Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids

D Jaeger; G Schoiswohl; P Hofer; R Schreiber; M Schweiger; T O Eichmann; Nina M Pollak; N Poecher; G F Grabner; K A Zierler; S Eder; D Kolb; F P W Radner; K Preiss-Landl; A Lass; R Zechner; E E Kershaw; G Haemmerle

doi:10.1016/j.jhep.2015.02.035

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Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids

Journal article

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Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids

D Jaeger, G Schoiswohl, P Hofer, R Schreiber, M Schweiger, T O Eichmann, Nina M Pollak, N Poecher, G F Grabner, K A Zierler, …

Journal of Hepatology, Vol.63(2), pp.437-445

2015

DOI: https://doi.org/10.1016/j.jhep.2015.02.035

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Abstract

hepatic steatosis

G0/G1 switch gene 2

fibroblast growth factor 21

CGI-58

ATGL

lipolysis

PPARa

CREBH

obesity

Background & Aims: Adipose tissue (AT)-derived fatty acids (FAs) are utilized for hepatic triacylglycerol (TG) generation upon fasting. However, their potential impact as signaling molecules is not established. Herein we examined the role of exogenous AT-derived FAs in the regulation of hepatic gene expression by investigating mice with a defect in AT-derived FA supply to the liver. Methods: Plasma FA levels, tissue TG hydrolytic activities and lipid content were determined in mice lacking the lipase co-activator comparative gene identification-58 (CGI-58) selectively in AT (CGI-58-ATko) applying standard protocols. Hepatic expression of lipases, FA oxidative genes, transcription factors, ER stress markers, hormones and cytokines were determined by qRT-PCR, Western blotting and ELISA. Results: Impaired AT-derived FA supply upon fasting of CGI-58-ATko mice causes a marked defect in liver PPARα-signaling and nuclear CREBH translocation. This severely reduced the expression of respective target genes such as the ATGL inhibitor G0/G1 switch gene-2 (G0S2) and the endocrine metabolic regulator FGF21. These changes could be reversed by lipid administration and raising plasma FA levels. Impaired AT-lipolysis failed to induce hepatic G0S2 expression in fasted CGI-58-ATko mice leading to enhanced ATGL-mediated TG-breakdown strongly reducing hepatic TG deposition. On high fat diet, impaired AT-lipolysis counteracts hepatic TG accumulation and liver stress linked to improved systemic insulin sensitivity. Conclusions: AT-derived FAs are a critical regulator of hepatic fasting gene expression required for the induction of G0S2-expression in the liver to control hepatic TG-breakdown. Interfering with AT-lipolysis or hepatic G0S2 expression represents an effective strategy for the treatment of hepatic steatosis. © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Title: Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids
Authors: D Jaeger (Author) - University of Graz, Austria
G Schoiswohl (Author) - University of Pittsburgh, United States
P Hofer (Author) - University of Graz, Austria
R Schreiber (Author) - University of Graz, Austria
M Schweiger (Author) - University of Graz, Austria
T O Eichmann (Author) - University of Graz, Austria
Nina M Pollak (Author) - University of Graz, Austria
N Poecher (Author) - University of Graz, Austria
G F Grabner (Author) - University of Graz, Austria
K A Zierler (Author) - University of Graz, Austria
S Eder (Author) - University of Graz, Austria
D Kolb (Author) - Medical University of Graz, Austria
F P W Radner (Author) - University of Graz, Austria
K Preiss-Landl (Author) - University of Graz, Austria
A Lass (Author) - University of Graz, Austria
R Zechner (Author) - University of Graz, Austria
E E Kershaw (Author) - University of Pittsburgh, United States
G Haemmerle (Author) - University of Graz, Austria
Publication details: Journal of Hepatology, Vol.63(2), pp.437-445
Publisher: Elsevier BV
Date published: 2015
DOI: 10.1016/j.jhep.2015.02.035
ISSN: 0168-8278
Organisation Unit: School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99451281802621
Output Type: Journal article

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