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

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.