title: Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism.
abstract: To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism.
  
  
  
  To study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion ofMyD88. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH).
  
  
  
  Hepatocyte-specific deletion ofMyD88predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion ofMyD88in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis.
  
  
  
  Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans.
authors.affiliation: WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.|Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Duparc
authors.affiliation: WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.|Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Hubert
authors.initials: H
authors.lastname: Plovier
authors.affiliation: Fundación de Investigación del Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain.
authors.forename: Vannina G
authors.initials: VG
authors.lastname: Marrachelli
authors.affiliation: WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.|Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Matthias
authors.initials: M
authors.lastname: Van Hul
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Essaghir
authors.affiliation: Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Gothenburg, Sweden.|Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ståhlman
authors.affiliation: WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.|Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Matamoros
authors.affiliation: WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.|Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Lucie
authors.initials: L
authors.lastname: Geurts
authors.affiliation: Fundación de Investigación del Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain.
authors.forename: Mercedes M
authors.initials: MM
authors.lastname: Pardo-Tendero
authors.affiliation: WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.|Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Céline
authors.initials: C
authors.lastname: Druart
authors.affiliation: Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Delzenne
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Demoulin
authors.affiliation: Laboratory of Hepatology, University of Leuven (KUL), Belgium.|Department of Gastroenterology and Hepatology, Division of Liver and Biliopancreatic Disorders, KUL, Leuven, Belgium.
authors.forename: Schalk W
authors.initials: SW
authors.lastname: van der Merwe
authors.affiliation: Laboratory of Hepatology, University of Leuven (KUL), Belgium.
authors.forename: Jos
authors.initials: J
authors.lastname: van Pelt
authors.affiliation: Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Gothenburg, Sweden.|Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.|Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.affiliation: Fundación de Investigación del Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Monleon
authors.affiliation: WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.|Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Amandine
authors.initials: A
authors.lastname: Everard
authors.affiliation: WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.|Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
mesh_terms: D050154:Adiposity; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001647:Bile Acids and Salts / Q000378:metabolism*; D001835:Body Weight; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D000069196:Gastrointestinal Microbiome / Q000235:genetics*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors / Q000378:metabolism; D055442:Metabolome / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D001647:Bile Acids and Salts; D003577:Cytochrome P-450 Enzyme System; D005947:Glucose; D000071518:Liver X Receptors; D053594:Myeloid Differentiation Factor 88; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; D050796:STAT3 Transcription Factor; D000099150:Receptor, Farnesoid X-Activated; C507780:Myd88 protein, mouse
keywords: BILE ACID METABOLISM; DIABETES MELLITUS; GLUCOSE METABOLISM; INTESTINAL BACTERIA; LIPID METABOLISM