title: Angiopoietin-like 4 (ANGPTL4, fasting-induced adipose factor) is a direct glucocorticoid receptor target and participates in glucocorticoid-regulated triglyceride metabolism.
abstract: Glucocorticoids are important regulators of lipid homeostasis, and chronically elevated glucocorticoid levels induce hypertriglyceridemia, hepatic steatosis, and visceral obesity. The occupied glucocorticoid receptor (GR) is a transcription factor. However, those genes regulating lipid metabolism under GR control are not fully known. Angiopoietin-like 4 (ANGPTL4, fasting-induced adipose factor), a protein inhibitor of lipoprotein lipase, is synthesized and secreted during fasting, when circulating glucocorticoid levels are physiologically increased. We therefore tested whether the ANGPTL4 gene (Angptl4) is transcriptionally controlled by GR. We show that treatment with the synthetic glucocorticoid dexamethasone increased Angptl4 mRNA levels in primary hepatocytes and adipocytes (2-3-fold) and in the livers and white adipose tissue of mice (approximately 4-fold). We tested the mechanism of this increase in H4IIE hepatoma cells and found that dexamethasone treatment increased the transcriptional rate of Angptl4. Using bioinformatics and chromatin immunoprecipitation, we identified a GR binding site within the rat Angptl4 sequence. A reporter plasmid containing this site was markedly activated by dexamethasone, indicative of a functional glucocorticoid response element. Dexamethasone treatment also increased histone H4 acetylation and DNase I accessibility in genomic regions near this site, further supporting that it is a glucocorticoid response element. Glucocorticoids promote the flux of triglycerides from white adipose tissue to liver. We found that mice lacking ANGPTL4 (Angptl4(-/-)) had reductions in dexamethasone-induced hypertriglyceridemia and hepatic steatosis, suggesting that ANGPTL4 is required for this flux. Overall, we establish that ANGPTL4 is a direct GR target that participates in glucocorticoid-regulated triglyceride metabolism.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94143, USA.
authors.forename: Suneil K
authors.initials: SK
authors.lastname: Koliwad
authors.forename: Taiyi
authors.initials: T
authors.lastname: Kuo
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Shipp
authors.forename: Nora E
authors.initials: NE
authors.lastname: Gray
authors.forename: Fredrik
authors.initials: F
authors.lastname: Backhed
authors.forename: Alex Yick-Lun
authors.initials: AY
authors.lastname: So
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.forename: Jen-Chywan
authors.initials: JC
authors.lastname: Wang
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D052436:Adipose Tissue, White; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D005938:Glucocorticoids / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015228:Hypertriglyceridemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism*
chemical_list: C474772:ANGPTL4 protein, human; C528241:ANGPTL4 protein, rat; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D014280:Triglycerides; D003907:Dexamethasone; D008071:Lipoprotein Lipase