Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations.

Abstract

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.

• Authors: 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
• Journal: JCI insight (JCI Insight) Vol. 6 Issue 9 (05 10 2021) ISSN: 2379-3708 [Electronic] United States
• PMID: 33986192 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiolipins
• Cardiotonic Agents
• Diglycerides
• Phosphatidic Acids
• Triglycerides
• Dobutamine
• Pyruvic Acid
• Succinic Acid
• Cyclic AMP-Dependent Protein Kinases
• Lpin1 protein, mouse
• Phosphatidate Phosphatase

Topics

• Animals
• Cardiolipins (metabolism)
• Cardiomegaly (genetics, metabolism)
• Cardiotonic Agents (pharmacology)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Diglycerides (metabolism)
• Disease Models, Animal
• Dobutamine (pharmacology)
• Exercise Tolerance (drug effects, genetics)
• Mice
• Mice, Knockout
• Mitochondria, Heart (metabolism)
• Myocardial Contraction (drug effects, genetics)
• Myocardium (metabolism)
• Phosphatidate Phosphatase (genetics)
• Phosphatidic Acids (metabolism)
• Pyruvic Acid (metabolism)
• Succinic Acid (metabolism)
• Triglycerides (metabolism)