{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T07:08:02Z","timestamp":1778915282006,"version":"3.51.4"},"reference-count":31,"publisher":"American Diabetes Association","issue":"6","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,6,1]]},"abstract":"<jats:p>Although thiazolidinediones suppress hyperglycemia in diabetic (NON \u00d7 NZO)F1 males, these mice exhibit unusual sensitivity to drug-induced exacerbation of an underlying hepatosteatosis only rarely experienced in human patients. To establish the pharmacogenetic basis for this sensitivity, a panel of recombinant congenic strains (RCSs) with varying degrees of obesity and diabetes was generated by fixing selected NZO HlLt alleles on the diabetes- and hepatosteatosis-resistant NON\/Lt background. Four new strains in this panel were exposed to chronic rosiglitazone treatment. Only one, NONcNZO8 (designated RCS8), exhibited an F1-like hepatosteatotic response. In both the F1 and RCS8 males, this adverse effect correlated with rosiglitazone suppression of already impaired hepatic phosphatidylcholine biosynthetic enzymes in both arms of the biosynthetic pathway, the phosphatidylethanolamine methyl- transferase pathway, and the CDP-choline pathway, including choline kinase and CTP-cholinephosphate cytidylyltransferase. This adverse response was not reproduced by CL316,243, a \u03b23-adrenergic receptor agonist with potent antihyperlipemic effects. Genome comparison showed that RCS8 differed from the other strains in carrying NZO-derived genome on virtually all of chromosome 16 and in smaller segments on chromosomes 6, 14, and 17. Thus, these RCSs present a panel of new mouse models exhibiting differential levels of obesity and diabetes as well as different drug responses. This panel can be used to screen for treatments for type 2 diabetes and its complications.<\/jats:p>","DOI":"10.2337\/diabetes.54.6.1854","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"1854-1862","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":31,"title":["Pharmacogenetic Analysis of Rosiglitazone-Induced Hepatosteatosis in New Mouse Models of Type 2 Diabetes"],"prefix":"10.2337","volume":"54","author":[{"given":"Huei-Ju","family":"Pan","sequence":"first","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Reifsnyder","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis E.","family":"Vance","sequence":"additional","affiliation":[{"name":"Group on Molecular and Cell Biology of Lipids, Canadian Institutes of Health Research, Edmonton, Alberta, Canada"},{"name":"Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Xiao","sequence":"additional","affiliation":[{"name":"Linco Research, St. Charles, Missouri"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward H.","family":"Leiter","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","reference":[{"key":"2022031209124523800_R1","doi-asserted-by":"crossref","unstructured":"Leiter EH, Reifsnyder PC, Flurkey K, Partke H-J, Junger E, Herberg L: Non-insulin dependent diabetes genes in mice: deleterious synergism by both parental genomes contributes to diabetogenic thresholds. Diabetes\u200847:1287\u20131295, 1998","DOI":"10.2337\/diab.47.8.1287"},{"key":"2022031209124523800_R2","doi-asserted-by":"crossref","unstructured":"Reifsnyder PC, Churchill G, Leiter EH: Maternal environment and genotype interact to establish diabesity in mice. Genome Res\u200810:1568\u20131578, 2000","DOI":"10.1101\/gr.147000"},{"key":"2022031209124523800_R3","doi-asserted-by":"crossref","unstructured":"Watkins SM, Reifsnyder PC, Pan H-J, German B, Leiter EH: Lipid metabolome-wide effects of the peroxisome proliferator-activated receptor gamma agonist rosiglitazone on a new mouse model of type 2 diabetes. J Lipid Res\u200843:1809\u20131817, 2002","DOI":"10.1194\/jlr.M200169-JLR200"},{"key":"2022031209124523800_R4","doi-asserted-by":"crossref","unstructured":"Waite KA, Cabilio NR, Vance DE: Choline deficiency-induced liver damage is reversible in Pemt(\u2212\/\u2212) mice. J Nutr\u2008132:68\u201371, 2002","DOI":"10.1093\/jn\/132.1.68"},{"key":"2022031209124523800_R5","doi-asserted-by":"crossref","unstructured":"Zhu X, Song J, Mar MH, Edwards LJ, Zeisel SH: Phosphatidylethanolamine N-methyltransferase (PEMT) knockout mice have hepatic steatosis and abnormal hepatic choline metabolite concentrations despite ingesting a recommended dietary intake of choline. Biochem J\u2008370:987\u2013993, 2003","DOI":"10.1042\/bj20021523"},{"key":"2022031209124523800_R6","doi-asserted-by":"crossref","unstructured":"Noga AA, Vance DE: A gender-specific role for phosphatidylethanolamine N-methyltransferase-derived phosphatidylcholine in the regulation of plasma high density and very low density lipoproteins in mice. J Biol Chem\u2008278:21851\u201321859, 2003","DOI":"10.1074\/jbc.M301982200"},{"key":"2022031209124523800_R7","doi-asserted-by":"crossref","unstructured":"Noga AA, Vance DE: Insights into the requirement of phosphatidylcholine synthesis for liver function in mice. J Lipid Res\u200844:1998\u20132005, 2003","DOI":"10.1194\/jlr.M300226-JLR200"},{"key":"2022031209124523800_R8","doi-asserted-by":"crossref","unstructured":"Noga AA, Zhao Y, Vance DE: An unexpected requirement for phosphatidylethanolamine N-methyltransferase in the secretion of very low density lipoproteins. J Biol Chem\u2008277:42358\u201342365, 2002","DOI":"10.1074\/jbc.M204542200"},{"key":"2022031209124523800_R9","doi-asserted-by":"crossref","unstructured":"Jacobs RL, Devlin C, Tabas I, Vance DE: Targeted deletion of hepatic CTP:phosphocholine cytidylyltransferase \u03b1 in mice decreases plasma high density and very low density lipoproteins. J Biol Chem\u2008279:47402\u201347410, 2004","DOI":"10.1074\/jbc.M404027200"},{"key":"2022031209124523800_R10","doi-asserted-by":"crossref","unstructured":"Vance DE: Phospholipid biosynthesis in eukaryotes. In Biochemistry of Lipids, Lipoproteins and Membranes. 4th ed. Vance DE, Vance JE, Eds. Amsterdam, Elsevier Science, 2002, p. 205\u2013232","DOI":"10.1016\/S0167-7306(02)36010-1"},{"key":"2022031209124523800_R11","doi-asserted-by":"crossref","unstructured":"Banchio C, Schang LM, Vance DE: Phosphorylation of Sp1 by cyclin-dependent kinase 2 modulates the role of Sp1 in CTP: phosphocholine cytidylyltransferase alpha regulation during the S phase of the cell cycle. J Biol Chem\u2008279:40220\u201340226, 2004","DOI":"10.1074\/jbc.M406468200"},{"key":"2022031209124523800_R12","doi-asserted-by":"crossref","unstructured":"Reifsnyder PC, Leiter EH: Deconstructing and reconstructing obesity-induced diabetes (diabesity) in mice. Diabetes\u200851:825\u2013832, 2002","DOI":"10.2337\/diabetes.51.3.825"},{"key":"2022031209124523800_R13","doi-asserted-by":"crossref","unstructured":"Koza RA, Flurkey K, Graunke DM, Braun C, Pan HJ, Reifsnyder PC, Kozak LP, Leiter EH: Contributions of dysregulated energy metabolism to type 2 diabetes development in NZO\/H1Lt mice with polygenic obesity. Metabolism\u200853:799\u2013808, 2004","DOI":"10.1016\/j.metabol.2003.12.024"},{"key":"2022031209124523800_R14","doi-asserted-by":"crossref","unstructured":"Fujiwara T, Okuno A, Yoshioka S, Horikoshi H: Suppression of hepatic gluconeogenesis in long-term troglitazone treated diabetic KK and C57BL\/KsJ-db\/db mice. Metabolism\u200844:486\u2013490, 1995","DOI":"10.1016\/0026-0495(95)90056-X"},{"key":"2022031209124523800_R15","doi-asserted-by":"crossref","unstructured":"Ridgway ND, Vance DE: Phosphatidylethanolamine N-methyltransferase from rat liver. Methods Enzymol\u2008209:366\u2013374, 1992","DOI":"10.1016\/0076-6879(92)09045-5"},{"key":"2022031209124523800_R16","doi-asserted-by":"crossref","unstructured":"Weinhold PA, Rethy VB: The separation, purification, and characterization of ethanolamine kinase and choline kinase from rat liver. Biochemistry\u200813:5135\u20135141, 1974","DOI":"10.1021\/bi00722a013"},{"key":"2022031209124523800_R17","doi-asserted-by":"crossref","unstructured":"Aoyama C, Ohtani A, Ishidate K: Expression and characterization of the active molecular forms of choline\/ethanolamine kinase-alpha and -beta in mouse tissues, including carbon tetrachloride-induced liver. Biochem J\u2008363:777\u2013784, 2002","DOI":"10.1042\/bj3630777"},{"key":"2022031209124523800_R18","unstructured":"Higashimori T, Kim H-J, Park S-Y, Choi CS, Danton C, Xiao Q, Reifsnyder PC, Leiter EH: NONcNZO10 mice develop obesity, insulin resistance, and hyperglycemia resembling human type 2 diabetes (Abstract). Diabetes\u200853:A407, 2004"},{"key":"2022031209124523800_R19","doi-asserted-by":"crossref","unstructured":"Faich GA, Moseley RH: Troglitazone (Rezulin) and hepatic injury. Pharmacoepidemiol Drug Saf\u200810:537\u2013547, 2001","DOI":"10.1002\/pds.652"},{"key":"2022031209124523800_R20","doi-asserted-by":"crossref","unstructured":"Tiikkainen M, Hakkinen AM, Korsheninnikova E, Nyman T, Makimattila S, Yki-Jarvinen H: Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes\u200853:2169\u20132176, 2004","DOI":"10.2337\/diabetes.53.8.2169"},{"key":"2022031209124523800_R21","doi-asserted-by":"crossref","unstructured":"Wen XY, Stewart AK, Skaug J, Wei E, Tsui LC: Murine phosphatidylserine-specific phospholipase A1 (Ps-pla1) maps to chromosome 16 but is distinct from the lpd (lipid defect) locus. Mamm Genome\u200812:129\u2013132, 2001","DOI":"10.1007\/s003350010256"},{"key":"2022031209124523800_R22","doi-asserted-by":"crossref","unstructured":"Wen XY, Bryce DM, Breitman ML: Characterization of lpd (lipid defect): a novel mutation on mouse chromosome 16 associated with a defect in triglyceride metabolism. Hum Mol Genet\u20087:743\u2013750, 1998","DOI":"10.1093\/hmg\/7.4.743"},{"key":"2022031209124523800_R23","doi-asserted-by":"crossref","unstructured":"Kim JH, Sen S, Avery CS, Simpson E, Chandler P, Nishina PM, Churchill GA, Naggert JK: Genetic analysis of a new mouse model for non-insulin-dependent diabetes. Genomics\u200874:273\u2013286, 2001","DOI":"10.1006\/geno.2001.6569"},{"key":"2022031209124523800_R24","doi-asserted-by":"crossref","unstructured":"Dolinsky VW, Gilham D, Alam M, Vance DE, Lehner R: Triacylglycerol hydrolase: role in intracellular lipid metabolism. Cell Mol Life Sci\u200861:1633\u20131651, 2004","DOI":"10.1007\/s00018-004-3426-3"},{"key":"2022031209124523800_R25","doi-asserted-by":"crossref","unstructured":"Ueki K, Kondo T, Tseng YH, Kahn CR: Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci U S A\u2008101:10422\u201310427, 2004","DOI":"10.1073\/pnas.0402511101"},{"key":"2022031209124523800_R26","doi-asserted-by":"crossref","unstructured":"Nishimaki-Mogami T, Yao Z, Fujimori K: Inhibition of phosphatidylcholine synthesis via the phosphatidylethanolamine methylation pathway impairs incorporation of bulk lipids into VLDL in cultured rat hepatocytes. J Lipid Res\u200843:1035\u20131045, 2002","DOI":"10.1194\/jlr.M100354-JLR200"},{"key":"2022031209124523800_R27","doi-asserted-by":"crossref","unstructured":"Hazra S, Xiong S, Wang J, Rippe RA, Krishna V, Chatterjee K, Tsukamoto H: Peroxisome proliferator-activated receptor \u03b3 induces a phenotypic switch from activated to quiescent hepatic stellate cells. J Biol Chem\u2008279:11392\u201311401, 2004","DOI":"10.1074\/jbc.M310284200"},{"key":"2022031209124523800_R28","doi-asserted-by":"crossref","unstructured":"Kumar AP, Piedrafita FJ, Reynolds WF: Peroxisome proliferator-activated receptor gamma ligands regulate myeloperoxidase expression in macrophages by an estrogen-dependent mechanism involving the \u2212463GA promoter polymorphism. J Biol Chem\u2008279:8300\u20138315, 2004","DOI":"10.1074\/jbc.M311625200"},{"key":"2022031209124523800_R29","doi-asserted-by":"crossref","unstructured":"Becker W, Kluge R, Kantner T, Linnartz K, Korn M, Tschank G, Plum L, Giesen K, Joost HG: Differential hepatic gene expression in a polygenic mouse model with insulin resistance and hyperglycemia: evidence for a combined transcriptional dysregulation of gluconeogenesis and fatty acid synthesis. J Mol Endocrinol\u200832:195\u2013208, 2004","DOI":"10.1677\/jme.0.0320195"},{"key":"2022031209124523800_R30","doi-asserted-by":"crossref","unstructured":"Gavrilova O, Haluzik M, Matsusue K, Cutson JJ, Johnson L, Dietz KR, Nicol CJ, Vinson C, Gonzalez FJ, Reitman ML: Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem\u2008278:34268\u201334276, 2003","DOI":"10.1074\/jbc.M300043200"},{"key":"2022031209124523800_R31","doi-asserted-by":"crossref","unstructured":"Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, Brewer B Jr, Reitman ML, Gonzalez FJ: Liver-specific disruption of PPAR\u03b3 in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest\u2008111:737\u2013747, 2003","DOI":"10.1172\/JCI200317223"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/54\/6\/1854\/382294\/zdb00605001854.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/54\/6\/1854\/382294\/zdb00605001854.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:26:43Z","timestamp":1667406403000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/54\/6\/1854\/14004\/Pharmacogenetic-Analysis-of-Rosiglitazone-Induced"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,6,1]]},"references-count":31,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2005,6,1]]}},"URL":"https:\/\/doi.org\/10.2337\/diabetes.54.6.1854","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,6,1]]}}}