Elsevier

Journal of Hepatology

Volume 63, Issue 2, August 2015, Pages 437-445
Journal of Hepatology

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

https://doi.org/10.1016/j.jhep.2015.02.035Get rights and content
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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.

Abbreviations

AT
Adipose tissue
FA(s)
fatty acid(s)
TG
triacylglycerol
CGI-58
comparative gene identification-58
ATGL
Adipose triglyceride lipase
CGI-58-ATko
AT-selective ablation of CGI-58
ATGL-ATko
AT-specific deficiency of ATGL
LD
lipid droplet
NAFLD
nonalcoholic fatty liver disease
NLSD
Neutral lipid storage disease
PPARα
peroxisome proliferator-activated receptor alpha
CREBH
cAMP-responsive element binding protein, hepatocyte specific
G0S2
G0/G1 Switch Gene 2
FGF21
fibroblast growth factor 21
PGC-1α
PPARgamma co-activator-1alpha
HNF4α
hepatocyte nuclear factor 4alpha
PEPCK
Phosphoenolpyruvate carboxykinase
G6Pase
Glucose-6-phosphatase
ER
endoplasmic reticulum

Keywords

Hepatic steatosis
G0/G1 switch gene 2
Fibroblast growth factor 21
CGI-58
ATGL
Lipolysis
PPARα
CREBH
Obesity

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