title: Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism.
abstract: Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition.
authors.affiliation: Monash Biomedicine Discovery Institute, Metabolic Disease and Obesity Program, and Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Meex
authors.affiliation: Monash Biomedicine Discovery Institute, Metabolic Disease and Obesity Program, and Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hoy
authors.affiliation: Monash Biomedicine Discovery Institute, Metabolic Disease and Obesity Program, and Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Morris
authors.affiliation: Monash Biomedicine Discovery Institute, Metabolic Disease and Obesity Program, and Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Russell D
authors.initials: RD
authors.lastname: Brown
authors.affiliation: Monash Biomedicine Discovery Institute, Metabolic Disease and Obesity Program, and Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Jennifer C Y
authors.initials: JC
authors.lastname: Lo
authors.affiliation: Biotechnology Research Laboratories, Department of Physiology, Monash University, Clayton, VIC 3800, Australia; Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Melissa
authors.initials: M
authors.lastname: Burke
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Robert J A
authors.initials: RJ
authors.lastname: Goode
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
authors.forename: Bronwyn A
authors.initials: BA
authors.lastname: Kingwell
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kraakman
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; The Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.affiliation: NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Department of General Surgery, Maastricht, the Netherlands.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Greve
authors.affiliation: NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Department of General Surgery, Maastricht, the Netherlands.
authors.forename: Sander S
authors.initials: SS
authors.lastname: Rensen
authors.affiliation: Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Molloy
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Lancaster
authors.affiliation: Monash Biomedicine Discovery Institute, Metabolic Disease and Obesity Program, and Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Bruce
authors.affiliation: Monash Biomedicine Discovery Institute, Metabolic Disease and Obesity Program, and Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, VIC 3800, Australia. Electronic address: matthew.watt@monash.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D005260:Female; D060752:Fetuin-B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008875:Middle Aged; D034622:RNA Interference; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D060752:Fetuin-B; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose