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Endotoxin as a missed link among all the metabolic abnormalities in the metabolic syndrome
Atherosclerosis 206 (2009) 36
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Letter to the Editor Endotoxin as a missed link among all the metabolic abnormalities in the metabolic syndrome Dear Editor, In a recent issue of the Journal [1], Miller et al. report significant differences in circulating endotoxin levels among a British multi-ethnic population (N = 192) of white, black African and Asian individuals. The Authors found the highest levels of endotoxin in Asians and the lowest ones in black Africans, apart from different levels between sexes. It is remarkable how these differences resemble inter ethnic and between gender different prevalence of not only cardiovascular disease, but, of note, of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) [2]. In a past issue of the Journal, Targher and Arcaro [3] described NAFLD/NASH as the hepatic component of the metabolic syndrome, suggesting the disease for being an independent cardiovascular risk factor and not just as a marker. Increased levels of endotoxin may represent the missed link among metabolic abnormalities clustering in the metabolic syndrome, and, particularly, between NAFLD/NASH and cardiovascular disease. Levels of endotoxin may affect the development of phenotype of obesity at “high cardiovascular risk” (otherwise, known as central obesity) respect with a relatively healthy phenotype of obesity. In this context, data reported do not mean just an association, but suggest a strong causative role for endotoxin. What the Authors do not recognise as limitation to the study is the lack of information on dietary habits of the three groups. As product of gram negative bacteria, circulating lipopolysaccharide (LPS) depends, at least in physiological condition, upon gut microbiota. Diets containing fats and carbohydrate in different amount and quality influence endotoxin levels via changes in gut microbiota and intestinal permeability, favouring development of obesity and insulin resistance according to the hypothesis of a “metabolic endotoxinemia” [4]. As the Authors state, the generation of an inflammatory response to LPS depends upon the complex interaction between specific protein and receptors, particularly, the soluble receptor CD14 (sCD14). However, LPS concentration is affected by circulating lipids, particularly triglycerides and very low density lipoproteins [5]. Therefore, no linear association is expected between circulating LPS and CD14. Another limit for the study is the lack of obese individuals or subjects with abnormities of the metabolic syndrome. In the Table 3 of the Miller’s manuscript, predictors of % difference in endotoxin levels between individuals of African origin and whites were waist, triglycerides, waist to hip ratio and body mass index apart from
0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.03.047
sex and age; whilst all these variables together did not predict % difference in endotoxin levels when South Asians were compared to whites. In the latter case, only waist and waist plus cholesterol associated significantly with difference in levels of the molecule. The question to be answered is why increased levels of endotoxin associates with markers of central adiposity? Endotoxin coming from gut is drained to portal veins, which means basically to the liver and to the visceral fat. In the liver, LPS will activate response from both parts of the immune system (innate and adaptive) and promote hepatic insulin resistance. In the visceral adipose tissue, LPS will promote macrophage polarization and, therefore, secretion of a number of pro-inflammatory adipocitokines, with consequent systemic insulin resistance and ectopic accumulation of excess fat in a vicious cycle. The hypothesis of lipopolysaccharide as a key actor in the pathogenesis of inflammation associated with obesity is very intriguing. Evidence is mounting on its association with cardio-metabolic abnormalities. Close interaction and talk among cardiologists, endocrinologists and immunologists are needed to understand the fine mechanisms of these association and to bet on new therapeutic strategies to counteract epidemic cardio-metabolic abnormalities. References [1] Miller MA, McTernan PG, Harte AL, et al. Ethnic and sex differences in circulating endotoxin levels: a novel marker of atherosclerotic and cardiovascular risk in a British multi-ethnic population. Atherosclerosis 2009;203:494–502. [2] Kallwitz ER, Guzman G, TenCate V, et al. The histologic spectrum of liver disease in African–American, non-Hispanic white, and Hispanic obesity surgery patients. Am J Gastroenterol 2009;104(January (1)):64–9. [3] Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2007;191:235–40. [4] DiBaise JK, Zhang H, Crowell MD, et al. Gut microbiota and its possible relationship with obesity. Mayo Clin Proc 2008;83:460–9. [5] Levels JHM, Marquart JA, Abraham PR, et al. Lipopolysaccharide is transferred from high-density to low-density lipoproteins by Lipopolysaccharide-Binding Protein and Phospholipid Transfer Protein. Infect Immun 2003;44:2339–48.
Melania Manco ∗ Scientific Directorate, Bambino Gesù Hospital, I-00165, Rome, Italy ∗ Tel.:
+39 06 6859 2649; fax: +39 06 6859 2904. E-mail address: [email protected] 17 March 2009
Available online 5 April 2009
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Letter to the Editor Endotoxin as a missed link among all the metabolic abnormalities in the metabolic syndrome Dear Editor, In a recent issue of the Journal [1], Miller et al. report significant differences in circulating endotoxin levels among a British multi-ethnic population (N = 192) of white, black African and Asian individuals. The Authors found the highest levels of endotoxin in Asians and the lowest ones in black Africans, apart from different levels between sexes. It is remarkable how these differences resemble inter ethnic and between gender different prevalence of not only cardiovascular disease, but, of note, of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) [2]. In a past issue of the Journal, Targher and Arcaro [3] described NAFLD/NASH as the hepatic component of the metabolic syndrome, suggesting the disease for being an independent cardiovascular risk factor and not just as a marker. Increased levels of endotoxin may represent the missed link among metabolic abnormalities clustering in the metabolic syndrome, and, particularly, between NAFLD/NASH and cardiovascular disease. Levels of endotoxin may affect the development of phenotype of obesity at “high cardiovascular risk” (otherwise, known as central obesity) respect with a relatively healthy phenotype of obesity. In this context, data reported do not mean just an association, but suggest a strong causative role for endotoxin. What the Authors do not recognise as limitation to the study is the lack of information on dietary habits of the three groups. As product of gram negative bacteria, circulating lipopolysaccharide (LPS) depends, at least in physiological condition, upon gut microbiota. Diets containing fats and carbohydrate in different amount and quality influence endotoxin levels via changes in gut microbiota and intestinal permeability, favouring development of obesity and insulin resistance according to the hypothesis of a “metabolic endotoxinemia” [4]. As the Authors state, the generation of an inflammatory response to LPS depends upon the complex interaction between specific protein and receptors, particularly, the soluble receptor CD14 (sCD14). However, LPS concentration is affected by circulating lipids, particularly triglycerides and very low density lipoproteins [5]. Therefore, no linear association is expected between circulating LPS and CD14. Another limit for the study is the lack of obese individuals or subjects with abnormities of the metabolic syndrome. In the Table 3 of the Miller’s manuscript, predictors of % difference in endotoxin levels between individuals of African origin and whites were waist, triglycerides, waist to hip ratio and body mass index apart from
0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.03.047
sex and age; whilst all these variables together did not predict % difference in endotoxin levels when South Asians were compared to whites. In the latter case, only waist and waist plus cholesterol associated significantly with difference in levels of the molecule. The question to be answered is why increased levels of endotoxin associates with markers of central adiposity? Endotoxin coming from gut is drained to portal veins, which means basically to the liver and to the visceral fat. In the liver, LPS will activate response from both parts of the immune system (innate and adaptive) and promote hepatic insulin resistance. In the visceral adipose tissue, LPS will promote macrophage polarization and, therefore, secretion of a number of pro-inflammatory adipocitokines, with consequent systemic insulin resistance and ectopic accumulation of excess fat in a vicious cycle. The hypothesis of lipopolysaccharide as a key actor in the pathogenesis of inflammation associated with obesity is very intriguing. Evidence is mounting on its association with cardio-metabolic abnormalities. Close interaction and talk among cardiologists, endocrinologists and immunologists are needed to understand the fine mechanisms of these association and to bet on new therapeutic strategies to counteract epidemic cardio-metabolic abnormalities. References [1] Miller MA, McTernan PG, Harte AL, et al. Ethnic and sex differences in circulating endotoxin levels: a novel marker of atherosclerotic and cardiovascular risk in a British multi-ethnic population. Atherosclerosis 2009;203:494–502. [2] Kallwitz ER, Guzman G, TenCate V, et al. The histologic spectrum of liver disease in African–American, non-Hispanic white, and Hispanic obesity surgery patients. Am J Gastroenterol 2009;104(January (1)):64–9. [3] Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2007;191:235–40. [4] DiBaise JK, Zhang H, Crowell MD, et al. Gut microbiota and its possible relationship with obesity. Mayo Clin Proc 2008;83:460–9. [5] Levels JHM, Marquart JA, Abraham PR, et al. Lipopolysaccharide is transferred from high-density to low-density lipoproteins by Lipopolysaccharide-Binding Protein and Phospholipid Transfer Protein. Infect Immun 2003;44:2339–48.
Melania Manco ∗ Scientific Directorate, Bambino Gesù Hospital, I-00165, Rome, Italy ∗ Tel.:
+39 06 6859 2649; fax: +39 06 6859 2904. E-mail address: [email protected] 17 March 2009
Available online 5 April 2009