A human liver chimeric mouse model for non-alcoholic fatty liver disease
| العنوان: | A human liver chimeric mouse model for non-alcoholic fatty liver disease |
|---|---|
| المؤلفون: | N. Thao N. Galvan, Mercedes Barzi, John A. Goss, William R. Lagor, David D. Moore, Adam Dean, Neil J. McKenna, Pavel Sumazin, Barry Zorman, Diane Yang, Beatrice Bissig-Choisat, Karl-Dimiter Bissig, Xavier Legras, David E. Cohen, Robert Brian York, Malgorzata Borowiak, Michele Alves-Bezerra, Scott A. Ochsner |
| المصدر: | JHEP reports : innovation in hepatology, vol 3, iss 3 JHEP Reports JHEP Reports, Vol 3, Iss 3, Pp 100281-(2021) |
| بيانات النشر: | eScholarship, University of California, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | phosphatidylinositol, Cirrhosis, Steatosis, ALT, hexosylceramide, Humanised mice, SREBP, sterol regulatory element-binding protein, PI, RC799-869, CMHs, chimeric mouse hepatocytes, 0302 clinical medicine, GGT, gamma-glutamyl transpeptidase, aspartate aminotransferase, HCC, gamma-glutamyl transpeptidase, chemistry.chemical_classification, 0303 health sciences, education.field_of_study, Western-type diet, Gastroenterology, NASH, CHHs, Diseases of the digestive system. Gastroenterology, 3. Good health, confidence transcript, HCT, cholesteryl ester, human albumin, DCER, dihydroceramide, 030211 gastroenterology & hepatology, PC, non-alcoholic steatohepatitis, PE, transgene-free Il2rg-/-/Rag2-/-/Fah, free fatty acid, LPE, lysophosphatidylethanolamine, DCER, NASH, non-alcoholic steatohepatitis, HCER, hexosylceramide, NC, normal chow, TIRF, PE, phosphatidylethanolamine, nitisinone, lysophosphatidylethanolamine, 03 medical and health sciences, dihydroceramide, Human disease modelling, NAFLD, FFA, free fatty acid, LCER, DEG, MUFA, education, phosphatidylcholine, chimeric mouse hepatocytes, FAH, SM, sphingomyelin, ALP, alkaline phosphatase, FA, fatty acid, NTBC, Fatty acid, medicine.disease, differentially expressed gene, lactosylceramide, PNPLA3, patatin-like-phospholipase domain-containing protein 3, Lipid metabolism, chemistry, fatty acid, PUFA, hALB, human albumin, TIRF, transgene-free Il2rg-/-/Rag2-/-/Fah, AST, aspartate aminotransferase, CT, confidence transcript, PC, phosphatidylcholine, monounsaturated fatty acid, DEG, differentially expressed gene, MUFA, monounsaturated fatty acid, Immunology and Allergy, MAG, monoacylglycerol, PUFA, polyunsaturated free FA, CE, cholesteryl ester, CER, diacylglycerol, FAH, fumarylacetoacetate hydrolase, Fatty liver, SM, chimeric human hepatocytes, hepatocellular carcinoma, CBPEGs, cholesterol biosynthesis pathway enzyme genes, CE, MAG, LPC, patatin-like-phospholipase domain-containing protein 3, triacylglycerol, LPE, alkaline phosphatase, sterol regulatory element-binding protein, Polyunsaturated fatty acid, Research Article, CT, NAFLD, non-alcoholic fatty liver disease, FA, HCER, TAG, triacylglycerol, fumarylacetoacetate hydrolase, monoacylglycerol, alanine aminotransferase, Population, cholesterol biosynthesis pathway enzyme genes, Biology, SREBP, PI, phosphatidylinositol, sphingomyelin, lysophosphatidylcholine, WD, ALT, alanine aminotransferase, high confidence transcriptional target, Internal Medicine, medicine, CBPEGs, ceramide, hALB, LCER, lactosylceramide, normal chow, AST, polyunsaturated free FA, WD, Western-type diet, PNPLA3, 030304 developmental biology, Hepatitis, LPC, lysophosphatidylcholine, Hepatology, DAG, non-alcoholic fatty liver disease, NTBC, nitisinone, CMHs, GGT, HCT, high confidence transcriptional target, phosphatidylethanolamine, TAG, Cancer research, CHHs, chimeric human hepatocytes, ALP, Liver function, NC, CER, ceramide, HCC, hepatocellular carcinoma, FFA, DAG, diacylglycerol, Non-alcoholic fatty liver disease |
| الوصف: | Background & Aims The accumulation of neutral lipids within hepatocytes underlies non-alcoholic fatty liver disease (NAFLD), which affects a quarter of the world’s population and is associated with hepatitis, cirrhosis, and hepatocellular carcinoma. Despite insights gained from both human and animal studies, our understanding of NAFLD pathogenesis remains limited. To better study the molecular changes driving the condition we aimed to generate a humanised NAFLD mouse model. Methods We generated TIRF (transgene-free Il2rg-/-/Rag2-/-/Fah-/-) mice, populated their livers with human hepatocytes, and fed them a Western-type diet for 12 weeks. Results Within the same chimeric liver, human hepatocytes developed pronounced steatosis whereas murine hepatocytes remained normal. Unbiased metabolomics and lipidomics revealed signatures of clinical NAFLD. Transcriptomic analyses showed that molecular responses diverged sharply between murine and human hepatocytes, demonstrating stark species differences in liver function. Regulatory network analysis indicated close agreement between our model and clinical NAFLD with respect to transcriptional control of cholesterol biosynthesis. Conclusions These NAFLD xenograft mice reveal an unexpected degree of evolutionary divergence in food metabolism and offer a physiologically relevant, experimentally tractable model for studying the pathogenic changes invoked by steatosis. Lay summary Fatty liver disease is an emerging health problem, and as there are no good experimental animal models, our understanding of the condition is poor. We here describe a novel humanised mouse system and compare it with clinical data. The results reveal that the human cells in the mouse liver develop fatty liver disease upon a Western-style fatty diet, whereas the mouse cells appear normal. The molecular signature (expression profiles) of the human cells are distinct from the mouse cells and metabolic analysis of the humanised livers mimic the ones observed in humans with fatty liver. This novel humanised mouse system can be used to study human fatty liver disease. Graphical abstract Highlights • Human liver chimeric mice fed a western diet develop NAFLD. • Within the same chimeric liver, human hepatocytes developed pronounced steatosis while murine hepatocytes remained normal. • Unbiased metabolomics and lipidomics of fatty humanised mouse livers revealed signatures of clinical NAFLD. • Transcriptomic analyses showed that molecular responses diverged sharply between murine and human hepatocytes. • This humanised NAFLD model is a physiologically relevant, experimentally tractable model for the study of steatosis. |
| وصف الملف: | application/pdf |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::52b0393a5555874a5526c491b8421dfdTest https://escholarship.org/uc/item/2hg8h2x9Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....52b0393a5555874a5526c491b8421dfd |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |