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| Status |
Public on Jan 25, 2019 |
| Title |
Engineered FGF19 promotes HDL biogenesis and transhepatic cholesterol efflux to prevent atherosclerosis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Cholesterol is an essential cell membrane component and precursor in metabolic pathways. Control of cholesterol levels is essential to human health. The endocrine hormone FGF19 potently inhibits CYP7A1, which controls a key step in cholesterol catabolism. However, the molecular mechanisms that integrate FGF19 with other cholesterol metabolic pathways are incompletely understood. Here we show that FGF19 and analogue promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating liver X receptor signaling without inducing hepatic steatosis. We further identify ATP-binding cassette transporter A1 and FGFR4 as mediators of this effect. In dyslipidemic Apoe-/- mice fed a Western diet, treatment with FGF19 analogue dramatically reduced atherosclerotic lesion area in aortas. In healthy human volunteers, FGF19 analogue caused a placebo-adjusted increase in HDL cholesterol levels of 26% in seven days. These findings outline a regulatory role for FGF19 in cholesterol metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis.
We used microarrays to detail the global programme of gene expression affected by FGF19 treatment in mice.
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| Overall design |
Mouse livers were selected for RNA extraction and hybridization on Affymetrix microarrays. RNA was isolated from the livers of db/db mice 2 weeks after administration of AAV-FGF19 or a control virus. RNA integrity and purity were confirmed by Bioanalyzer with RIN numbers > 8.0. Affymetrix mouse gene 1.0 ST whole-transcript arrays were used for hybridization.
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| Contributor(s) |
Zhou M, Learned M, Rossi SJ, Tian H, DePaoli AM, Ling L |
| Citation(s) |
30679232 |
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doi:10.1194/jlr.M089961
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| Submission date |
Jul 30, 2018 |
| Last update date |
Mar 12, 2019 |
| Contact name |
Lei Ling |
| Organization name |
NGM Biopharmaceuticals
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| Street address |
333 Oyster Point Blvd
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| City |
South San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94080 |
| Country |
USA |
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| Platforms (1) |
| GPL6246 |
[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA483446 |
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