Dysregulated palmitic acid metabolism promotes the formation of renal calcium-oxalate stones through ferroptosis induced by polyunsaturated fatty acids/phosphatidic acid
The pathogenesis of renal calcium-oxalate (CaOx) stones is complex and influenced by various metabolic factors. In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this stu...
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| description | The pathogenesis of renal calcium-oxalate (CaOx) stones is complex and influenced by various metabolic factors. In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this study aimed to mechanistically assess whether PA is involved in stone formation. Lipidomics analysis of PA-treated renal tubular epithelial cells compared with the control samples revealed that α-linoleic acid and α-linolenic acid were desaturated and elongated, resulting in the formation of downstream polyunsaturated fatty acids (PUFAs). In correlation, the levels of fatty acid desaturase 1 and 2 (FADS1 and FADS2) and peroxisome proliferator-activated receptor α (PPARα) in these cells treated with PA were increased relative to the control levels, suggesting that PA-induced upregulation of PPARα, which in turn upregulated these two enzymes, forming the observed PUFAs. Lipid peroxidation occurred in these downstream PUFAs under oxidative stress and Fenton Reaction. Furthermore, transcriptomics analysis revealed significant changes in the expression levels of ferroptosis-related genes in PA-treated renal tubular epithelial cells, induced by PUFA peroxides. In addition, phosphatidyl ethanolamine binding protein 1 (PEBP1) formed a complex with 15-lipoxygenase (15-LO) to exacerbate PUFA peroxidation under protein kinase C ζ (PKC ζ) phosphorylation, and PKC ζ was activated by phosphatidic acid derived from PA. In conclusion, this study found that the formation of renal CaOx stones is promoted by ferroptosis of renal tubular epithelial cells resulting from PA-induced dysregulation of PUFA and phosphatidic acid metabolism, and PA can promote the renal adhesion and deposition of CaOx crystals by injuring renal tubular epithelial cells, consequently upregulating adhesion molecules. Accordingly, this study provides a new theoretical basis for understanding the correlation between fatty acid metabolism and the formation of renal CaOx stones, offering potential targets for clinical applications. |
| doi_str_mv | 10.1007/s00018-024-05145-y |
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In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this study aimed to mechanistically assess whether PA is involved in stone formation. Lipidomics analysis of PA-treated renal tubular epithelial cells compared with the control samples revealed that α-linoleic acid and α-linolenic acid were desaturated and elongated, resulting in the formation of downstream polyunsaturated fatty acids (PUFAs). In correlation, the levels of fatty acid desaturase 1 and 2 (FADS1 and FADS2) and peroxisome proliferator-activated receptor α (PPARα) in these cells treated with PA were increased relative to the control levels, suggesting that PA-induced upregulation of PPARα, which in turn upregulated these two enzymes, forming the observed PUFAs. Lipid peroxidation occurred in these downstream PUFAs under oxidative stress and Fenton Reaction. Furthermore, transcriptomics analysis revealed significant changes in the expression levels of ferroptosis-related genes in PA-treated renal tubular epithelial cells, induced by PUFA peroxides. In addition, phosphatidyl ethanolamine binding protein 1 (PEBP1) formed a complex with 15-lipoxygenase (15-LO) to exacerbate PUFA peroxidation under protein kinase C ζ (PKC ζ) phosphorylation, and PKC ζ was activated by phosphatidic acid derived from PA. In conclusion, this study found that the formation of renal CaOx stones is promoted by ferroptosis of renal tubular epithelial cells resulting from PA-induced dysregulation of PUFA and phosphatidic acid metabolism, and PA can promote the renal adhesion and deposition of CaOx crystals by injuring renal tubular epithelial cells, consequently upregulating adhesion molecules. Accordingly, this study provides a new theoretical basis for understanding the correlation between fatty acid metabolism and the formation of renal CaOx stones, offering potential targets for clinical applications.</description><identifier>ISSN: 1420-682X</identifier><identifier>EISSN: 1420-9071</identifier><identifier>DOI: 10.1007/s00018-024-05145-y</identifier><identifier>PMID: 38345762</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Adhesion ; arachidonate 15-lipoxygenase ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; blood serum ; Calcium ; Calcium oxalate ; Calcium Oxalate - chemistry ; Cell adhesion molecules ; Cell Biology ; Crystals ; Desaturase ; Epithelial cells ; Epithelium ; Ethanolamine ; fatty acid desaturase ; fatty acid metabolism ; Fatty acids ; Fatty Acids, Unsaturated ; Ferroptosis ; Gene expression ; Humans ; Kidneys ; Kinases ; Life Sciences ; Linoleic acid ; Linolenic acid ; Lipid metabolism ; Lipid peroxidation ; lipidomics ; Lipids ; Lipoxygenase ; Metabolism ; Metabolites ; Metabolomics ; Original ; Original Article ; Oxalic acid ; Oxidative stress ; Palmitic acid ; Palmitic Acids ; Pathogenesis ; Peroxidation ; Peroxides ; Peroxisome proliferator-activated receptors ; Phosphatidic acid ; phosphatidic acids ; Phosphorylation ; Polyunsaturated fatty acids ; PPAR alpha ; Protein kinase C ; Proteins ; Stone ; Transcriptomics ; urine</subject><ispartof>Cellular and molecular life sciences : CMLS, 2024-12, Vol.81 (1), p.85-85, Article 85</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-bb0277aacd2223657a8118e27904223fd037a731b9a5ad6192b4e62bfb2e4ee33</citedby><cites>FETCH-LOGICAL-c508t-bb0277aacd2223657a8118e27904223fd037a731b9a5ad6192b4e62bfb2e4ee33</cites><orcidid>0000-0001-5357-3716 ; 0000-0002-1833-491X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10861707/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10861707/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41096,41464,42165,42533,51294,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38345762$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Rui</creatorcontrib><creatorcontrib>Zhang, Jingdong</creatorcontrib><creatorcontrib>Ren, Haotian</creatorcontrib><creatorcontrib>Qi, Shiyong</creatorcontrib><creatorcontrib>Xie, Linguo</creatorcontrib><creatorcontrib>Xie, Haijie</creatorcontrib><creatorcontrib>Shang, Zhiqun</creatorcontrib><creatorcontrib>Liu, Chunyu</creatorcontrib><title>Dysregulated palmitic acid metabolism promotes the formation of renal calcium-oxalate stones through ferroptosis induced by polyunsaturated fatty acids/phosphatidic acid</title><title>Cellular and molecular life sciences : CMLS</title><addtitle>Cell. Mol. Life Sci</addtitle><addtitle>Cell Mol Life Sci</addtitle><description>The pathogenesis of renal calcium-oxalate (CaOx) stones is complex and influenced by various metabolic factors. In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this study aimed to mechanistically assess whether PA is involved in stone formation. Lipidomics analysis of PA-treated renal tubular epithelial cells compared with the control samples revealed that α-linoleic acid and α-linolenic acid were desaturated and elongated, resulting in the formation of downstream polyunsaturated fatty acids (PUFAs). In correlation, the levels of fatty acid desaturase 1 and 2 (FADS1 and FADS2) and peroxisome proliferator-activated receptor α (PPARα) in these cells treated with PA were increased relative to the control levels, suggesting that PA-induced upregulation of PPARα, which in turn upregulated these two enzymes, forming the observed PUFAs. Lipid peroxidation occurred in these downstream PUFAs under oxidative stress and Fenton Reaction. Furthermore, transcriptomics analysis revealed significant changes in the expression levels of ferroptosis-related genes in PA-treated renal tubular epithelial cells, induced by PUFA peroxides. In addition, phosphatidyl ethanolamine binding protein 1 (PEBP1) formed a complex with 15-lipoxygenase (15-LO) to exacerbate PUFA peroxidation under protein kinase C ζ (PKC ζ) phosphorylation, and PKC ζ was activated by phosphatidic acid derived from PA. In conclusion, this study found that the formation of renal CaOx stones is promoted by ferroptosis of renal tubular epithelial cells resulting from PA-induced dysregulation of PUFA and phosphatidic acid metabolism, and PA can promote the renal adhesion and deposition of CaOx crystals by injuring renal tubular epithelial cells, consequently upregulating adhesion molecules. Accordingly, this study provides a new theoretical basis for understanding the correlation between fatty acid metabolism and the formation of renal CaOx stones, offering potential targets for clinical applications.</description><subject>Adhesion</subject><subject>arachidonate 15-lipoxygenase</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>blood serum</subject><subject>Calcium</subject><subject>Calcium oxalate</subject><subject>Calcium Oxalate - chemistry</subject><subject>Cell adhesion molecules</subject><subject>Cell Biology</subject><subject>Crystals</subject><subject>Desaturase</subject><subject>Epithelial cells</subject><subject>Epithelium</subject><subject>Ethanolamine</subject><subject>fatty acid desaturase</subject><subject>fatty acid metabolism</subject><subject>Fatty acids</subject><subject>Fatty Acids, Unsaturated</subject><subject>Ferroptosis</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Kidneys</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Linoleic acid</subject><subject>Linolenic acid</subject><subject>Lipid metabolism</subject><subject>Lipid peroxidation</subject><subject>lipidomics</subject><subject>Lipids</subject><subject>Lipoxygenase</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Metabolomics</subject><subject>Original</subject><subject>Original Article</subject><subject>Oxalic acid</subject><subject>Oxidative stress</subject><subject>Palmitic acid</subject><subject>Palmitic Acids</subject><subject>Pathogenesis</subject><subject>Peroxidation</subject><subject>Peroxides</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>Phosphatidic acid</subject><subject>phosphatidic acids</subject><subject>Phosphorylation</subject><subject>Polyunsaturated fatty acids</subject><subject>PPAR alpha</subject><subject>Protein kinase C</subject><subject>Proteins</subject><subject>Stone</subject><subject>Transcriptomics</subject><subject>urine</subject><issn>1420-682X</issn><issn>1420-9071</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNqFksuO1DAQRSMEYoaBH2CBLLFhE8aPOHZWCA1PaSQ2ILGzKo7T7ZETBz8Q-ST-Ene6GR4LWNlynbq3bN-qekzwc4KxuIwYYyJrTJsac9Lwer1TnZOG4rrDgtw97VtJP59VD2K8KTSXtL1fnTHJGi5ael59f7XGYHbZQTIDWsBNNlmNQNsBTSZB752NE1qCn3wyEaW9QaMPEyTrZ-RHFMwMDmlw2uap9t_goIRi8vNGB593ezSaEPySfLQR2XnIunj1K1q8W_McIeWw2Y-Q0rp5x8tl7-OyLzbDaZyH1b0RXDSPTutF9enN649X7-rrD2_fX728rjXHMtV9j6kQAHqglLKWC5CESENFh5tyMA6YCRCM9B1wGFrS0b4xLe3HnprGGMYuqhdH3SX3kxm0mVMAp5ZgJwir8mDVn5XZ7tXOf1UEy5YILIrCs5NC8F-yiUlNNmrjHMzG56gY4YwL3HT_R2lHWyxkt6FP_0JvfA7l8TeKU1kkD9PTI6WDj-Vnx9vBCVaH1KhjalRJjdpSo9bS9OT3K9-2_IxJAdgRiKU070z45f0P2R94zNN6</recordid><startdate>20241201</startdate><enddate>20241201</enddate><creator>Wang, Rui</creator><creator>Zhang, Jingdong</creator><creator>Ren, Haotian</creator><creator>Qi, Shiyong</creator><creator>Xie, Linguo</creator><creator>Xie, Haijie</creator><creator>Shang, Zhiqun</creator><creator>Liu, Chunyu</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5357-3716</orcidid><orcidid>https://orcid.org/0000-0002-1833-491X</orcidid></search><sort><creationdate>20241201</creationdate><title>Dysregulated palmitic acid metabolism promotes the formation of renal calcium-oxalate stones through ferroptosis induced by polyunsaturated fatty acids/phosphatidic acid</title><author>Wang, Rui ; Zhang, Jingdong ; Ren, Haotian ; Qi, Shiyong ; Xie, Linguo ; Xie, Haijie ; Shang, Zhiqun ; Liu, Chunyu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-bb0277aacd2223657a8118e27904223fd037a731b9a5ad6192b4e62bfb2e4ee33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adhesion</topic><topic>arachidonate 15-lipoxygenase</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>blood serum</topic><topic>Calcium</topic><topic>Calcium oxalate</topic><topic>Calcium Oxalate - chemistry</topic><topic>Cell adhesion molecules</topic><topic>Cell Biology</topic><topic>Crystals</topic><topic>Desaturase</topic><topic>Epithelial cells</topic><topic>Epithelium</topic><topic>Ethanolamine</topic><topic>fatty acid desaturase</topic><topic>fatty acid metabolism</topic><topic>Fatty acids</topic><topic>Fatty Acids, Unsaturated</topic><topic>Ferroptosis</topic><topic>Gene expression</topic><topic>Humans</topic><topic>Kidneys</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Linoleic acid</topic><topic>Linolenic acid</topic><topic>Lipid metabolism</topic><topic>Lipid peroxidation</topic><topic>lipidomics</topic><topic>Lipids</topic><topic>Lipoxygenase</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Metabolomics</topic><topic>Original</topic><topic>Original Article</topic><topic>Oxalic acid</topic><topic>Oxidative stress</topic><topic>Palmitic acid</topic><topic>Palmitic Acids</topic><topic>Pathogenesis</topic><topic>Peroxidation</topic><topic>Peroxides</topic><topic>Peroxisome proliferator-activated receptors</topic><topic>Phosphatidic acid</topic><topic>phosphatidic acids</topic><topic>Phosphorylation</topic><topic>Polyunsaturated fatty acids</topic><topic>PPAR alpha</topic><topic>Protein kinase C</topic><topic>Proteins</topic><topic>Stone</topic><topic>Transcriptomics</topic><topic>urine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Rui</creatorcontrib><creatorcontrib>Zhang, Jingdong</creatorcontrib><creatorcontrib>Ren, Haotian</creatorcontrib><creatorcontrib>Qi, Shiyong</creatorcontrib><creatorcontrib>Xie, Linguo</creatorcontrib><creatorcontrib>Xie, Haijie</creatorcontrib><creatorcontrib>Shang, Zhiqun</creatorcontrib><creatorcontrib>Liu, Chunyu</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cellular and molecular life sciences : CMLS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Rui</au><au>Zhang, Jingdong</au><au>Ren, Haotian</au><au>Qi, Shiyong</au><au>Xie, Linguo</au><au>Xie, Haijie</au><au>Shang, Zhiqun</au><au>Liu, Chunyu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dysregulated palmitic acid metabolism promotes the formation of renal calcium-oxalate stones through ferroptosis induced by polyunsaturated fatty acids/phosphatidic acid</atitle><jtitle>Cellular and molecular life sciences : CMLS</jtitle><stitle>Cell. Mol. Life Sci</stitle><addtitle>Cell Mol Life Sci</addtitle><date>2024-12-01</date><risdate>2024</risdate><volume>81</volume><issue>1</issue><spage>85</spage><epage>85</epage><pages>85-85</pages><artnum>85</artnum><issn>1420-682X</issn><eissn>1420-9071</eissn><abstract>The pathogenesis of renal calcium-oxalate (CaOx) stones is complex and influenced by various metabolic factors. In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this study aimed to mechanistically assess whether PA is involved in stone formation. Lipidomics analysis of PA-treated renal tubular epithelial cells compared with the control samples revealed that α-linoleic acid and α-linolenic acid were desaturated and elongated, resulting in the formation of downstream polyunsaturated fatty acids (PUFAs). In correlation, the levels of fatty acid desaturase 1 and 2 (FADS1 and FADS2) and peroxisome proliferator-activated receptor α (PPARα) in these cells treated with PA were increased relative to the control levels, suggesting that PA-induced upregulation of PPARα, which in turn upregulated these two enzymes, forming the observed PUFAs. Lipid peroxidation occurred in these downstream PUFAs under oxidative stress and Fenton Reaction. Furthermore, transcriptomics analysis revealed significant changes in the expression levels of ferroptosis-related genes in PA-treated renal tubular epithelial cells, induced by PUFA peroxides. In addition, phosphatidyl ethanolamine binding protein 1 (PEBP1) formed a complex with 15-lipoxygenase (15-LO) to exacerbate PUFA peroxidation under protein kinase C ζ (PKC ζ) phosphorylation, and PKC ζ was activated by phosphatidic acid derived from PA. In conclusion, this study found that the formation of renal CaOx stones is promoted by ferroptosis of renal tubular epithelial cells resulting from PA-induced dysregulation of PUFA and phosphatidic acid metabolism, and PA can promote the renal adhesion and deposition of CaOx crystals by injuring renal tubular epithelial cells, consequently upregulating adhesion molecules. Accordingly, this study provides a new theoretical basis for understanding the correlation between fatty acid metabolism and the formation of renal CaOx stones, offering potential targets for clinical applications.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>38345762</pmid><doi>10.1007/s00018-024-05145-y</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0001-5357-3716</orcidid><orcidid>https://orcid.org/0000-0002-1833-491X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adhesion arachidonate 15-lipoxygenase Biochemistry Biomedical and Life Sciences Biomedicine blood serum Calcium Calcium oxalate Calcium Oxalate - chemistry Cell adhesion molecules Cell Biology Crystals Desaturase Epithelial cells Epithelium Ethanolamine fatty acid desaturase fatty acid metabolism Fatty acids Fatty Acids, Unsaturated Ferroptosis Gene expression Humans Kidneys Kinases Life Sciences Linoleic acid Linolenic acid Lipid metabolism Lipid peroxidation lipidomics Lipids Lipoxygenase Metabolism Metabolites Metabolomics Original Original Article Oxalic acid Oxidative stress Palmitic acid Palmitic Acids Pathogenesis Peroxidation Peroxides Peroxisome proliferator-activated receptors Phosphatidic acid phosphatidic acids Phosphorylation Polyunsaturated fatty acids PPAR alpha Protein kinase C Proteins Stone Transcriptomics urine |
| title | Dysregulated palmitic acid metabolism promotes the formation of renal calcium-oxalate stones through ferroptosis induced by polyunsaturated fatty acids/phosphatidic acid |
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