{"doi":"10.1172/jci.insight.134340","title":"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.","journal":"JCI Insight","year":2021,"id":170842,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":703978,"name":"Michael A. Cooper","orcid":"0000-0002-9312-0399","position":1,"is_corresponding":false},{"id":704473,"name":"Alison R. Swearingen","orcid":null,"position":2,"is_corresponding":false},{"id":687971,"name":"Rita T. Brookheart","orcid":"0000-0003-3247-3243","position":3,"is_corresponding":false},{"id":679064,"name":"George G. Schweitzer","orcid":null,"position":4,"is_corresponding":false},{"id":258404,"name":"Carla J. Weinheimer","orcid":"0000-0001-7922-7512","position":5,"is_corresponding":false},{"id":258403,"name":"Attila Kovács","orcid":"0000-0003-2320-6434","position":6,"is_corresponding":false},{"id":258405,"name":"Timothy R. Koves","orcid":"0000-0001-8763-5866","position":7,"is_corresponding":false},{"id":226780,"name":"Deborah M. Muoio","orcid":"0000-0003-3760-9277","position":8,"is_corresponding":false},{"id":258402,"name":"Kyle S. McCommis","orcid":"0000-0003-2381-1589","position":9,"is_corresponding":false},{"id":258412,"name":"Brian N. Finck","orcid":"0000-0001-5411-3674","position":10,"is_corresponding":false},{"id":704472,"name":"Kari T. Chambers","orcid":null,"position":0,"is_corresponding":true}],"reference_count":24,"raw_metadata":null,"created_at":"2026-07-18T23:46:24.040760Z","pmid":"33986192","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}