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Lipodystrophy Due to Adipose Tissue–Specific Insulin Receptor Knockout Results in Progressive NAFLD

Ectopic lipid accumulation in the liver is an almost universal feature of human and rodent models of generalized lipodystrophy and is also a common feature of type 2 diabetes, obesity, and metabolic syndrome. Here we explore the progression of fatty liver disease using a mouse model of lipodystrophy...

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Autores principales: Softic, Samir, Boucher, Jeremie, Solheim, Marie H., Fujisaka, Shiho, Haering, Max-Felix, Homan, Erica P., Winnay, Jonathon, Perez-Atayde, Antonio R., Kahn, C. Ronald
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955986/
https://www.ncbi.nlm.nih.gov/pubmed/27207510
http://dx.doi.org/10.2337/db16-0213
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author Softic, Samir
Boucher, Jeremie
Solheim, Marie H.
Fujisaka, Shiho
Haering, Max-Felix
Homan, Erica P.
Winnay, Jonathon
Perez-Atayde, Antonio R.
Kahn, C. Ronald
author_facet Softic, Samir
Boucher, Jeremie
Solheim, Marie H.
Fujisaka, Shiho
Haering, Max-Felix
Homan, Erica P.
Winnay, Jonathon
Perez-Atayde, Antonio R.
Kahn, C. Ronald
author_sort Softic, Samir
collection PubMed
description Ectopic lipid accumulation in the liver is an almost universal feature of human and rodent models of generalized lipodystrophy and is also a common feature of type 2 diabetes, obesity, and metabolic syndrome. Here we explore the progression of fatty liver disease using a mouse model of lipodystrophy created by a fat-specific knockout of the insulin receptor (F-IRKO) or both IR and insulin-like growth factor 1 receptor (F-IR/IGFRKO). These mice develop severe lipodystrophy, diabetes, hyperlipidemia, and fatty liver disease within the first weeks of life. By 12 weeks of age, liver demonstrated increased reactive oxygen species, lipid peroxidation, histological evidence of balloon degeneration, and elevated serum alanine aminotransferase and aspartate aminotransferase levels. In these lipodystrophic mice, stored liver lipids can be used for energy production, as indicated by a marked decrease in liver weight with fasting and increased liver fibroblast growth factor 21 expression and intact ketogenesis. By 52 weeks of age, liver accounted for 25% of body weight and showed continued balloon degeneration in addition to inflammation, fibrosis, and highly dysplastic liver nodules. Progression of liver disease was associated with improvement in blood glucose levels, with evidence of altered expression of gluconeogenic and glycolytic enzymes. However, these mice were able to mobilize stored glycogen in response to glucagon. Feeding F-IRKO and F-IR/IGFRKO mice a high-fat diet for 12 weeks accelerated the liver injury and normalization of blood glucose levels. Thus, severe fatty liver disease develops early in lipodystrophic mice and progresses to advanced nonalcoholic steatohepatitis with highly dysplastic liver nodules. The liver injury is propagated by lipotoxicity and is associated with improved blood glucose levels.
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spelling pubmed-49559862017-08-01 Lipodystrophy Due to Adipose Tissue–Specific Insulin Receptor Knockout Results in Progressive NAFLD Softic, Samir Boucher, Jeremie Solheim, Marie H. Fujisaka, Shiho Haering, Max-Felix Homan, Erica P. Winnay, Jonathon Perez-Atayde, Antonio R. Kahn, C. Ronald Diabetes Metabolism Ectopic lipid accumulation in the liver is an almost universal feature of human and rodent models of generalized lipodystrophy and is also a common feature of type 2 diabetes, obesity, and metabolic syndrome. Here we explore the progression of fatty liver disease using a mouse model of lipodystrophy created by a fat-specific knockout of the insulin receptor (F-IRKO) or both IR and insulin-like growth factor 1 receptor (F-IR/IGFRKO). These mice develop severe lipodystrophy, diabetes, hyperlipidemia, and fatty liver disease within the first weeks of life. By 12 weeks of age, liver demonstrated increased reactive oxygen species, lipid peroxidation, histological evidence of balloon degeneration, and elevated serum alanine aminotransferase and aspartate aminotransferase levels. In these lipodystrophic mice, stored liver lipids can be used for energy production, as indicated by a marked decrease in liver weight with fasting and increased liver fibroblast growth factor 21 expression and intact ketogenesis. By 52 weeks of age, liver accounted for 25% of body weight and showed continued balloon degeneration in addition to inflammation, fibrosis, and highly dysplastic liver nodules. Progression of liver disease was associated with improvement in blood glucose levels, with evidence of altered expression of gluconeogenic and glycolytic enzymes. However, these mice were able to mobilize stored glycogen in response to glucagon. Feeding F-IRKO and F-IR/IGFRKO mice a high-fat diet for 12 weeks accelerated the liver injury and normalization of blood glucose levels. Thus, severe fatty liver disease develops early in lipodystrophic mice and progresses to advanced nonalcoholic steatohepatitis with highly dysplastic liver nodules. The liver injury is propagated by lipotoxicity and is associated with improved blood glucose levels. American Diabetes Association 2016-08 2016-05-10 /pmc/articles/PMC4955986/ /pubmed/27207510 http://dx.doi.org/10.2337/db16-0213 Text en © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Metabolism
Softic, Samir
Boucher, Jeremie
Solheim, Marie H.
Fujisaka, Shiho
Haering, Max-Felix
Homan, Erica P.
Winnay, Jonathon
Perez-Atayde, Antonio R.
Kahn, C. Ronald
Lipodystrophy Due to Adipose Tissue–Specific Insulin Receptor Knockout Results in Progressive NAFLD
title Lipodystrophy Due to Adipose Tissue–Specific Insulin Receptor Knockout Results in Progressive NAFLD
title_full Lipodystrophy Due to Adipose Tissue–Specific Insulin Receptor Knockout Results in Progressive NAFLD
title_fullStr Lipodystrophy Due to Adipose Tissue–Specific Insulin Receptor Knockout Results in Progressive NAFLD
title_full_unstemmed Lipodystrophy Due to Adipose Tissue–Specific Insulin Receptor Knockout Results in Progressive NAFLD
title_short Lipodystrophy Due to Adipose Tissue–Specific Insulin Receptor Knockout Results in Progressive NAFLD
title_sort lipodystrophy due to adipose tissue–specific insulin receptor knockout results in progressive nafld
topic Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955986/
https://www.ncbi.nlm.nih.gov/pubmed/27207510
http://dx.doi.org/10.2337/db16-0213
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