ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules
Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study, we used kidney-specific expression of quantitative traits and single-nucleus open chromatin analysis to show that genetic variants...
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| Veröffentlicht in: | The Journal of clinical investigation 2024-02, Vol.134 (4), p.1-16 |
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| creator | Mukhi, Dhanunjay Li, Lingzhi Liu, Hongbo Doke, Tomohito Kolligundla, Lakshmi P Ha, Eunji Kloetzer, Konstantin Abedini, Amin Mukherjee, Sarmistha Wu, Junnan Dhillon, Poonam Hu, Hailong Guan, Dongyin Funai, Katsuhiko Uehara, Kahealani Titchenell, Paul M Baur, Joseph A Wellen, Kathryn E Susztak, Katalin |
| description | Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study, we used kidney-specific expression of quantitative traits and single-nucleus open chromatin analysis to show that genetic variants linked to kidney dysfunction on chromosome 20 target the acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2-KO mice, we demonstrated their protection from kidney fibrosis in multiple disease models. Our analysis of primary tubular cells revealed that ACSS2 regulated de novo lipogenesis (DNL), causing NADPH depletion and increasing ROS levels, ultimately leading to NLRP3-dependent pyroptosis. Additionally, we discovered that pharmacological inhibition or genetic ablation of fatty acid synthase safeguarded kidney cells against profibrotic gene expression and prevented kidney disease in mice. Lipid accumulation and the expression of genes related to DNL were elevated in the kidneys of patients with fibrosis. Our findings pinpoint ACSS2 as a critical kidney disease gene and reveal the role of DNL in kidney disease. |
| doi_str_mv | 10.1172/JCI172963 |
| format | Article |
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In this study, we used kidney-specific expression of quantitative traits and single-nucleus open chromatin analysis to show that genetic variants linked to kidney dysfunction on chromosome 20 target the acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2-KO mice, we demonstrated their protection from kidney fibrosis in multiple disease models. Our analysis of primary tubular cells revealed that ACSS2 regulated de novo lipogenesis (DNL), causing NADPH depletion and increasing ROS levels, ultimately leading to NLRP3-dependent pyroptosis. Additionally, we discovered that pharmacological inhibition or genetic ablation of fatty acid synthase safeguarded kidney cells against profibrotic gene expression and prevented kidney disease in mice. Lipid accumulation and the expression of genes related to DNL were elevated in the kidneys of patients with fibrosis. Our findings pinpoint ACSS2 as a critical kidney disease gene and reveal the role of DNL in kidney disease.</description><identifier>ISSN: 1558-8238</identifier><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI172963</identifier><identifier>PMID: 38051585</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Acetate-CoA Ligase - genetics ; Acetyl coenzyme A synthetase ; Animals ; Chromatin ; Chromosome 20 ; Chromosomes ; CRISPR ; Drug development ; Fatalities ; Fatty acids ; Fatty-acid synthase ; Fibrosis ; Gene expression ; Gene loci ; Genes ; Genetic aspects ; Genetic diversity ; Genetic research ; Genetic variation ; Health aspects ; Humans ; Infection control ; Kidney - metabolism ; Kidney diseases ; Kidney Diseases - genetics ; Kidney Diseases - metabolism ; Kidney Tubules - metabolism ; Lipids ; Lipogenesis ; Lipogenesis - genetics ; Medical research ; Medicine, Experimental ; Mice ; Pathogenesis ; Physiological aspects ; Prevention ; Protein expression ; Proteins ; Pyroptosis ; Risk factors ; Synthesis ; Tubules</subject><ispartof>The Journal of clinical investigation, 2024-02, Vol.134 (4), p.1-16</ispartof><rights>COPYRIGHT 2024 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Feb 2024</rights><rights>2023 Mukhi et al. 2023 Mukhi et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c608t-86ea1e590a8e711cb8ac144d376be833098bd6d75098a671ac3d04df256975c63</citedby><cites>FETCH-LOGICAL-c608t-86ea1e590a8e711cb8ac144d376be833098bd6d75098a671ac3d04df256975c63</cites><orcidid>0000-0003-1142-3466 ; 0000-0002-1005-3726 ; 0000-0003-1641-9351 ; 0000-0002-0624-2057 ; 0000-0001-6179-5220 ; 0000-0001-8262-6549 ; 0000-0003-3802-4756</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/PMC10866669/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10866669/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38051585$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mukhi, Dhanunjay</creatorcontrib><creatorcontrib>Li, Lingzhi</creatorcontrib><creatorcontrib>Liu, Hongbo</creatorcontrib><creatorcontrib>Doke, Tomohito</creatorcontrib><creatorcontrib>Kolligundla, Lakshmi P</creatorcontrib><creatorcontrib>Ha, Eunji</creatorcontrib><creatorcontrib>Kloetzer, Konstantin</creatorcontrib><creatorcontrib>Abedini, Amin</creatorcontrib><creatorcontrib>Mukherjee, Sarmistha</creatorcontrib><creatorcontrib>Wu, Junnan</creatorcontrib><creatorcontrib>Dhillon, Poonam</creatorcontrib><creatorcontrib>Hu, Hailong</creatorcontrib><creatorcontrib>Guan, Dongyin</creatorcontrib><creatorcontrib>Funai, Katsuhiko</creatorcontrib><creatorcontrib>Uehara, Kahealani</creatorcontrib><creatorcontrib>Titchenell, Paul M</creatorcontrib><creatorcontrib>Baur, Joseph A</creatorcontrib><creatorcontrib>Wellen, Kathryn E</creatorcontrib><creatorcontrib>Susztak, Katalin</creatorcontrib><title>ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study, we used kidney-specific expression of quantitative traits and single-nucleus open chromatin analysis to show that genetic variants linked to kidney dysfunction on chromosome 20 target the acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2-KO mice, we demonstrated their protection from kidney fibrosis in multiple disease models. Our analysis of primary tubular cells revealed that ACSS2 regulated de novo lipogenesis (DNL), causing NADPH depletion and increasing ROS levels, ultimately leading to NLRP3-dependent pyroptosis. Additionally, we discovered that pharmacological inhibition or genetic ablation of fatty acid synthase safeguarded kidney cells against profibrotic gene expression and prevented kidney disease in mice. Lipid accumulation and the expression of genes related to DNL were elevated in the kidneys of patients with fibrosis. Our findings pinpoint ACSS2 as a critical kidney disease gene and reveal the role of DNL in kidney disease.</description><subject>Acetate-CoA Ligase - genetics</subject><subject>Acetyl coenzyme A synthetase</subject><subject>Animals</subject><subject>Chromatin</subject><subject>Chromosome 20</subject><subject>Chromosomes</subject><subject>CRISPR</subject><subject>Drug development</subject><subject>Fatalities</subject><subject>Fatty acids</subject><subject>Fatty-acid synthase</subject><subject>Fibrosis</subject><subject>Gene expression</subject><subject>Gene loci</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic diversity</subject><subject>Genetic research</subject><subject>Genetic variation</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Infection control</subject><subject>Kidney - metabolism</subject><subject>Kidney diseases</subject><subject>Kidney Diseases - genetics</subject><subject>Kidney Diseases - metabolism</subject><subject>Kidney Tubules - metabolism</subject><subject>Lipids</subject><subject>Lipogenesis</subject><subject>Lipogenesis - genetics</subject><subject>Medical research</subject><subject>Medicine, Experimental</subject><subject>Mice</subject><subject>Pathogenesis</subject><subject>Physiological aspects</subject><subject>Prevention</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Pyroptosis</subject><subject>Risk factors</subject><subject>Synthesis</subject><subject>Tubules</subject><issn>1558-8238</issn><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkt-P1CAQxxuj8c7TB_8B08TE6ENPKIXSJ7PZ-GPNJZe46iuhMO1yx8IetBv3v5fGu3XX7INAMhP4zJeBmSx7idElxnX5_ut8kUzDyKPsHFPKC14S_vjAP8uexXiDEK4qWj3NzghHFFNOz7NuNl8uy7wHB_lWBiPdEHMNA4S1SVu3RjvY5dpEkBHyYOJt3u5y5d0QvLXG9QnOnd_63JqNn2SiiblxD5HD2I4W4vPsSSdthBf39iL78enj9_mX4ur682I-uyoUQ3woOAOJgTZIcqgxVi2XKuWsSc1a4ISghrea6ZomR7IaS0U0qnRXUtbUVDFykX34o7sZ2zVoBSlPacUmmLUMO-GlEccnzqxE77cCI87SaJLC23uF4O9GiINYm6jAWunAj1GUvOENraoaJfT1P-iNH4NL7xNlQ6oyrYb-pXppQRjX-XSxmkTFrOYMMZLkElWcoKb_TFl6B51J20f85Qk-TQ1ro04GvDsKmEoIv4ZejjGKxfLb_7PXP4_ZNwfsCqQdVtHbcTDexZOiKvgYA3T7qmAkpjYW-zZO7KvDMu7Jh74lvwEUnuj6</recordid><startdate>20240215</startdate><enddate>20240215</enddate><creator>Mukhi, Dhanunjay</creator><creator>Li, Lingzhi</creator><creator>Liu, Hongbo</creator><creator>Doke, Tomohito</creator><creator>Kolligundla, Lakshmi P</creator><creator>Ha, Eunji</creator><creator>Kloetzer, Konstantin</creator><creator>Abedini, Amin</creator><creator>Mukherjee, Sarmistha</creator><creator>Wu, Junnan</creator><creator>Dhillon, Poonam</creator><creator>Hu, Hailong</creator><creator>Guan, Dongyin</creator><creator>Funai, Katsuhiko</creator><creator>Uehara, Kahealani</creator><creator>Titchenell, Paul M</creator><creator>Baur, Joseph A</creator><creator>Wellen, Kathryn E</creator><creator>Susztak, Katalin</creator><general>American Society for Clinical Investigation</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1142-3466</orcidid><orcidid>https://orcid.org/0000-0002-1005-3726</orcidid><orcidid>https://orcid.org/0000-0003-1641-9351</orcidid><orcidid>https://orcid.org/0000-0002-0624-2057</orcidid><orcidid>https://orcid.org/0000-0001-6179-5220</orcidid><orcidid>https://orcid.org/0000-0001-8262-6549</orcidid><orcidid>https://orcid.org/0000-0003-3802-4756</orcidid></search><sort><creationdate>20240215</creationdate><title>ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules</title><author>Mukhi, Dhanunjay ; Li, Lingzhi ; Liu, Hongbo ; Doke, Tomohito ; Kolligundla, Lakshmi P ; Ha, Eunji ; Kloetzer, Konstantin ; Abedini, Amin ; Mukherjee, Sarmistha ; Wu, Junnan ; Dhillon, Poonam ; Hu, Hailong ; Guan, Dongyin ; Funai, Katsuhiko ; Uehara, Kahealani ; Titchenell, Paul M ; Baur, Joseph A ; Wellen, Kathryn E ; Susztak, Katalin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c608t-86ea1e590a8e711cb8ac144d376be833098bd6d75098a671ac3d04df256975c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Acetate-CoA Ligase - 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In this study, we used kidney-specific expression of quantitative traits and single-nucleus open chromatin analysis to show that genetic variants linked to kidney dysfunction on chromosome 20 target the acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2-KO mice, we demonstrated their protection from kidney fibrosis in multiple disease models. Our analysis of primary tubular cells revealed that ACSS2 regulated de novo lipogenesis (DNL), causing NADPH depletion and increasing ROS levels, ultimately leading to NLRP3-dependent pyroptosis. Additionally, we discovered that pharmacological inhibition or genetic ablation of fatty acid synthase safeguarded kidney cells against profibrotic gene expression and prevented kidney disease in mice. Lipid accumulation and the expression of genes related to DNL were elevated in the kidneys of patients with fibrosis. Our findings pinpoint ACSS2 as a critical kidney disease gene and reveal the role of DNL in kidney disease.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>38051585</pmid><doi>10.1172/JCI172963</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-1142-3466</orcidid><orcidid>https://orcid.org/0000-0002-1005-3726</orcidid><orcidid>https://orcid.org/0000-0003-1641-9351</orcidid><orcidid>https://orcid.org/0000-0002-0624-2057</orcidid><orcidid>https://orcid.org/0000-0001-6179-5220</orcidid><orcidid>https://orcid.org/0000-0001-8262-6549</orcidid><orcidid>https://orcid.org/0000-0003-3802-4756</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Acetate-CoA Ligase - genetics Acetyl coenzyme A synthetase Animals Chromatin Chromosome 20 Chromosomes CRISPR Drug development Fatalities Fatty acids Fatty-acid synthase Fibrosis Gene expression Gene loci Genes Genetic aspects Genetic diversity Genetic research Genetic variation Health aspects Humans Infection control Kidney - metabolism Kidney diseases Kidney Diseases - genetics Kidney Diseases - metabolism Kidney Tubules - metabolism Lipids Lipogenesis Lipogenesis - genetics Medical research Medicine, Experimental Mice Pathogenesis Physiological aspects Prevention Protein expression Proteins Pyroptosis Risk factors Synthesis Tubules |
| title | ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules |
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