P194 - ECE_1680 - Ultrastructural and molecular effects of pioglitazone on cardiac steatosis and endoplasmic reticulum stress in a high-fat diet–induced rat model

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Abstract Background While lipotoxicity in organs such as the liver, skeletal muscle, and pancreas has been well described, myocardial steatosis remains less well characterized. This study aimed to investigate cardiac steatosis in a high-fat diet (HFD)-fed rat model and to evaluate the effects of pioglitazone, a PPAR-γ agonist, on myocardial lipid accumulation, endoplasmic reticulum (ER) stress, and ultrastructural changes. Methods A total of 32 male Wistar rats were fed either a normal chow diet (NCD) or a HFD for 17 weeks and treated with pioglitazone during the final 4 weeks. Cardiac tissue was evaluated using histopathological analysis, Oil Red O staining, transmission electron microscopy (TEM), and quantitative real-time PCR to assess myocardial lipid accumulation, ultrastructural alterations, ER stress, and apoptosis-related gene expression. Circulating NT-proBNP levels were measured as a marker of cardiac stress. Results Epididymal white adipose tissue mass was significantly greater in HFD-fed rats compared with NCD-fed rats (5.13 ± 1.59 g vs 3.26 ± 0.94 g, P < .001), reflecting the impact of a HFD on adipose tissue expansion. In TEM analysis, HFD feeding resulted in significant myocardial lipid accumulation, accompanied by marked ultrastructural alterations, including mitochondrial crista disruption, ER dilation, increased intercellular space, and inflammatory cell infiltration. Pioglitazone treatment attenuated ER stress signaling, reduced intracellular lipid droplet accumulation, decreased inflammatory cell presence and partially preserved mitochondrial and ER morphology. These changes were associated with a significant reduction in circulating NT-proBNP levels, particularly in HFD–fed rats. Pioglitazone markedly decreased NT-proBNP concentrations (1769 ± 312 pg/mL vs 851 ± 116 pg/mL, P < .001) in HFD-fed rats, whereas untreated HFD-fed rats showed no significant change over time (P = .084). Additionally, PCR analysis showed that HFD-fed rats treated with pioglitazone, the HFD-associated induction of unfolded protein response (UPR)/ER stress markers was significantly attenuated, with reduced expression of CHOP, ATF4, PERK, XBP1, sXBP1 and eIF2α compared with untreated HFD rats, indicating attenuation of ER stress activation. Conclusions Pioglitazone partially mitigates diet-induced myocardial steatosis by reducing cardiomyocyte lipid accumulation, attenuating ER stress, and preserving ultrastructural integrity. These findings may support a cardioprotective role of PPAR-γ activation through modulation of myocardial lipotoxicity.

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