@misc{Wołosiewicz_Marcin_Rola_2024,
 author={Wołosiewicz, Marcin},
 editor={Dobrzyń, Paweł (1972– ) : Supervisor},
 copyright={Rights Reserved - Free Access},
 address={Warszawa},
 howpublished={online},
 school={Nencki Institute of Experimental Biology PAS},
 school={degree obtained: 2025},
 year={2024},
 publisher={Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN},
 language={pol},
 abstract={Accumulation of toxic lipid metabolites in cardiomyocytes leads to lipotoxicity, which is associated with activation or inhibition of signaling pathways, causing stress and dysfunction of organelles, energy deficit and apoptosis. Lipotoxicity also decreases cardiac insulin sensitivity, causing a shift in cardiac metabolism toward increased fatty acid (FA) uptake, storage and oxidation. The high rate of FA oxidation increases the production of reactive oxygen species (ROS), causing oxidative stress, mitochondrial damage and disruption of Ca2+ homeostasis. Stearoyl-CoA desaturase (SCD) is a key enzyme involved in the regulation of lipid metabolism in cardiomyocytes. In addition to the formation of monounsaturated fatty acids, this enzyme regulates lipolysis and β-oxidation, thereby affecting functional parameters of the heart. Four isoforms of SCD have been identified in mice, of which SCD4 is considered the cardiac- specific isoform. The loss of SCD4 in the mouse heart has been shown to reduce AMP-activated protein kinase activation induced by myocardial infarction (MI). Lack of Scd4 expression in the heart after MI also reduced ROS formation by decreasing protein levels of the NADPH oxidase subunit. Loss of SCD4 also decreased proangiogenic factors in the heart and plasma, suggesting that SCD4 positively regulates blood vessel formation in the mouse heart after MI. However, the role of SCD4 in regulating cardiac metabolism and function remains poorly understood. The main objective of this dissertation was to determine the effects of SCD4 deficiency on cardiac structure, function and metabolism under physiological conditions and in obesity. To test this: 1) the role of SCD4 in the regulation of systemic metabolism in mice was determined; 2) the effects of SCD4 deficiency on cardiac function and structure were investigated; 3) the metabolic pathways through which SCD4 regulates lipid metabolism in the heart were identified; 4) the effects of Scd4 expression on mitochondrial structure and activity in cardiomyocytes were determined. The study was conducted on wild-type (WT) mice and SCD4-deficient (SCD4-/-) mice kept under normal conditions or fed a high-fat diet (HFD) for 8 weeks to induce obesity. In vitro studies were performed using a mouse HL-1 cardiomyocytes with silenced Scd4 expression. The study showed that loss of SCD4 had systemic effects, reducing body adiposity, hyperinsulinemia and hypercholesterolemia, and increasing insulin sensitivity in HFD-fed mice, despite SCD4 being a cardiac-specific isoform. The absence of SCD4 under normal conditions caused minor changes in heart morphology, reducing left ventricular end-diastolic diameter and volume, but prevented concentric cardiac remodeling under HFD conditions. Scd4 deficiency reduced lipid accumulation in cardiomyocytes, but did not affect the expression of other Scd isoforms in the heart. Lower lipid levels in SCD4-deficient cardiomyocytes were associated with activation of adipose triglyceride lipase and lipolysis. Simultaneous activation of lipogenesis, β-oxidation and lipolysis indicated increased lipid droplet (LD) dynamics, and downregulation of SCD4 inhibited the HFD-induced increase in LDs growth in cardiomyocytes. These results indicate that SCD4 is involved in the regulation of cardiac energy metabolism. Mitochondrial hypertrophy and ROS overproduction caused by lipid accumulation and toxicity were inhibited in cardiomyocytes with silenced Scd4 expression under lipid overload conditions.This was associated with increased mitophagy and decreased NADH dehydrogenase activity. SCD4 was also found to be involved in the regulation of Ca2+ homeostasis in the heart under HFD conditions, through increased levels of phospholamban and sarcoplasmic Ca2+-ATPase type 2.In conclusion, the results of this study showed that SCD4 not only regulates lipid metabolism in the heart,but also affects myocardial function and systemic metabolism,especially in the HFD condition.},
 type={Text},
 title={Rola desaturazy stearoilo-CoA 4 w regulacji metabolizmu i funkcji mięśnia sercowego myszy : praca doktorska},
 URL={http://rcin.org.pl./Content/244797/WA488_281536_20655_Wolosiewicz-Marcin-2024.pdf},
 keywords={Calcium ions, Cardiomyocytes, Lipids, Lipolysis, Mitochondria, Obesity},
}