Astrocyte Elevated Gene-1 (AEG-1) Regulates Lipid Homeostasis.

Abstract

Astrocyte elevated gene-1 (AEG-1), also known as MTDH (metadherin) or LYRIC, is an established oncogene. However, the physiological function of AEG-1 is not known. To address this question, we generated an AEG-1 knock-out mouse (AEG-1KO) and characterized it. Although AEG-1KO mice were viable and fertile, they were significantly leaner with prominently less body fat and lived significantly longer compared with wild type (WT). When fed a high fat and cholesterol diet (HFD), WT mice rapidly gained weight, whereas AEG-1KO mice did not gain weight at all. This phenotype of AEG-1KO mice is due to decreased fat absorption from the intestines, not because of decreased fat synthesis or increased fat consumption. AEG-1 interacts with retinoid X receptor (RXR) and inhibits RXR function. In enterocytes of AEG-1KO mice, we observed increased activity of RXR heterodimer partners, liver X receptor and peroxisome proliferator-activated receptor-α, key inhibitors of intestinal fat absorption. Inhibition of fat absorption in AEG-1KO mice was further augmented when fed an HFD providing ligands to liver X receptor and peroxisome proliferator-activated receptor-α. Our studies reveal a novel role of AEG-1 in regulating nuclear receptors controlling lipid metabolism. AEG-1 may significantly modulate the effects of HFD and thereby function as a unique determinant of obesity.

• Authors: Chadia L Robertson, Jyoti Srivastava, Ayesha Siddiq, Rachel Gredler, Luni Emdad, Devaraja Rajasekaran, Maaged Akiel, Xue-Ning Shen, Frank Corwin, Gobalakrishnan Sundaresan, Jamal Zweit, Colleen Croniger, Xiaoli Gao, Shobha Ghosh, Philip B Hylemon, Mark A Subler, Jolene J Windle, Paul B Fisher, Devanand Sarkar
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 29 Pg. 18227-18236 (Jul 17 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26070567 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Liver X Receptors
• Membrane Proteins
• Mtdh protein, mouse
• Orphan Nuclear Receptors
• Peroxisome Proliferator-Activated Receptors
• RNA-Binding Proteins
• Retinoid X Receptors

Topics

• Adipose Tissue (metabolism)
• Animals
• Homeostasis
• Intestinal Mucosa (metabolism)
• Lipid Metabolism
• Liver (metabolism)
• Liver X Receptors
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Obesity (genetics, metabolism)
• Orphan Nuclear Receptors (metabolism)
• Peroxisome Proliferator-Activated Receptors (metabolism)
• RNA-Binding Proteins
• Retinoid X Receptors (metabolism)
• Weight Gain