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Series GSE5538 Query DataSets for GSE5538
Status Public on Aug 16, 2006
Title lipin 1beta overexpression in mouse liver
Organism Mus musculus
Experiment type Expression profiling by array
Summary Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. Lipin 1 appears to be highly involved in the control of fatty acid metabolism. Lipin 1 is most often located in the nucleus, but other studies suggest that lipin also has effects in the cytoplasm. However, the molecular function of lipin 1 is unclear. To evaluate the effects of activation of the lipin 1 system in liver, lipin 1beta was overexpressed in mouse liver using an adenoviral vector. We found that lipin 1 overexpression increased the expression of many genes involved in mitochondrial fatty acid oxidation while repressing expression of genes involved in lipogenesis. We believe that lipin is a transcriptional coactivator of the peroxisome proliferator-activated receptor (PPAR) complex. However, the many molecular aspects of its function remain unclear.

Abstract of published manuscript follows:
Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway.Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence JC Jr, Kelly DP.
Center for Cardiovascular Research and Washington University School of Medicine, St. Louis, Missouri 63110; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.

Perturbations in hepatic lipid homeostasis are linked to the development of obesity-related steatohepatitis. Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. However, the molecular function of lipin 1 is unclear. Herein, we demonstrate that the expression of lipin 1 is induced by peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a transcriptional coactivator controlling several key hepatic metabolic pathways. Gain-of-function and loss-of-function strategies demonstrated that lipin selectively activates a subset of PGC-1alpha target pathways, including fatty acid oxidation and mitochondrial oxidative phosphorylation, while suppressing the lipogenic program and lowering circulating lipid levels. Lipin activates mitochondrial fatty acid oxidative metabolism by inducing expression of the nuclear receptor PPARalpha, a known PGC-1alpha target, and via direct physical interactions with PPARalpha and PGC-1alpha. These results identify lipin 1 as a selective physiological amplifier of the PGC-1alpha/PPARalpha-mediated control of hepatic lipid metabolism.

Keywords: response to lipin 1 activation
 
Overall design Adult male C57BL6 mice were injected with adenovirus driving expression of mouse lipin 1beta or green fluorescent protein (GFP). Mice were recovered and sacrificed 6 days after injection. Total RNA was isolated and analyzed using Affymetrix microarray.
 
Contributor(s) Finck BN, Kelly DP
Citation(s) 16950137
Submission date Aug 15, 2006
Last update date Jan 08, 2019
Contact name Brian Finck
Organization name Washington University
Street address 660 S. Euclid Ave
City St. Louis
State/province MO
ZIP/Postal code 63110
Country USA
 
Platforms (1)
GPL339 [MOE430A] Affymetrix Mouse Expression 430A Array
Samples (4)
GSM127088 GFP control rep 1
GSM127090 Ad-lipin rep 1
GSM127091 GFP control rep 2
Relations
BioProject PRJNA96025

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