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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,12,26]]},"abstract":"<jats:p>\n                    AGPAT2 (1-acyl-sn-glycerol-3-phosphate-acyltransferase-2) converts lysophosphatidic acid (LPA) into phosphatidic acid (PA), and mutations of the\n                    <jats:italic>AGPAT2<\/jats:italic>\n                    gene cause the most common form of congenital generalized lipodystrophy which leads to steatohepatitis. The underlying mechanism by which AGPAT2 deficiency leads to lipodystrophy and steatohepatitis has not been elucidated. We addressed this question using an antisense oligonucleotide (ASO) to knockdown expression of\n                    <jats:italic>Agpat2<\/jats:italic>\n                    in the liver and white adipose tissue (WAT) of adult male Sprague-Dawley rats.\n                    <jats:italic>Agpat2<\/jats:italic>\n                    ASO treatment induced lipodystrophy and inflammation in WAT and the liver, which was associated with increased LPA content in both tissues, whereas PA content was unchanged. We found that a controlled-release mitochondrial protonophore (CRMP) prevented LPA accumulation and inflammation in WAT whereas an ASO against\n                    <jats:italic>glycerol-3-phosphate acyltransferase, mitochondrial<\/jats:italic>\n                    (\n                    <jats:italic>Gpam<\/jats:italic>\n                    ) prevented LPA content and inflammation in the liver in\n                    <jats:italic>Agpat2<\/jats:italic>\n                    ASO-treated rats. In addition, we show that overnutrition, due to high sucrose feeding, resulted in increased hepatic LPA content and increased activated macrophage content which were both abrogated with\n                    <jats:italic>Gpam<\/jats:italic>\n                    ASO treatment. Taken together, these data identify LPA as a key mediator of liver and WAT inflammation and lipodystrophy due to AGPAT2 deficiency as well as liver inflammation due to overnutrition and identify LPA as a potential therapeutic target to ameliorate these conditions.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2312666120","type":"journal-article","created":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T13:54:39Z","timestamp":1703166879000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":26,"title":["Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition"],"prefix":"10.1073","volume":"120","author":[{"given":"Ikki","family":"Sakuma","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520"},{"name":"Department of Molecular Diagnosis, Graduate School of Medicine Chiba University, Chiba 260-8670, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael C.","family":"Gaspar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2085-679X","authenticated-orcid":false,"given":"Panu K.","family":"Luukkonen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Kahn","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4036-3987","authenticated-orcid":false,"given":"Dongyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuchen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue","family":"Murray","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Carlsbad, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaya Prakash","family":"Golla","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2073-0273","authenticated-orcid":false,"given":"Daniel F.","family":"Vatner","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varman T.","family":"Samuel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2664-670X","authenticated-orcid":false,"given":"Kitt Falk","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1529-5668","authenticated-orcid":false,"given":"Gerald 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