Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids.
OBJECTIVE
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.
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Doris
D
Jaeger
Division of Endocrinology, Diabetes, and Metabolism, University of Pittsburgh, PA 15261, USA.
Gabriele
G
Schoiswohl
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Peter
P
Hofer
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Renate
R
Schreiber
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Martina
M
Schweiger
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Thomas O
TO
Eichmann
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Nina M
NM
Pollak
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Nadja
N
Poecher
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Gernot F
GF
Grabner
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Kathrin A
KA
Zierler
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Sandra
S
Eder
ZMF, Center for Medical Research, Medical University of Graz, A-8010 Graz, Austria.
Dagmar
D
Kolb
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Franz P W
FP
Radner
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Karina
K
Preiss-Landl
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Achim
A
Lass
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Rudolf
R
Zechner
Division of Endocrinology, Diabetes, and Metabolism, University of Pittsburgh, PA 15261, USA.
Erin E
EE
Kershaw
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria. Electronic address: guenter.haemmerle@uni-graz.at.
Guenter
G
Haemmerle
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005215:Fasting / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D005812:Genes, Switch; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
D005227:Fatty Acids; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D012313:RNA
ATGL; CGI-58; CREBH; Fibroblast growth factor 21; G0/G1 switch gene 2; Hepatic steatosis; Lipolysis; Obesity; PPARα