Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis
Background & Aims: Increasing evidence highlights dietary fructose as a major driver of non-alcoholic fatty liver disease (NAFLD) pathogenesis, the majority of which is cleared on first pass through the hepatic circulation by enzymatic phosphorylation to fructose-1-phosphate via the ketohexo...
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Format: | Article |
Language: | English |
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Elsevier
2021-04-01
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Series: | JHEP Reports |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555920301518 |
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doaj-4340ddc01197436fbd613f61ff255144 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Emma L. Shepherd Raquel Saborano Ellie Northall Kae Matsuda Hitomi Ogino Hiroaki Yashiro Jason Pickens Ryan E. Feaver Banumathi K. Cole Stephen A. Hoang Mark J. Lawson Matthew Olson Robert A. Figler John E. Reardon Nobuhiro Nishigaki Brian R. Wamhoff Ulrich L. Günther Gideon Hirschfield Derek M. Erion Patricia F. Lalor |
spellingShingle |
Emma L. Shepherd Raquel Saborano Ellie Northall Kae Matsuda Hitomi Ogino Hiroaki Yashiro Jason Pickens Ryan E. Feaver Banumathi K. Cole Stephen A. Hoang Mark J. Lawson Matthew Olson Robert A. Figler John E. Reardon Nobuhiro Nishigaki Brian R. Wamhoff Ulrich L. Günther Gideon Hirschfield Derek M. Erion Patricia F. Lalor Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis JHEP Reports NAFLD Metabolism Fructose Fibrosis Treatment NASH |
author_facet |
Emma L. Shepherd Raquel Saborano Ellie Northall Kae Matsuda Hitomi Ogino Hiroaki Yashiro Jason Pickens Ryan E. Feaver Banumathi K. Cole Stephen A. Hoang Mark J. Lawson Matthew Olson Robert A. Figler John E. Reardon Nobuhiro Nishigaki Brian R. Wamhoff Ulrich L. Günther Gideon Hirschfield Derek M. Erion Patricia F. Lalor |
author_sort |
Emma L. Shepherd |
title |
Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis |
title_short |
Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis |
title_full |
Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis |
title_fullStr |
Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis |
title_full_unstemmed |
Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis |
title_sort |
ketohexokinase inhibition improves nash by reducing fructose-induced steatosis and fibrogenesis |
publisher |
Elsevier |
series |
JHEP Reports |
issn |
2589-5559 |
publishDate |
2021-04-01 |
description |
Background & Aims: Increasing evidence highlights dietary fructose as a major driver of non-alcoholic fatty liver disease (NAFLD) pathogenesis, the majority of which is cleared on first pass through the hepatic circulation by enzymatic phosphorylation to fructose-1-phosphate via the ketohexokinase (KHK) enzyme. Without a current approved therapy, disease management emphasises lifestyle interventions, but few patients adhere to such strategies. New targeted therapies are urgently required. Methods: We have used a unique combination of human liver specimens, a murine dietary model of NAFLD and human multicellular co-culture systems to understand the hepatocellular consequences of fructose administration. We have also performed a detailed nuclear magnetic resonance-based metabolic tracing of the fate of isotopically labelled fructose upon administration to the human liver. Results: Expression of KHK isoforms is found in multiple human hepatic cell types, although hepatocyte expression predominates. KHK knockout mice show a reduction in serum transaminase, reduced steatosis and altered fibrogenic response on an Amylin diet. Human co-cultures exposed to fructose exhibit steatosis and activation of lipogenic and fibrogenic gene expression, which were reduced by pharmacological inhibition of KHK activity. Analysis of human livers exposed to 13C-labelled fructose confirmed that steatosis, and associated effects, resulted from the accumulation of lipogenic precursors (such as glycerol) and enhanced glycolytic activity. All of these were dose-dependently reduced by administration of a KHK inhibitor. Conclusions: We have provided preclinical evidence using human livers to support the use of KHK inhibition to improve steatosis, fibrosis, and inflammation in the context of NAFLD. Lay summary: We have used a mouse model, human cells, and liver tissue to test how exposure to fructose can cause the liver to store excess fat and become damaged and scarred. We have then inhibited a key enzyme within the liver that is responsible for fructose metabolism. Our findings show that inhibition of fructose metabolism reduces liver injury and fibrosis in mouse and human livers and thus this may represent a potential route for treating patients with fatty liver disease in the future. |
topic |
NAFLD Metabolism Fructose Fibrosis Treatment NASH |
url |
http://www.sciencedirect.com/science/article/pii/S2589555920301518 |
work_keys_str_mv |
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doaj-4340ddc01197436fbd613f61ff2551442021-03-25T04:31:11ZengElsevierJHEP Reports2589-55592021-04-0132100217Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesisEmma L. Shepherd0Raquel Saborano1Ellie Northall2Kae Matsuda3Hitomi Ogino4Hiroaki Yashiro5Jason Pickens6Ryan E. Feaver7Banumathi K. Cole8Stephen A. Hoang9Mark J. Lawson10Matthew Olson11Robert A. Figler12John E. Reardon13Nobuhiro Nishigaki14Brian R. Wamhoff15Ulrich L. Günther16Gideon Hirschfield17Derek M. Erion18Patricia F. Lalor19Centre for Liver and Gastroenterology Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UKCentre for Liver and Gastroenterology Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UKCentre for Liver and Gastroenterology Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UKTakeda Pharmaceuticals Cardiovascular and Metabolic Drug Discovery Unit, Kanagawa, JapanTakeda Pharmaceuticals Cardiovascular and Metabolic Drug Discovery Unit, Kanagawa, JapanTakeda Pharmaceuticals Gastroenterology Drug Discovery Unit, Cambridge, MA, USATakeda Pharmaceuticals Gastroenterology Drug Discovery Unit, Cambridge, MA, USAHemoShear Therapeutics, Charlottesville, VA, USAHemoShear Therapeutics, Charlottesville, VA, USAHemoShear Therapeutics, Charlottesville, VA, USAHemoShear Therapeutics, Charlottesville, VA, USAHemoShear Therapeutics, Charlottesville, VA, USAHemoShear Therapeutics, Charlottesville, VA, USAHemoShear Therapeutics, Charlottesville, VA, USATakeda Pharmaceuticals Cardiovascular and Metabolic Drug Discovery Unit, Kanagawa, JapanHemoShear Therapeutics, Charlottesville, VA, USAInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UKCentre for Liver and Gastroenterology Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Toronto Centre for Liver Disease, University of Toronto, Toronto General Hospital, Toronto, CanadaTakeda Pharmaceuticals Gastroenterology Drug Discovery Unit, Cambridge, MA, USACentre for Liver and Gastroenterology Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Corresponding author. Address: Centre for Liver and Gastroenterology Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK. Tel.: +44 121 4146967.Background & Aims: Increasing evidence highlights dietary fructose as a major driver of non-alcoholic fatty liver disease (NAFLD) pathogenesis, the majority of which is cleared on first pass through the hepatic circulation by enzymatic phosphorylation to fructose-1-phosphate via the ketohexokinase (KHK) enzyme. Without a current approved therapy, disease management emphasises lifestyle interventions, but few patients adhere to such strategies. New targeted therapies are urgently required. Methods: We have used a unique combination of human liver specimens, a murine dietary model of NAFLD and human multicellular co-culture systems to understand the hepatocellular consequences of fructose administration. We have also performed a detailed nuclear magnetic resonance-based metabolic tracing of the fate of isotopically labelled fructose upon administration to the human liver. Results: Expression of KHK isoforms is found in multiple human hepatic cell types, although hepatocyte expression predominates. KHK knockout mice show a reduction in serum transaminase, reduced steatosis and altered fibrogenic response on an Amylin diet. Human co-cultures exposed to fructose exhibit steatosis and activation of lipogenic and fibrogenic gene expression, which were reduced by pharmacological inhibition of KHK activity. Analysis of human livers exposed to 13C-labelled fructose confirmed that steatosis, and associated effects, resulted from the accumulation of lipogenic precursors (such as glycerol) and enhanced glycolytic activity. All of these were dose-dependently reduced by administration of a KHK inhibitor. Conclusions: We have provided preclinical evidence using human livers to support the use of KHK inhibition to improve steatosis, fibrosis, and inflammation in the context of NAFLD. Lay summary: We have used a mouse model, human cells, and liver tissue to test how exposure to fructose can cause the liver to store excess fat and become damaged and scarred. We have then inhibited a key enzyme within the liver that is responsible for fructose metabolism. Our findings show that inhibition of fructose metabolism reduces liver injury and fibrosis in mouse and human livers and thus this may represent a potential route for treating patients with fatty liver disease in the future.http://www.sciencedirect.com/science/article/pii/S2589555920301518NAFLDMetabolismFructoseFibrosisTreatmentNASH |