Intestinal alkaline phosphatase prevents metabolic syndrome in mice

Metabolic syndrome comprises a cluster of related disorders that includes obesity, glucose intolerance, insulin resistance, dyslipidemia, and fatty liver. Recently, gut-derived chronic endotoxemia has been identified as a primary mediator for triggering the low-grade inflammation responsible for the development of metabolic syndrome. In the present study we examined the role of the small intestinal brush-border enzyme, intestinal alkaline phosphatase (IAP), in preventing a high-fat-diet–induced metabolic syndrome in mice. We found that both endogenous and orally supplemented IAP inhibits absorption of endotoxin (lipopolysaccharides) that occurs with dietary fat, and oral IAP supplementation prevents as well as reverses metabolic syndrome. Furthermore, IAP supplementation improves the lipid profile in mice fed a standard, low-fat chow diet. These results point to a potentially unique therapy against metabolic syndrome in at-risk humans.

[1]  Kun Huang,et al.  Injury, Large-Scale Collaborative Research Program , 2015 .

[2]  Hisashi Adachi,et al.  Inflammation, atherosclerosis, and coronary artery disease. , 2005, The New England journal of medicine.

[3]  R. Gamelli,et al.  Genomic responses in mouse models poorly mimic human inflammatory diseases , 2013, Proceedings of the National Academy of Sciences.

[4]  P. Holt,et al.  A high-fat diet is associated with endotoxemia that originates from the gut. , 2012, Gastroenterology.

[5]  R. Alfenas,et al.  Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia , 2012, British Journal of Nutrition.

[6]  J. Millán,et al.  Intestinal alkaline phosphatase preserves the normal homeostasis of gut microbiota , 2010, Gut.

[7]  C. Jobin,et al.  High-Fat Diet: Bacteria Interactions Promote Intestinal Inflammation Which Precedes and Correlates with Obesity and Insulin Resistance in Mouse , 2010, PloS one.

[8]  E. Hohmann,et al.  Identification of specific targets for the gut mucosal defense factor intestinal alkaline phosphatase. , 2010, American journal of physiology. Gastrointestinal and liver physiology.

[9]  J. Rutledge,et al.  Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. , 2010, American journal of physiology. Gastrointestinal and liver physiology.

[10]  P. Gionchetti,et al.  Exogenous alkaline phosphatase for the treatment of patients with moderate to severe ulcerative colitis , 2010, Inflammatory bowel diseases.

[11]  K. Wallace,et al.  Interleukin-1 participates in the progression from liver injury to fibrosis. , 2009, American journal of physiology. Gastrointestinal and liver physiology.

[12]  W. D. de Villiers,et al.  Chylomicrons promote intestinal absorption of lipopolysaccharides Published, JLR Papers in Press, September 24, 2008. , 2009, Journal of Lipid Research.

[13]  R. Bibiloni,et al.  Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice , 2008, Diabetes.

[14]  Jennifer M. Bates,et al.  Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota. , 2007, Cell host & microbe.

[15]  J. Carvalheira,et al.  Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Insulin Resistance , 2007, Diabetes.

[16]  J. Ferrières,et al.  Metabolic Endotoxemia Initiates Obesity and Insulin Resistance , 2007, Diabetes.

[17]  E. Park,et al.  DIETARY GANGLIOSIDE INHIBITS ACUTE INFLAMMATORY SIGNALS IN INTESTINAL MUCOSA AND BLOOD INDUCED BY SYSTEMIC INFLAMMATION OF ESCHERICHIA COLI LIPOPOLYSACCHARIDE , 2007, Shock.

[18]  G. Hotamisligil,et al.  Inflammation and metabolic disorders , 2006, Nature.

[19]  S. Akira,et al.  Toll-like receptor function and signaling. , 2006, The Journal of allergy and clinical immunology.

[20]  J. Sowers,et al.  Metabolic syndrome in the elderly , 2006, Current diabetes reports.

[21]  E. Ford,et al.  Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the U.S. , 2005, Diabetes care.

[22]  S. Simpson.  Of Mice . . . , 2004, Science.

[23]  Nathan D. Wong,et al.  Impact of the Metabolic Syndrome on Mortality From Coronary Heart Disease, Cardiovascular Disease, and All Causes in United States Adults , 2004, Circulation.

[24]  Claude Lenfant,et al.  Definition of Metabolic Syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[25]  A. Hopkins,et al.  Proinflammatory Cytokines Disrupt Epithelial Barrier Function by Apoptosis-Independent Mechanisms 1 , 2003, The Journal of Immunology.

[26]  J. Millán,et al.  Accelerated Fat Absorption in Intestinal Alkaline Phosphatase Knockout Mice , 2003, Molecular and Cellular Biology.

[27]  D. Alpers,et al.  Rat enterocytes secrete SLPs containing alkaline phosphatase and cubilin in response to corn oil feeding. , 2003, American journal of physiology. Gastrointestinal and liver physiology.

[28]  C. Newgard,et al.  Inflammatory mechanisms in diabetes: lessons from the beta-cell. , 2003, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[29]  T. Matsunaga,et al.  Alkaline phosphatases reduce toxicity of lipopolysaccharides in vivo and in vitro through dephosphorylation. , 2002, Clinical biochemistry.

[30]  I. Jang,et al.  Influence of age on duodenal brush border membrane and specific activities of brush border membrane enzymes in Wistar rats. , 2000, Experimental animals.

[31]  D. Alpers,et al.  Rat intestinal alkaline phosphatase secretion into lumen and serum is coordinately regulated. , 1991, Biochimica et biophysica acta.

[32]  H. Harris,et al.  Expression of alkaline phosphatase loci in mammalian tissues. , 1980, Proceedings of the National Academy of Sciences of the United States of America.