{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T05:32:05Z","timestamp":1784179925464,"version":"3.55.0"},"reference-count":32,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2017,3,22]],"date-time":"2017-03-22T00:00:00Z","timestamp":1490140800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK40936"],"award-info":[{"award-number":["R01 DK40936"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Lipodystrophy is a rare disorder characterized by complete or partial loss of adipose tissue. Patients with lipodystrophy exhibit hypertriglyceridemia, severe insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). Efforts to ameliorate NASH in lipodystrophies with pharmacologic agents have met with limited success. We examined whether a controlled\u2010release mitochondrial protonophore (CRMP) that produces mild liver\u2010targeted mitochondrial uncoupling could decrease hypertriglyceridemia and reverse NASH and diabetes in a mouse model (fatless AZIP\/F\u20101 mice) of severe lipodystrophy and diabetes. After 4 wk of oral CRMP (2 mg\/kg body weight per day) or vehicle treatment, mice underwent hyperinsulinemic\u2010euglycemic clamps combined with radiolabeled glucose to assess liver and muscle insulin responsiveness and tissue lipid measurements. CRMP treatment reversed hypertriglyceridemia and insulin resistance in liver and skeletal muscle. Reversal of insulin resistance could be attributed to reductions in diacylglycerol content and reduced PKC\u2010\u03b5 and PKC\u2010\u03b8 activity in liver and muscle respectively. CRMP treatment also reversed NASH as reflected by reductions in plasma aspartate aminotransferase and alanine aminotransferase concentrations; hepatic steatosis; and hepatic expression of IL\u20101\u03b1, \u2010\u03b2, \u20102, \u20104, \u20106, \u201010, \u201012, CD69, and caspase 3 and attenuated activation of the IRE\u20101\u03b1 branch of the unfolded protein response. Taken together, these results provide proof of concept for the development of liver\u2010targeted mitochondrial uncoupling agents as a potential novel therapy for lipodystrophy\u2010associated hypertriglyceridemia, NASH and diabetes.\u2014Abulizi, A., Perry, R. J., Camporez, J. P. G., Jurczak, M. J., Petersen, K. F., Aspichueta, P., Shulman, G. I. A controlled\u2010release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice. FASEB J. 31, 2916\u20132924 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201700001r","type":"journal-article","created":{"date-parts":[[2017,3,22]],"date-time":"2017-03-22T20:56:52Z","timestamp":1490216212000},"page":"2916-2924","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["A controlled\u2010release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice"],"prefix":"10.1096","volume":"31","author":[{"given":"Abudukadier","family":"Abulizi","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Yale University School of Medicine New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel J.","family":"Perry","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Yale University School of Medicine New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Paulo G.","family":"Camporez","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Yale University School of Medicine New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Jurczak","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Yale University School of Medicine New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kitt Falk","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Yale University School of Medicine New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Aspichueta","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Yale University School of Medicine New Haven Connecticut USA"},{"name":"Department of Physiology Faculty of Medicine and Nursing University of Basque Country (UPV\/EHU) Leioa Spain"},{"name":"Biocruces Research Institute Barakaldo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald I.","family":"Shulman","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Yale University School of Medicine New Haven Connecticut USA"},{"name":"Department of Cellular and Molecular Physiology Yale University School of Medicine New Haven Connecticut USA"},{"name":"Howard Hughes Medical Institute Yale University School of Medicine New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,3,22]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(99)00414-3"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.002907"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.20.3168"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20672"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2013.02.007"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012437"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0215001"},{"key":"e_1_2_7_9_1","doi-asserted-by":"crossref","DOI":"10.1210\/jcem.87.5.8624","article-title":"Serum adiponectin and leptin levels in patients with lipodystrophies","volume":"87","author":"Haque W. A.","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2006.11.010"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2229"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa0672"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.25.14623"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.316760"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1139\/y59-099"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.6.1270"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M200958200"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.12.8456"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1409229111"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60408-4"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2277"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.04.002"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M313478200"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30400"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI86013"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07203"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(01)00265-9"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.10.039"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2010.199"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0803404"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5453.664"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1113359108"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201700001R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.201700001R","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201700001R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T23:16:53Z","timestamp":1761693413000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.201700001R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,22]]},"references-count":32,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2017,7]]}},"alternative-id":["10.1096\/fj.201700001R"],"URL":"https:\/\/doi.org\/10.1096\/fj.201700001r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,22]]},"assertion":[{"value":"2017-01-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-03-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-03-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}