Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency
Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease caused by the loss of function mutations in the <i>LCAT</i> gene. LCAT deficiency is characterized by an abnormal lipoprotein profile with severe reduction in plasma levels of high-density lip...
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MDPI AG
2023-07-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/8/1498 |
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| author | Monica Gomaraschi Marta Turri Arianna Strazzella Marie Lhomme Chiara Pavanello Wilfried Le Goff Anatol Kontush Laura Calabresi Alice Ossoli |
| author_facet | Monica Gomaraschi Marta Turri Arianna Strazzella Marie Lhomme Chiara Pavanello Wilfried Le Goff Anatol Kontush Laura Calabresi Alice Ossoli |
| author_sort | Monica Gomaraschi |
| collection | DOAJ |
| description | Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease caused by the loss of function mutations in the <i>LCAT</i> gene. LCAT deficiency is characterized by an abnormal lipoprotein profile with severe reduction in plasma levels of high-density lipoprotein (HDL) cholesterol and the accumulation of lipoprotein X (LpX). Renal failure is the major cause of morbidity and mortality in FLD patients; the pathogenesis of renal disease is only partly understood, but abnormalities in the lipoprotein profile could play a role in disease onset and progression. Serum and lipoprotein fractions from LCAT deficient carriers and controls were tested for renal toxicity on podocytes and tubular cells, and the underlying mechanisms were investigated at the cellular level. Both LpX and HDL from LCAT-deficient carriers triggered oxidative stress in renal cells, which culminated in cell apoptosis. These effects are partly explained by lipoprotein enrichment in unesterified cholesterol and ceramides, especially in the HDL fraction. Thus, alterations in lipoprotein composition could explain some of the nephrotoxic effects of LCAT deficient lipoproteins on podocytes and tubular cells. |
| first_indexed | 2024-03-11T00:10:53Z |
| format | Article |
| id | doaj.art-c16b3f1222f641988ef0199d86d7d1c1 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T00:10:53Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-c16b3f1222f641988ef0199d86d7d1c12023-11-19T00:00:42ZengMDPI AGAntioxidants2076-39212023-07-01128149810.3390/antiox12081498Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT DeficiencyMonica Gomaraschi0Marta Turri1Arianna Strazzella2Marie Lhomme3Chiara Pavanello4Wilfried Le Goff5Anatol Kontush6Laura Calabresi7Alice Ossoli8Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, ItalyCenter E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, ItalyCenter E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, ItalyFoundation for Innovation in Cardiometabolism and Nutrition (ANR-10-IAHU-05), IHU ICAN (ICAN OMICS and ICAN I/O), 75013 Paris, FranceCenter E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, ItalyNational Institute for Health and Medical Research (INSERM), UMRS 1166 ICAN, Faculty of Medicine Pitié-Salpêtrière, Sorbonne University, 75013 Paris, FranceNational Institute for Health and Medical Research (INSERM), UMRS 1166 ICAN, Faculty of Medicine Pitié-Salpêtrière, Sorbonne University, 75013 Paris, FranceCenter E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, ItalyCenter E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, ItalyFamilial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease caused by the loss of function mutations in the <i>LCAT</i> gene. LCAT deficiency is characterized by an abnormal lipoprotein profile with severe reduction in plasma levels of high-density lipoprotein (HDL) cholesterol and the accumulation of lipoprotein X (LpX). Renal failure is the major cause of morbidity and mortality in FLD patients; the pathogenesis of renal disease is only partly understood, but abnormalities in the lipoprotein profile could play a role in disease onset and progression. Serum and lipoprotein fractions from LCAT deficient carriers and controls were tested for renal toxicity on podocytes and tubular cells, and the underlying mechanisms were investigated at the cellular level. Both LpX and HDL from LCAT-deficient carriers triggered oxidative stress in renal cells, which culminated in cell apoptosis. These effects are partly explained by lipoprotein enrichment in unesterified cholesterol and ceramides, especially in the HDL fraction. Thus, alterations in lipoprotein composition could explain some of the nephrotoxic effects of LCAT deficient lipoproteins on podocytes and tubular cells.https://www.mdpi.com/2076-3921/12/8/1498LCAT deficiencyrenal diseaseLpXpreβ-HDLlipoprotein toxicitynephrotoxicity |
| spellingShingle | Monica Gomaraschi Marta Turri Arianna Strazzella Marie Lhomme Chiara Pavanello Wilfried Le Goff Anatol Kontush Laura Calabresi Alice Ossoli Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency Antioxidants LCAT deficiency renal disease LpX preβ-HDL lipoprotein toxicity nephrotoxicity |
| title | Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency |
| title_full | Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency |
| title_fullStr | Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency |
| title_full_unstemmed | Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency |
| title_short | Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency |
| title_sort | abnormal lipoproteins trigger oxidative stress mediated apoptosis of renal cells in lcat deficiency |
| topic | LCAT deficiency renal disease LpX preβ-HDL lipoprotein toxicity nephrotoxicity |
| url | https://www.mdpi.com/2076-3921/12/8/1498 |
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