title: Glucose transporter 8 (GLUT8) mediates fructose-induced de novo lipogenesis and macrosteatosis.
abstract: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, and it is thought to be the hepatic manifestation of the metabolic syndrome. Excess dietary fructose causes both metabolic syndrome and NAFLD in rodents and humans, but the pathogenic mechanisms of fructose-induced metabolic syndrome and NAFLD are poorly understood. GLUT8 (Slc2A8) is a facilitative glucose and fructose transporter that is highly expressed in liver, heart, and other oxidative tissues. We previously demonstrated that female mice lacking GLUT8 exhibit impaired first-pass hepatic fructose metabolism, suggesting that fructose transport into the hepatocyte, the primary site of fructose metabolism, is in part mediated by GLUT8. Here, we tested the hypothesis that GLUT8 is required for hepatocyte fructose uptake and for the development of fructose-induced NAFLD. We demonstrate that GLUT8 is a cell surface-localized transporter and that GLUT8 overexpression or GLUT8 shRNA-mediated gene silencing significantly induces and blocks radiolabeled fructose uptake in cultured hepatocytes. We further show diminished fructose uptake and de novo lipogenesis in fructose-challenged GLUT8-deficient hepatocytes. Finally, livers from long term high-fructose diet-fed GLUT8-deficient mice exhibited attenuated fructose-induced hepatic triglyceride and cholesterol accumulation without changes in hepatocyte insulin-stimulated Akt phosphorylation. GLUT8 is thus essential for hepatocyte fructose transport and fructose-induced macrosteatosis. Fructose delivery across the hepatocyte membrane is thus a proximal, modifiable disease mechanism that may be exploited to prevent NAFLD.
authors: From the Departments of Pediatrics, University School of Medicine, St. Louis, Missouri 63110.
authors: Brian J
authors: BJ
authors: DeBosch
authors: Departments of Medicine, and University School of Medicine, St. Louis, Missouri 63110.
authors: Zhouji
authors: Z
authors: Chen
authors: Departments of Obstetrics and Gynecology Washington University School of Medicine, St. Louis, Missouri 63110.
authors: Jessica L
authors: JL
authors: Saben
authors: Departments of Medicine, and University School of Medicine, St. Louis, Missouri 63110.
authors: Brian N
authors: BN
authors: Finck
authors: Departments of Obstetrics and Gynecology Washington University School of Medicine, St. Louis, Missouri 63110. Electronic address: moleyk@wustl.edu.
authors: Kelle H
authors: KH
authors: Moley
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005632:Fructose / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D050155:Lipogenesis; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D007004:Hypoglycemic Agents; D007328:Insulin; C405325:SLC2A8 protein, human; C498628:Slc2a8 protein, mouse; D014280:Triglycerides; D005632:Fructose; D002784:Cholesterol; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Diabetes; Fructose Metabolism; Glucose Transport; Hepatocyte; Metabolic Syndrome