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, inc...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2021-05-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.134340 |
| _version_ | 1818858867779436544 |
|---|---|
| author | Kari T. Chambers Michael A. Cooper Alison R. Swearingen Rita T. Brookheart George G. Schweitzer Carla J. Weinheimer Attila Kovacs Timothy R. Koves Deborah M. Muoio Kyle S. McCommis Brian N. Finck |
| author_facet | Kari T. Chambers Michael A. Cooper Alison R. Swearingen Rita T. Brookheart George G. Schweitzer Carla J. Weinheimer Attila Kovacs Timothy R. Koves Deborah M. Muoio Kyle S. McCommis Brian N. Finck |
| author_sort | Kari T. Chambers |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T09:03:07Z |
| format | Article |
| id | doaj.art-4e406f9b70c944e9aad9c1f34b024475 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-19T09:03:07Z |
| publishDate | 2021-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-4e406f9b70c944e9aad9c1f34b0244752022-12-21T20:28:25ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-05-0169Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutationsKari T. ChambersMichael A. CooperAlison R. SwearingenRita T. BrookheartGeorge G. SchweitzerCarla J. WeinheimerAttila KovacsTimothy R. KovesDeborah M. MuoioKyle S. McCommisBrian N. FinckLipin 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.https://doi.org/10.1172/jci.insight.134340CardiologyMetabolism |
| spellingShingle | Kari T. Chambers Michael A. Cooper Alison R. Swearingen Rita T. Brookheart George G. Schweitzer Carla J. Weinheimer Attila Kovacs Timothy R. Koves Deborah M. Muoio Kyle S. McCommis Brian N. Finck Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations JCI Insight Cardiology Metabolism |
| title | Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations |
| title_full | Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations |
| title_fullStr | Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations |
| title_full_unstemmed | Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations |
| title_short | Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations |
| title_sort | myocardial lipin 1 knockout in mice approximates cardiac effects of human lpin1 mutations |
| topic | Cardiology Metabolism |
| url | https://doi.org/10.1172/jci.insight.134340 |
| work_keys_str_mv | AT karitchambers myocardiallipin1knockoutinmiceapproximatescardiaceffectsofhumanlpin1mutations AT michaelacooper myocardiallipin1knockoutinmiceapproximatescardiaceffectsofhumanlpin1mutations AT alisonrswearingen myocardiallipin1knockoutinmiceapproximatescardiaceffectsofhumanlpin1mutations AT ritatbrookheart myocardiallipin1knockoutinmiceapproximatescardiaceffectsofhumanlpin1mutations AT georgegschweitzer myocardiallipin1knockoutinmiceapproximatescardiaceffectsofhumanlpin1mutations AT carlajweinheimer myocardiallipin1knockoutinmiceapproximatescardiaceffectsofhumanlpin1mutations AT attilakovacs myocardiallipin1knockoutinmiceapproximatescardiaceffectsofhumanlpin1mutations AT timothyrkoves myocardiallipin1knockoutinmiceapproximatescardiaceffectsofhumanlpin1mutations AT deborahmmuoio myocardiallipin1knockoutinmiceapproximatescardiaceffectsofhumanlpin1mutations AT kylesmccommis myocardiallipin1knockoutinmiceapproximatescardiaceffectsofhumanlpin1mutations AT briannfinck myocardiallipin1knockoutinmiceapproximatescardiaceffectsofhumanlpin1mutations |