Angiopoietin-like 4 (ANGPTL4, Fasting-induced Adipose Factor) Is a Direct Glucocorticoid Receptor Target and Participates in Glucocorticoid-regulated Triglyceride Metabolism
Open accessAbstract
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.
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Additional genes outside the classic lipolytic pathway have been implicated in the lipolytic effects of glucocorticoids, such as phosphodiesterase 3b, pigment epithelium derived factor, and angiopoietin-like 4.
“Additional genes outside the classic lipolytic pathway have been implicated in the lipolytic effects of glucocorticoids, such as phosphodiesterase 3b,4 pigment epithelium derived factor24 and angiopoietin‐like 4;25”
From Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct (2017) · cites this paper as [25]
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- Authors
- Koliwad, S. K., Kuo, T., Shipp, L. E., Gray, N. E., Backhed, F., So, A. Y.-L., Farese, R. V., & Wang, J.-C.
- Affiliations
- Gladstone Institutes (US)
- University of California, Berkeley (US)
- Corresponding author
- Wang, Jen-Chywan
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 284
- Issue
- 38
- Pages
- 25593-25601
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2757961
- OpenAlex
- W2093583036
- Cited by
- 164
- References
- 6
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 6 · 2021: 10 · 2020: 10 · 2019: 10 · 2018: 10 · 2017: 18 · 2016: 6 · 2015: 10 · 2014: 21 · 2013: 9 · 2012: 8
- FWCI
- 6.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- A.P. Giannini Foundation
- Giannini Foundation of Agricultural Economics
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- ANGPTL4, FIAF, glucocorticoid receptor, glucocorticoid response element, dexamethasone, triglyceride metabolism, lipoprotein lipase inhibition, hepatic steatosis, hypertriglyceridemia, histone H4 acetylation, transcriptional regulation
- MeSH terms
- Angiopoietin-Like Protein 4, Adipose Tissue, Animals, Dexamethasone, Fatty Liver, Glucocorticoids, Humans, Lipoprotein Lipase, Liver, Receptors, Glucocorticoid, Transcription, Genetic, Triglycerides, Hypertriglyceridemia, Mice, Knockout, Response Elements, Hepatocytes, Angiopoietins, Cell Line, Tumor, Mice, Rats, Adipose Tissue, White
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