title: 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.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298; Departments of Biochemistry, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Chadia L
authors.initials: CL
authors.lastname: Robertson
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Srivastava
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Siddiq
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Rachel
authors.initials: R
authors.lastname: Gredler
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Devaraja
authors.initials: D
authors.lastname: Rajasekaran
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Maaged
authors.initials: M
authors.lastname: Akiel
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.affiliation: Departments of Radiology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Frank
authors.initials: F
authors.lastname: Corwin
authors.affiliation: Departments of Radiology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Gobalakrishnan
authors.initials: G
authors.lastname: Sundaresan
authors.affiliation: Departments of Radiology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Jamal
authors.initials: J
authors.lastname: Zweit
authors.affiliation: Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Colleen
authors.initials: C
authors.lastname: Croniger
authors.affiliation: Institutional Mass Spectrometry Laboratory, University of Texas Health Science Center, San Antonio, Texas 78229.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gao
authors.affiliation: Departments of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Shobha
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Departments of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Hylemon
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Subler
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298; Departments of VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Jolene J
authors.initials: JJ
authors.lastname: Windle
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298; Departments of VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298; VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298; Departments of VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298; VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia 23298. Electronic address: dsarkar@vcu.edu.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D016601:RNA-Binding Proteins; D047488:Retinoid X Receptors / Q000378:metabolism; D015430:Weight Gain
chemical_list: D000071518:Liver X Receptors; D008565:Membrane Proteins; C483038:Mtdh protein, mouse; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D016601:RNA-Binding Proteins; D047488:Retinoid X Receptors
keywords: gene regulation; intestine; lipid; liver metabolism; peroxisome proliferator-activated receptor (PPAR)