Work

Pioglitazone mitigates high-fat diet-induced cardiac lipotoxicity and vulnerable arrhythmias by reducing excess lipid intermediates

Year: 2025

Type: article

Abstract: Previous studies showed conflicting results regarding pioglitazone's effects on cardiac lipid metabolism. We aim to examine whether pioglitazone treatment predisposes or mitigates disrupted energy metabolism in cardiac intracellular lipid accumulation and the susceptibility to ventricular tachyarrhythmia. We used a rat model fed with a high-fat diet (HFD) and palmitate-treated cardiomyocytes to investigate whether pioglitazone administration affects disrupted energy metabolism and cardiac arrhythmia susceptibility. The HFD group had increased body weight, blood glucose, triglycerides, and cholesterol, as well as increased levels of HOMA-IR, leptin, and resistin in comparison to the control diet group. Sixteen-weeks pioglitazone (10 mg/kg/day) therapy in HFD rats resulted in improvements in triglyceride, blood glucose, and HOMA-IR compared to HFD rats. The HFD resulted in intracellular lipid droplet accumulation, oxidative stress, and increased cellular apoptosis. Comprehensive global ventricle metabolomic profiling revealed alterations in various diacylglycerols (DG), predominantly long-chain DGs ≥34 carbons, and dysregulation of key metabolic genes and enzymes. Notable gene/protein upregulation was observed in HMGCS2 (ketogenesis), PLPPR4 (regulation of phosphatic acid conversion to DG), PNLIPRP1 (TG hydrolysis), CES1C (TG hydrolysis), and ACSS2 (acetyl-CoA synthesis), while MVD/MVK (cholesterol synthesis) and PGAM2 (glycolysis) exhibited downregulation. The alternations in protein expression were partly restored with co-administration with pioglitazone. Palmitate administration in H9C2 and HL1 cardiac myocytes in vitro activated stress-responsive signaling cascades (p-ERK, p-JNK, p-CaMKII, and Caspase 3), resulting in cellular dysfunction, apoptosis, and increased calcium spark frequencies. Ex vivo, isolated HFD heart exhibited increased the frequency of ectopic focal activity and the vulnerability of ventricular fibrillation, which was mitigated by co-administration of pioglitazone. In conclusion, pioglitazone therapy may be a possible therapeutic strategy for obesity mediated cardiac lipotoxicity and arrhythmia.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2025.118672

Authors: Yung-Hsin Yeh, Mei-Ling Cheng, Cheng-Hung Yang, Wei-Jan Chen, Yi-Hsin Chan

Institutions: Chang Gung University, Taoyuan Chang Gung Memorial Hospital, Linkou Chang Gung Memorial Hospital, Chang Gung Memorial Hospital

Language: English

Topic: Cardiovascular Function and Risk Factors

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,610