Endothelial AMPKα1/PRKAA1 exacerbates inflammation in HFD-fed mice
© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society..
BACKGROUND AND PURPOSE: Excess nutrient-induced endothelial cell inflammation is a hallmark of high fat diet (HFD)-induced metabolic syndrome. Pharmacological activation of the protein kinase AMP-activated α1 (PRKAA1) also known as AMPKα1, shows its beneficial effects in many studies of cardiometabolic disorders. However, AMPKα1, as a major cellular sensor of energy and nutrients in endothelial cells, has not been studied for its physiological role in excess nutrient-induced endothelial cell (EC) inflammation.
EXPERIMENTAL APPROACH: Wild-type and EC-specific Prkaa1 knockout mice were fed with an HFD. Body weight, fat mass composition, glucose, and lipid levels were monitored regularly. Insulin sensitivity was analysed systemically and in major metabolic organs/tissues. Inflammation status in metabolic organs/tissues were examined with quantitative RT-PCR and flow cytometry. Additionally, metabolic status, inflammation severity, and signalling in cultured ECs were assayed with multiple approaches at the molecular level.
KEY RESULTS: EC Prkaa1 deficiency unexpectedly alleviated HFD-induced metabolic syndromes including decreased body weight and fat mass, enhanced glucose clearance and insulin sensitivity, and relieved adipose inflammation and hepatic steatosis. Mechanistically, PRKAA1 knockdown in cultured ECs reduced endothelial glycolysis and fatty acid oxidation, decreased levels of acetyl-CoA and suppressed transcription of inflammatory molecules mediated by ATP citrate lyase and histone acetyltransferase p300.
CONCLUSIONS AND IMPLICATIONS: This unexpected pro-inflammatory effect of endothelial AMPKα1/PRKAA1 in a metabolic context provides additional insight in AMPKα1/PRKAA1 activities. An in-depth study and thoughtful consideration should be applied when AMPKα1/PRKAA1 is used as a therapeutic target in the treatment of metabolic syndrome.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:179 |
|---|---|
| Enthalten in: |
British journal of pharmacology - 179(2022), 8 vom: 19. Apr., Seite 1661-1678 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Yang, Qiuhua [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 13.04.2022 Date Revised 12.11.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1111/bph.15742 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM333338731 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM333338731 | ||
| 003 | DE-627 | ||
| 005 | 20231225221449.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1111/bph.15742 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1111.xml |
| 035 | |a (DE-627)NLM333338731 | ||
| 035 | |a (NLM)34796475 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Yang, Qiuhua |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Endothelial AMPKα1/PRKAA1 exacerbates inflammation in HFD-fed mice |
| 264 | 1 | |c 2022 | |
| 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 13.04.2022 | ||
| 500 | |a Date Revised 12.11.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. | ||
| 520 | |a BACKGROUND AND PURPOSE: Excess nutrient-induced endothelial cell inflammation is a hallmark of high fat diet (HFD)-induced metabolic syndrome. Pharmacological activation of the protein kinase AMP-activated α1 (PRKAA1) also known as AMPKα1, shows its beneficial effects in many studies of cardiometabolic disorders. However, AMPKα1, as a major cellular sensor of energy and nutrients in endothelial cells, has not been studied for its physiological role in excess nutrient-induced endothelial cell (EC) inflammation | ||
| 520 | |a EXPERIMENTAL APPROACH: Wild-type and EC-specific Prkaa1 knockout mice were fed with an HFD. Body weight, fat mass composition, glucose, and lipid levels were monitored regularly. Insulin sensitivity was analysed systemically and in major metabolic organs/tissues. Inflammation status in metabolic organs/tissues were examined with quantitative RT-PCR and flow cytometry. Additionally, metabolic status, inflammation severity, and signalling in cultured ECs were assayed with multiple approaches at the molecular level | ||
| 520 | |a KEY RESULTS: EC Prkaa1 deficiency unexpectedly alleviated HFD-induced metabolic syndromes including decreased body weight and fat mass, enhanced glucose clearance and insulin sensitivity, and relieved adipose inflammation and hepatic steatosis. Mechanistically, PRKAA1 knockdown in cultured ECs reduced endothelial glycolysis and fatty acid oxidation, decreased levels of acetyl-CoA and suppressed transcription of inflammatory molecules mediated by ATP citrate lyase and histone acetyltransferase p300 | ||
| 520 | |a CONCLUSIONS AND IMPLICATIONS: This unexpected pro-inflammatory effect of endothelial AMPKα1/PRKAA1 in a metabolic context provides additional insight in AMPKα1/PRKAA1 activities. An in-depth study and thoughtful consideration should be applied when AMPKα1/PRKAA1 is used as a therapeutic target in the treatment of metabolic syndrome | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a AMPKA1/PRKAA1 | |
| 650 | 4 | |a endothelial cells | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a metabolism | |
| 650 | 7 | |a AMP-Activated Protein Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.31 |2 NLM | |
| 650 | 7 | |a Glucose |2 NLM | |
| 650 | 7 | |a IY9XDZ35W2 |2 NLM | |
| 700 | 1 | |a Ma, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Jiean |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhiping |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Xiaoxiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Yaqi |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Yongfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Da, Qingen |e verfasserin |4 aut | |
| 700 | 1 | |a Hong, Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Weintraub, Neal L |e verfasserin |4 aut | |
| 700 | 1 | |a Fulton, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Belin de Chantemèle, Eric J |e verfasserin |4 aut | |
| 700 | 1 | |a Huo, Yuqing |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t British journal of pharmacology |d 1968 |g 179(2022), 8 vom: 19. Apr., Seite 1661-1678 |w (DE-627)NLM000001325 |x 1476-5381 |7 nnns |
| 773 | 1 | 8 | |g volume:179 |g year:2022 |g number:8 |g day:19 |g month:04 |g pages:1661-1678 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1111/bph.15742 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 179 |j 2022 |e 8 |b 19 |c 04 |h 1661-1678 | ||