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EMBO Mol Med. 2016 Jun 1;8(6):654-69. doi: 10.15252/emmm.201505801. Print 2016 Jun.

Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health.

Author information

1
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany.
2
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Neuherberg, Germany.
3
Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
4
Department of Medicine, University of Leipzig, Leipzig, Germany.
5
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Neuherberg, Germany stephan.herzig@helmholtz-muenchen.de a.rose@dkfz.de.
6
Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany stephan.herzig@helmholtz-muenchen.de a.rose@dkfz.de.

Abstract

Recent studies have demonstrated that repeated short-term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered "growth arrest and DNA damage-inducible" GADD45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre-diabetes and type 2 diabetes, in both mice and humans. Using whole-body knockout mice as well as liver/hepatocyte-specific gain- and loss-of-function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity-driven hyperglycaemia. In summary, fasting stress-induced GADD45β represents a liver-specific molecular event promoting adaptive metabolic function.

KEYWORDS:

FABP1; hormesis; lipid; metabolism; stress

PMID:
27137487
PMCID:
PMC4888855
DOI:
10.15252/emmm.201505801
[Indexed for MEDLINE]
Free PMC Article

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