An ANGPTL4-ceramide-protein kinase Cζ axis mediates chronic glucocorticoid exposure-induced hepatic steatosis and hypertriglyceridemia in mice
© 2019 Chen et al..
Chronic or excess glucocorticoid exposure causes lipid disorders such as hypertriglyceridemia and hepatic steatosis. Angptl4 (angiopoietin-like 4), a primary target gene of the glucocorticoid receptor in hepatocytes and adipocytes, is required for hypertriglyceridemia and hepatic steatosis induced by the synthetic glucocorticoid dexamethasone. Angptl4 has also been shown to be required for dexamethasone-induced hepatic ceramide production. Here, we further examined the role of ceramide-mediated signaling in hepatic dyslipidemia caused by chronic glucocorticoid exposure. Using a stable isotope-labeling technique, we found that dexamethasone treatment induced the rate of hepatic de novo lipogenesis and triglyceride synthesis. These dexamethasone responses were compromised in Angptl4-null mice (Angptl4-/-). Treating mice with myriocin, an inhibitor of the rate-controlling enzyme of de novo ceramide synthesis, serine palmitoyltransferase long-chain base subunit 1 (SPTLC1)/SPTLC2, decreased dexamethasone-induced plasma and liver triglyceride levels in WT but not Angptl4-/- mice. We noted similar results in mice infected with adeno-associated virus-expressing small hairpin RNAs targeting Sptlc2. Protein phosphatase 2 phosphatase activator (PP2A) and protein kinase Cζ (PKCζ) are two known downstream effectors of ceramides. We found here that mice treated with an inhibitor of PKCζ, 2-acetyl-1,3-cyclopentanedione (ACPD), had lower levels of dexamethasone-induced triglyceride accumulation in plasma and liver. However, small hairpin RNA-mediated targeting of the catalytic PP2A subunit (Ppp2ca) had no effect on dexamethasone responses on plasma and liver triglyceride levels. Overall, our results indicate that chronic dexamethasone treatment induces an ANGPTL4-ceramide-PKCζ axis that activates hepatic de novo lipogenesis and triglyceride synthesis, resulting in lipid disorders.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:294 |
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| Enthalten in: |
The Journal of biological chemistry - 294(2019), 23 vom: 07. Juni, Seite 9213-9224 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Tzu-Chieh [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.02.2020 Date Revised 04.12.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1074/jbc.RA118.006259 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM296731676 |
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| 100 | 1 | |a Chen, Tzu-Chieh |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a An ANGPTL4-ceramide-protein kinase Cζ axis mediates chronic glucocorticoid exposure-induced hepatic steatosis and hypertriglyceridemia in mice |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.02.2020 | ||
| 500 | |a Date Revised 04.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2019 Chen et al. | ||
| 520 | |a Chronic or excess glucocorticoid exposure causes lipid disorders such as hypertriglyceridemia and hepatic steatosis. Angptl4 (angiopoietin-like 4), a primary target gene of the glucocorticoid receptor in hepatocytes and adipocytes, is required for hypertriglyceridemia and hepatic steatosis induced by the synthetic glucocorticoid dexamethasone. Angptl4 has also been shown to be required for dexamethasone-induced hepatic ceramide production. Here, we further examined the role of ceramide-mediated signaling in hepatic dyslipidemia caused by chronic glucocorticoid exposure. Using a stable isotope-labeling technique, we found that dexamethasone treatment induced the rate of hepatic de novo lipogenesis and triglyceride synthesis. These dexamethasone responses were compromised in Angptl4-null mice (Angptl4-/-). Treating mice with myriocin, an inhibitor of the rate-controlling enzyme of de novo ceramide synthesis, serine palmitoyltransferase long-chain base subunit 1 (SPTLC1)/SPTLC2, decreased dexamethasone-induced plasma and liver triglyceride levels in WT but not Angptl4-/- mice. We noted similar results in mice infected with adeno-associated virus-expressing small hairpin RNAs targeting Sptlc2. Protein phosphatase 2 phosphatase activator (PP2A) and protein kinase Cζ (PKCζ) are two known downstream effectors of ceramides. We found here that mice treated with an inhibitor of PKCζ, 2-acetyl-1,3-cyclopentanedione (ACPD), had lower levels of dexamethasone-induced triglyceride accumulation in plasma and liver. However, small hairpin RNA-mediated targeting of the catalytic PP2A subunit (Ppp2ca) had no effect on dexamethasone responses on plasma and liver triglyceride levels. Overall, our results indicate that chronic dexamethasone treatment induces an ANGPTL4-ceramide-PKCζ axis that activates hepatic de novo lipogenesis and triglyceride synthesis, resulting in lipid disorders | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a ceramide | |
| 650 | 4 | |a dyslipidemia | |
| 650 | 4 | |a fatty liver disease | |
| 650 | 4 | |a glucocorticoid | |
| 650 | 4 | |a hepatosteatosis | |
| 650 | 4 | |a hypertriglyceridemia | |
| 650 | 4 | |a lipogenesis | |
| 650 | 4 | |a liver | |
| 650 | 4 | |a metabolic syndrome | |
| 650 | 4 | |a steroid hormone | |
| 650 | 4 | |a triglyceride | |
| 650 | 7 | |a Angiopoietin-Like Protein 4 |2 NLM | |
| 650 | 7 | |a Angptl4 protein, mouse |2 NLM | |
| 650 | 7 | |a Basic Helix-Loop-Helix Leucine Zipper Transcription Factors |2 NLM | |
| 650 | 7 | |a Ceramides |2 NLM | |
| 650 | 7 | |a Fatty Acids, Monounsaturated |2 NLM | |
| 650 | 7 | |a Mlxipl protein, mouse |2 NLM | |
| 650 | 7 | |a RNA, Small Interfering |2 NLM | |
| 650 | 7 | |a Triglycerides |2 NLM | |
| 650 | 7 | |a Dexamethasone |2 NLM | |
| 650 | 7 | |a 7S5I7G3JQL |2 NLM | |
| 650 | 7 | |a Serine C-Palmitoyltransferase |2 NLM | |
| 650 | 7 | |a EC 2.3.1.50 |2 NLM | |
| 650 | 7 | |a Sptlc1 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.3.1.50 |2 NLM | |
| 650 | 7 | |a Fasn protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.3.1.85 |2 NLM | |
| 650 | 7 | |a Fatty Acid Synthase, Type I |2 NLM | |
| 650 | 7 | |a EC 2.3.1.85 |2 NLM | |
| 650 | 7 | |a protein kinase C zeta |2 NLM | |
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| 650 | 7 | |a Protein Phosphatase 2 |2 NLM | |
| 650 | 7 | |a EC 3.1.3.16 |2 NLM | |
| 650 | 7 | |a thermozymocidin |2 NLM | |
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| 700 | 1 | |a Lee, Rebecca A |e verfasserin |4 aut | |
| 700 | 1 | |a Tsai, Sam L |e verfasserin |4 aut | |
| 700 | 1 | |a Kanamaluru, Deepthi |e verfasserin |4 aut | |
| 700 | 1 | |a Gray, Nora E |e verfasserin |4 aut | |
| 700 | 1 | |a Yiv, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Cheang, Rachel T |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Jenna H |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Justin Y |e verfasserin |4 aut | |
| 700 | 1 | |a Fitch, Mark D |e verfasserin |4 aut | |
| 700 | 1 | |a Hellerstein, Marc K |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jen-Chywan |e verfasserin |4 aut | |
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