Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells
Lipotoxicity refers to the harmful effects of excess fatty acids on metabolic health, and it can vary depending on the type of fatty acids involved. Saturated and unsaturated fatty acids exhibit distinct effects, though the precise mechanisms behind these differences remain unclear. Here, we investi...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524001974 |
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| author | Camilla Moliterni Francesco Vari Emily Schifano Stefano Tacconi Eleonora Stanca Marzia Friuli Serena Longo Maria Conte Stefano Salvioli Davide Gnocchi Antonio Mazzocca Daniela Uccelletti Daniele Vergara Luciana Dini Anna Maria Giudetti |
| author_facet | Camilla Moliterni Francesco Vari Emily Schifano Stefano Tacconi Eleonora Stanca Marzia Friuli Serena Longo Maria Conte Stefano Salvioli Davide Gnocchi Antonio Mazzocca Daniela Uccelletti Daniele Vergara Luciana Dini Anna Maria Giudetti |
| author_sort | Camilla Moliterni |
| collection | DOAJ |
| description | Lipotoxicity refers to the harmful effects of excess fatty acids on metabolic health, and it can vary depending on the type of fatty acids involved. Saturated and unsaturated fatty acids exhibit distinct effects, though the precise mechanisms behind these differences remain unclear. Here, we investigated the lipotoxicity of palmitic acid (PA), a saturated fatty acid, compared with oleic acid (OA), a monounsaturated fatty acid, in the hepatic cell line HuH7. Our results demonstrated that PA, unlike OA, induces lipotoxicity, endoplasmic reticulum (ER) stress, and autophagy inhibition. Compared with OA, PA treatment leads to less lipid droplet (LD) accumulation and a significant reduction in the mRNA and protein level of diacylglycerol acyltransferase 1 (DGAT1), a key enzyme of triacylglycerol synthesis. Using modulators of ER stress and autophagy, we established that DGAT1 downregulation by PA is closely linked to these cellular pathways. Notably, the ER stress inhibitor 4-phenylbutyrate can suppress PA-induced DGAT1 downregulation. Furthermore, knockdown of DGAT1 by siRNA or with A922500, a specific DGAT1 inhibitor, resulted in cell death, even with OA. Both PA and OA increased the oxygen consumption rate; however, the increase associated with PA was only partially coupled to ATP synthesis. Importantly, treatment with GW7647 a specific PPARα agonist mitigated the lipotoxic effects of PA, restoring PA-induced ER stress, autophagy block, and DGAT1 suppression. In conclusion, our study highlights the crucial role of DGAT1 in PA-induced lipotoxicity, broadening the knowledge of the mechanisms underlying hepatic lipotoxicity and providing the basis for potential therapeutic interventions. |
| format | Article |
| id | doaj-art-61eebaa291e14353a2fa011b53422f4f |
| institution | DOAJ |
| issn | 0022-2275 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-61eebaa291e14353a2fa011b53422f4f2025-08-20T02:51:45ZengElsevierJournal of Lipid Research0022-22752024-12-01651210069210.1016/j.jlr.2024.100692Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cellsCamilla Moliterni0Francesco Vari1Emily Schifano2Stefano Tacconi3Eleonora Stanca4Marzia Friuli5Serena Longo6Maria Conte7Stefano Salvioli8Davide Gnocchi9Antonio Mazzocca10Daniela Uccelletti11Daniele Vergara12Luciana Dini13Anna Maria Giudetti14Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Rome, ItalyDepartment of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy; Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, Rome, ItalyDepartment of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Rome, ItalyDepartment of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Rome, ItalyDepartment of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, ItalyDepartment of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, Rome, ItalyDepartment of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, ItalyDepartment of Medical and Surgical Sciences, University of Bologna, Bologna, ItalyDepartment of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyInterdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, ItalyInterdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, ItalyDepartment of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Rome, ItalyDepartment of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, ItalyDepartment of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Rome, Italy; For correspondence: Anna Maria Giudetti; Luciana DiniDepartment of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy; For correspondence: Anna Maria Giudetti; Luciana DiniLipotoxicity refers to the harmful effects of excess fatty acids on metabolic health, and it can vary depending on the type of fatty acids involved. Saturated and unsaturated fatty acids exhibit distinct effects, though the precise mechanisms behind these differences remain unclear. Here, we investigated the lipotoxicity of palmitic acid (PA), a saturated fatty acid, compared with oleic acid (OA), a monounsaturated fatty acid, in the hepatic cell line HuH7. Our results demonstrated that PA, unlike OA, induces lipotoxicity, endoplasmic reticulum (ER) stress, and autophagy inhibition. Compared with OA, PA treatment leads to less lipid droplet (LD) accumulation and a significant reduction in the mRNA and protein level of diacylglycerol acyltransferase 1 (DGAT1), a key enzyme of triacylglycerol synthesis. Using modulators of ER stress and autophagy, we established that DGAT1 downregulation by PA is closely linked to these cellular pathways. Notably, the ER stress inhibitor 4-phenylbutyrate can suppress PA-induced DGAT1 downregulation. Furthermore, knockdown of DGAT1 by siRNA or with A922500, a specific DGAT1 inhibitor, resulted in cell death, even with OA. Both PA and OA increased the oxygen consumption rate; however, the increase associated with PA was only partially coupled to ATP synthesis. Importantly, treatment with GW7647 a specific PPARα agonist mitigated the lipotoxic effects of PA, restoring PA-induced ER stress, autophagy block, and DGAT1 suppression. In conclusion, our study highlights the crucial role of DGAT1 in PA-induced lipotoxicity, broadening the knowledge of the mechanisms underlying hepatic lipotoxicity and providing the basis for potential therapeutic interventions.http://www.sciencedirect.com/science/article/pii/S0022227524001974diacylglycerol acyltransferaseendoplasmic reticulum stresshepatic cellslipid dropletslipotoxicity |
| spellingShingle | Camilla Moliterni Francesco Vari Emily Schifano Stefano Tacconi Eleonora Stanca Marzia Friuli Serena Longo Maria Conte Stefano Salvioli Davide Gnocchi Antonio Mazzocca Daniela Uccelletti Daniele Vergara Luciana Dini Anna Maria Giudetti Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells Journal of Lipid Research diacylglycerol acyltransferase endoplasmic reticulum stress hepatic cells lipid droplets lipotoxicity |
| title | Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells |
| title_full | Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells |
| title_fullStr | Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells |
| title_full_unstemmed | Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells |
| title_short | Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells |
| title_sort | lipotoxicity of palmitic acid is associated with dgat1 downregulation and abolished by pparα activation in liver cells |
| topic | diacylglycerol acyltransferase endoplasmic reticulum stress hepatic cells lipid droplets lipotoxicity |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524001974 |
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