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Hepatic Notch1 deletion predisposes to diabetes and steatosis via glucose-6-phosphatase and perilipin-5 upregulation.

  • Bernsmeier C Hepatology Laboratory, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
  • Dill MT Hepatology Laboratory, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
  • Provenzano A Dipartimento di Medicina Interna, University of Florence, Florence, Italy.
  • Makowska Z Hepatology Laboratory, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
  • Krol I Hepatology Laboratory, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
  • Muscogiuri G Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Rome, Italy.
  • Semela D Hepatology Laboratory, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
  • Tornillo L Institute of Pathology, University Hospital Basel, Basel, Switzerland.
  • Marra F Dipartimento di Medicina Interna, University of Florence, Florence, Italy.
  • Heim MH Hepatology Laboratory, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
  • Duong FH Hepatology Laboratory, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
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  • 2016-07-19
Published in:
  • Laboratory investigation; a journal of technical methods and pathology. - 2016
Animals
Diabetes Mellitus
Diet, High-Fat
Fatty Liver
Gene Expression Profiling
Genetic Predisposition to Disease
Glucose-6-Phosphatase
Hepatocytes
Humans
Immunoblotting
Liver
Mice, Inbred C57BL
Mice, Knockout
Non-alcoholic Fatty Liver Disease
Perilipin-1
Phosphorylation
Proto-Oncogene Proteins c-akt
Receptor, Notch1
Reverse Transcriptase Polymerase Chain Reaction
Up-Regulation
English Notch signaling pathways have recently been implicated in the pathogenesis of metabolic diseases. However, the role of hepatic Notch signaling in glucose and lipid metabolism remains unclear and needs further investigation as it might be a candidate therapeutic target in metabolic diseases such as nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD). We used hepatocyte-specific Notch1 knockout (KO) mice and liver biopsies from NASH and NAFLD patients to analyze the role of Notch1 in glucose and lipid metabolism. Hepatocyte-specific Notch1 KO mice were fed with a high fat diet (HFD) or a regular diet (RD). We assessed the metabolic phenotype, glucose and insulin tolerance tests, and liver histology. Hepatic mRNA expression was profiled by Affymetrix Mouse Gene arrays and validated by quantitative reverse transcription PCR (qPCR). Akt phosphorylation was visualized by immunoblotting. Gene expression was analyzed in liver biopsies from NASH, NAFLD, and control patients by qPCR. We found that Notch1 KO mice had elevated fasting glucose. Gene expression analysis showed an upregulation of glucose-6-phosphatase, involved in the final step of gluconeogenesis and glucose release from glycogenolysis, and perilipin-5, a regulator of hepatic lipid accumulation. When fed with an HFD KO mice developed overt diabetes and hepatic steatosis. Akt was highly phosphorylated in KO animals and the Foxo1 target gene expression was altered. Accordingly, a reduction in Notch1 and increase in glucose-6-phosphatase and perilipin-5 expression was observed in liver biopsies from NAFLD/NASH compared with controls. Notch1 is a regulator of hepatic glucose and lipid homeostasis. Hepatic impairment of Notch1 expression may be involved in the pathogenesis of human NAFLD/NASH.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/18197
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