title: Liver X receptorαmediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression.
abstract: Liver X receptors (LXRs) are transcription factors essential for cholesterol homeostasis and lipogenesis. LXRα has been implicated in regulating hepatic triglyceride (TG) accumulation upon both influx of adipose-derived fatty acids (FAs) during fasting and stimulation of de novo FA synthesis by chemical agonism of LXR. However, whether or not a convergent mechanism is employed to drive deposition of FAs from these 2 different sources in TGs is undetermined. Here, we report that the G0/G1 Switch Gene 2 (G0S2), a selective inhibitor of intracellular TG hydrolysis/lipolysis, is a direct target gene of LXRα. Transcriptional activation is conferred by LXRα binding to a direct repeat 4 (DR4) motif in the G0S2 promoter. While LXRα-/-mice exhibited decreased hepatic G0S2 expression, adenoviral expression of G0S2 was sufficient to restore fasting-induced TG storage and glycogen depletion in the liver of these mice. In response to LXR agonist T0901317, G0S2 ablation prevented hepatic steatosis and hypertriglyceridemia without affecting the beneficial effects on HDL. Thus, the LXRα-G0S2 axis plays a distinct role in regulating hepatic TG during both fasting and pharmacological activation of LXR.
authors.affiliation: Department of Biochemistry and Molecular Biology.|HEALth Program, Mayo Clinic in Arizona, Scottsdale, Arizona, USA.|Mayo Graduate School, Rochester, Minnesota, USA.
authors.forename: Bradlee L
authors.initials: BL
authors.lastname: Heckmann
authors.affiliation: Department of Biochemistry and Molecular Biology.|HEALth Program, Mayo Clinic in Arizona, Scottsdale, Arizona, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology.|HEALth Program, Mayo Clinic in Arizona, Scottsdale, Arizona, USA.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Saarinen
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schoiswohl
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Kershaw
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: Department of Biochemistry and Molecular Biology.|HEALth Program, Mayo Clinic in Arizona, Scottsdale, Arizona, USA.|Division of Endocrinology, Mayo Clinic in Arizona, Scottsdale, Arizona, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D029681:Arabidopsis Proteins / Q000096:biosynthesis / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000187:drug effects / Q000378:metabolism; D005215:Fasting / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D006868:Hydrolysis; D015228:Hypertriglyceridemia / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D000071518:Liver X Receptors / Q000819:agonists / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D012091:Repetitive Sequences, Nucleic Acid; D013449:Sulfonamides / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D029681:Arabidopsis Proteins; D018797:Cell Cycle Proteins; D008076:Cholesterol, HDL; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D013449:Sulfonamides; D014280:Triglycerides; C411293:ERA1 protein, Arabidopsis; C508072:G0S2 protein, mouse; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides