Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations
Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. We generated mice with cardiac-specific lipin 1 KO (cs-Lpin1-/-) to examine the intrinsic effects of lipin 1 in the myocardium. Cs-Lpin1-/- mice had normal systolic cardiac function but mild cardiac hypertrophy. Compared with littermate control mice, PA content was higher in cs-Lpin1-/- hearts, which also had an unexpected increase in diacylglycerol and triglyceride content. Cs-Lpin1-/- mice exhibited diminished cardiac cardiolipin content and impaired mitochondrial respiration rates when provided with pyruvate or succinate as metabolic substrates. After transverse aortic constriction-induced pressure overload, loss of lipin 1 did not exacerbate cardiac hypertrophy or dysfunction. However, loss of lipin 1 dampened the cardiac ionotropic response to dobutamine and exercise endurance in association with reduced protein kinase A signaling. These data suggest that loss of lipin 1 impairs cardiac functional reserve, likely due to effects on glycerolipid homeostasis, mitochondrial function, and protein kinase A signaling.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2021 |
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Erschienen: |
2021 |
Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
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Enthalten in: |
JCI insight - 6(2021), 9 vom: 10. Mai |
Sprache: |
Englisch |
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Beteiligte Personen: |
Chambers, Kari T [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 14.02.2022 Date Revised 14.02.2022 published: Electronic Citation Status MEDLINE |
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doi: |
10.1172/jci.insight.134340 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM325375674 |
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245 | 1 | 0 | |a Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations |
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520 | |a Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. We generated mice with cardiac-specific lipin 1 KO (cs-Lpin1-/-) to examine the intrinsic effects of lipin 1 in the myocardium. Cs-Lpin1-/- mice had normal systolic cardiac function but mild cardiac hypertrophy. Compared with littermate control mice, PA content was higher in cs-Lpin1-/- hearts, which also had an unexpected increase in diacylglycerol and triglyceride content. Cs-Lpin1-/- mice exhibited diminished cardiac cardiolipin content and impaired mitochondrial respiration rates when provided with pyruvate or succinate as metabolic substrates. After transverse aortic constriction-induced pressure overload, loss of lipin 1 did not exacerbate cardiac hypertrophy or dysfunction. However, loss of lipin 1 dampened the cardiac ionotropic response to dobutamine and exercise endurance in association with reduced protein kinase A signaling. These data suggest that loss of lipin 1 impairs cardiac functional reserve, likely due to effects on glycerolipid homeostasis, mitochondrial function, and protein kinase A signaling | ||
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 Cardiology | |
650 | 4 | |a Cardiovascular disease | |
650 | 4 | |a Intermediary metabolism | |
650 | 4 | |a Metabolism | |
650 | 4 | |a Mitochondria | |
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700 | 1 | |a Cooper, Michael A |e verfasserin |4 aut | |
700 | 1 | |a Swearingen, Alison R |e verfasserin |4 aut | |
700 | 1 | |a Brookheart, Rita T |e verfasserin |4 aut | |
700 | 1 | |a Schweitzer, George G |e verfasserin |4 aut | |
700 | 1 | |a Weinheimer, Carla J |e verfasserin |4 aut | |
700 | 1 | |a Kovacs, Attila |e verfasserin |4 aut | |
700 | 1 | |a Koves, Timothy R |e verfasserin |4 aut | |
700 | 1 | |a Muoio, Deborah M |e verfasserin |4 aut | |
700 | 1 | |a McCommis, Kyle S |e verfasserin |4 aut | |
700 | 1 | |a Finck, Brian N |e verfasserin |4 aut | |
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