CJ, Birke F, Metcalfe S, Watson C, Jamieson N, Neild G. Serum PAF-acetylhydrolase in severe renal or hepatic disease in man: relationship to circulating levels of PAF and effects of nephrectomy or transplantation. J Lipid Mediat Cell Signal 1994; 9(3): 205-15.
[PMID: 7921780]
Feng LM, Feng G-F, Chen Y. Evaluation of lipoprotein-associated phospholipase A2 in healthy Chinese Han adult serum. Lipids Health Dis 2014; 13: 6.
[] [PMID: 24393260]
Jung S, Kim OY, Kim M, Song J, Lee SH, Lee JH. Age-related increase in alanine aminotransferase correlates with elevated levels of plasma amino acids, decanoylcarnitine, Lp-PLA2 Activity, oxidative stress, and arterial stiffness. J Proteome Res 2014; 13(7): 3467-75.
[] [PMID: 24874467]
Derbent A, Kargili A, Koca C, et al. Serum platelet-activating factor acetylhydrolase activity: relationship with metabolic syndrome in women with history of gestational diabetes mellitus. Gynecol Endocrinol 2011; 27(2): 128-33.
[] [PMID: 20504094]
Kartsoli S, Kostara CE, Tsimihodimos V, Bairaktari ET, Christodoulou DK. Lipidomics in non-alcoholic fatty liver disease. World J Hepatol 2020; 12(8): 436-50.
[] [PMID: 32952872]
Glickman SG, Marn CS, Supiano MA, Dengel DR. Validity and reliability of dual-energy X-ray absorptiometry for the assessment of abdominal adiposity. J Appl Physiol (1985) 2004; 97(2): 509-14.
[] [PMID: 15075304]
Detopoulou P, Nomikos T, Fragopoulou E, et al. Platelet activating factor (PAF) and activity of its biosynthetic and catabolic enzymes in blood and leukocytes of male patients with newly diagnosed heart failure. Clin Biochem 2009; 42(1-2): 44-9.
[] [PMID: 18955040]
Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-54.
[] [PMID: 942051]
Demopoulos CA, Andrikopoulos NK, Antonopoulou S. A simple and precise method for the routine determination of platelet-activating factor in blood and urine. Lipids 1994; 29(4): 305-9.
[] [PMID: 8177023]
Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol 1959; 37(8): 911-7.
[] [PMID: 13671378]
Detopoulou P, Nomikos T, Fragopoulou E, Stamatakis G, Panagiotakos DB, Antonopoulou S. PAF and its metabolic enzymes in healthy volunteers: interrelations and correlations with basic characteristics. Prostaglandins Other Lipid Mediat 2012; 97(1-2): 43-9.
[] [PMID: 22079887]
Grypioti AD, Theocharis SE, Papadimas GK, et al. Platelet-activating factor (PAF) involvement in acetaminophen-induced liver toxicity and regeneration. Arch Toxicol 2005; 79(8): 466-74.
[] [PMID: 15995853]
Yang Y, Nemoto EM, Harvey SA, Subbotin VM, Gandhi CR. Increased hepatic platelet activating factor (PAF) and PAF receptors in carbon tetrachloride induced liver cirrhosis. Gut 2004; 53(6): 877-83.
[] [PMID: 15138217]
Kerek M, Akyurek N, Sozuer EM, Arar M, Muhtaroglu S. Effects of recombinant platelet activating factor acetylhydrolase in obstructive jaundice. Hepatogastroenterology 2003; 50(52): 1097-100.
[PMID: 12845989]
Grypioti AD, Kostopanagiotou G, Mykoniatis M. Platelet-activating factor inactivator (rPAF-AH) enhances liver’s recovery after paracetamol intoxication. Dig Dis Sci 2007; 52(10): 2580-90.
[] [PMID: 17410443]
Grypioti AD, Mykoniatis M, Demopoulos CA, Kostopanagiotou G. Recombinant platelet-activating factor-acetylhydrolase attenuates paracetamol-induced liver oxidative stress, injury, and regeneration. Dig Dis Sci 2007; 52(1): 192-9.
[] [PMID: 17160478]
de Oliveira MC, Menezes-Garcia Z, Arifa RD, et al. Platelet-activating factor modulates fat storage in the liver induced by a high-refined carbohydrate-containing diet. J Nutr Biochem 2015; 26(9): 978-85.
[] [PMID: 26013469]
KoŞmaz K, Durhan A, SÜleyman M, et al. The effect of ankaferd blood stopper on liver damage in experimental obstructive jaundice. Turk J Med Sci 2020; 27 Epub ahead of print
[] [PMID: 32979898]
Ruan Z, Shibamoto T, Shimo T, et al. Effects of platelet-activating factor and thromboxane A2 on isolated perfused guinea pig liver. Prostaglandins Other Lipid Mediat 2004; 73(1-2): 73-85.
[] [PMID: 15165033]
Karantonis HC, Gribilas G, Stamoulis I, et al. Platelet-activating factor involvement in thioacetamide-induced experimental liver fibrosis and cirrhosis. Dig Dis Sci 2010; 55(2): 276-84.
[] [PMID: 19242794]
Stanca E, Serviddio G, Bellanti F, Vendemiale G, Siculella L, Giudetti AM. Down-regulation of LPCAT expression increases platelet-activating factor level in cirrhotic rat liver: potential antiinflammatory effect of silybin. Biochim Biophys Acta 2013; 1832(12): 2019-26.
[] [PMID: 23851051]
Shindou H, Shimizu T. Acyl-CoA:lysophospholipid acyltransferases. J Biol Chem 2009; 284(1): 1-5.
[] [PMID: 18718904]
Nakou ES, Filippatos TD, Georgoula M, et al. The effect of orlistat and ezetimibe, alone or in combination, on serum LDL and small dense LDL cholesterol levels in overweight and obese patients with hypercholesterolaemia. Curr Med Res Opin 2008; 24(7): 1919-29.
[] [PMID: 18513463]
Akyürek N, Salman B, Irkörücü O, et al. The effect of platelet activating factor antagonist BN 52021 on bacterial translocation and ICAM-I expression in experimental obstructive jaundice. J Invest Surg 2005; 18(5): 247-56.
[] [PMID: 16249168]
Grypioti AD, Kostopanagiotou G, Demopoulos CA, Roussos A, Mykoniatis M. Platelet activating factor (PAF) antagonism with ginkgolide B protects the liver against acute injury. importance of controlling the receptor of PAF. Dig Dis Sci 2008; 53(4): 1054-62.
[] [PMID: 17934819]
Steinke JW, Borish L. Leukotriene receptors in rhinitis and sinusitis. Curr Allergy Asthma Rep 2004; 4(3): 217-23.
[] [PMID: 15056404]
Clark MA, Bomalaski JS, Conway TM, Wartell J, Crooke ST. Differential effects of aspirin and dexamethasone on phospholipase A2 and C activities and arachidonic acid release from endothelial cells in response to bradykinin and leukotriene D4. Prostaglandins 1986; 32(5): 703-8.
[] [PMID: 3103170]
Suzuki Y, Miwa M, Harada M, Matsumoto M. Release of acetylhydrolase from platelets on aggregation with platelet-activating factor. Eur J Biochem 1988; 172(1): 117-20.
[] [PMID: 3345757]
Bolodeoku JA, Ganotakis ES, Mikhailidis DP, Winder AF. Correlation between serum gamma-glutamyl transferase activity and the platelet count. Platelets 1997; 8(5): 333-5.
[] [PMID: 16793665]
Gürdöl F, Nwose OM, Mikhailidis DP. Gamma-glutamyl transferase activity in human platelets: Quantification of activity, isoenzyme characterization and potential clinical relevance. Platelets 1995; 6(4): 200-3.
[] [PMID: 21043729]
Reuter S, Schnekenburger M, Cristofanon S, et al. Tumor necrosis factor α induces γ-glutamyltransferase expression via nuclear factor-kappaB in cooperation with Sp1. Biochem Pharmacol 2009; 77(3): 397-411.
[] [PMID: 18996094]
Shi Y, Zhang P, Zhang L, et al. Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses. Atherosclerosis 2007; 191(1): 54-62.
[] [PMID: 16765356]
Liu H, Yao Y, Wang Y, et al. Association between high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2 and carotid atherosclerosis: A cross-sectional study. J Cell Mol Med 2018; 22(10): 5145-50.
[] [PMID: 30094934]
Oldgren J, James SK, Siegbahn A, Wallentin L. Lipoprotein-associated phospholipase A2 does not predict mortality or new ischaemic events in acute coronary syndrome patients. Eur Heart J 2007; 28(6): 699-704.
[] [PMID: 17314110]
Kim JY, Hyun YJ, Jang Y, et al. Lipoprotein-associated phospholipase A2 activity is associated with coronary artery disease and markers of oxidative stress: a case-control study. Am J Clin Nutr 2008; 88(3): 630-7.
[] [PMID: 18779277]
Liapikos TA, Antonopoulou S, Karabina SP, Tsoukatos DC, Demopoulos CA, Tselepis AD. Platelet-activating factor formation during oxidative modification of low-density lipoprotein when PAF-acetylhydrolase has been inactivated. Biochim Biophys Acta 1994; 1212(3): 353-60.
[] [PMID: 8199206]
Tsimikas S, Willeit J, Knoflach M, et al. Lipoprotein-associated phospholipase A2 activity, ferritin levels, metabolic syndrome, and 10-year cardiovascular and non-cardiovascular mortality: results from the Bruneck study. Eur Heart J 2009; 30(1): 107-15.
[] [PMID: 19019993]
Yoshimura T, Ohshige A, Maeda T, Ito M, Okamura H. Estrogen replacement therapy decreases platelet-activating factor-acetylhydrolase activity in post-menopausal women. Maturitas 1999; 31(3): 249-53.
[] [PMID: 10340285]
Fragopoulou E, Detopoulou P, Alepoudea E, Nomikos T, Kalogeropoulos N, Antonopoulou S. Associations between red blood cells fatty acids, desaturases indices and metabolism of platelet activating factor in healthy volunteers. Prostaglandins Leukot Essent Fatty Acids 2021; 164: 102234.
[] [PMID: 33373961]
Detopoulou P, Fragopoulou E, Nomikos T, et al. The relation of diet with PAF and its metabolic enzymes in healthy volunteers. Eur J Nutr 2015; 54(1): 25-34.
[] [PMID: 24639073]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy