TY - JOUR
T1 - Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations
AU - Chambers, Kari T.
AU - Cooper, Michael A.
AU - Swearingen, Alison R.
AU - Brookheart, Rita T.
AU - Schweitzer, George G.
AU - Weinheimer, Carla J.
AU - Kovacs, Attila
AU - Koves, Timothy R.
AU - Muoio, Deborah M.
AU - McCommis, Kyle S.
AU - Finck, Brian N.
N1 - Funding Information:
This work was funded by NIH grant R01 HL119225 (BNF). The Core services of the Diabetes Research Center (P30 DK020579) and the Nutrition Obesity Research Center (P30 DK56341) at the Washington University School of Medicine also supported this work. MAC was supported by T32 HL134635. DMM and TRK are funded by R01 HL128349. KSM is supported by R00 HL136658. RTB is funded by K01 HL145326. Lipidomic mass spectrometry was performed in the Metabolomics Facility at Washington University (NIH P30 DK056341). The graphical abstract was created with BioRender.com.
Publisher Copyright:
© 2021, Chambers et al.
PY - 2021/5/10
Y1 - 2021/5/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105966299&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.134340
DO - 10.1172/jci.insight.134340
M3 - Article
C2 - 33986192
AN - SCOPUS:85105966299
SN - 2379-3708
VL - 6
JO - JCI insight
JF - JCI insight
IS - 9
M1 - e134340
ER -