title: Steatohepatitis in laboratory opossums exhibiting a high lipemic response to dietary cholesterol and fat.
abstract: Plasma VLDL and LDL cholesterol were markedly elevated (>40-fold) in high-responding opossums, but moderately elevated (6-fold) in low-responding opossums after they had consumed a high-cholesterol and high-fat diet for 24 wk. In both high- and low-responding opossums, plasma triglycerides were slightly elevated, threefold and twofold, respectively. Dietary challenge also induced fatty livers in high responders, but not in low responders. We studied the lipid composition, histopathological features, and gene expression patterns of the fatty livers. Free cholesterol (2-fold), esterified cholesterol (11-fold), and triglycerides (2-fold) were higher in the livers of high responders than those in low responders, whereas free fatty acid levels were similar. The fatty livers of high responders showed extensive lobular disarray by histology. Inflammatory cells and ballooned hepatocytes were also present, as were perisinusoidal fibrosis and ductular proliferation. In contrast, liver histology was normal in low responders. Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders. The accumulation of hepatic cholesterol was concomitant with upregulation of the HMGCR gene and downregulation of the CYP27A1, ABCG8, and ABCB4 genes. Genes involved in inflammation (TNF, NFKB1, and COX2) and in oxidative stress (CYBA and NCF1) were upregulated. Upregulation of the growth factor genes (PDGF and TGFB1) and collagen genes (Col1A1, Col3A1, and Col4A1) was consistent with fibrosis. Some of the histological characteristics of the fatty livers of high-responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis.
authors.affiliation: Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78245, USA. jchan@txbiomedgenetics.org
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chan
authors.forename: Francis E
authors.initials: FE
authors.lastname: Sharkey
authors.forename: Rampratap S
authors.initials: RS
authors.lastname: Kushwaha
authors.forename: Jane F
authors.initials: JF
authors.lastname: VandeBerg
authors.forename: John L
authors.initials: JL
authors.lastname: VandeBerg
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D008078:Cholesterol, LDL / Q000097:blood / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000097:blood / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology*; D005234:Fatty Liver / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006949:Hyperlipidemias / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D009893:Opossums / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D002791:Cholesterol, Dietary; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D004041:Dietary Fats; D014157:Transcription Factors; D014280:Triglycerides