Einzeltreffer — DigiBib

Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific, altered in human disease, and currently thought to be regulated through endocrine and cell-autonomous mechanisms. Here, we show that key metabolic functions of human hepatocytes are controlled by non-parenchymal cells (NPCs) in their microenvironment. We developed mice bearing human hepatic tissue composed of human hepatocytes and NPCs, including human immune, endothelial, and stellate cells. Humanized livers reproduce human liver architecture, perform vital human-specific metabolic/homeostatic processes, and model human pathologies, including fibrosis and non-alcoholic fatty liver disease (NAFLD). Leveraging species mismatch and lipidomics, we demonstrate that human NPCs control metabolic functions of human hepatocytes in a paracrine manner. Mechanistically, we uncover a species-specific interaction whereby WNT2 secreted by sinusoidal endothelial cells controls cholesterol uptake and bile acid conjugation in hepatocytes through receptor FZD5. These results reveal the essential microenvironmental regulation of hepatic metabolism and its human-specific aspects.

Competing Interests: Declaration of interests R.A.F. is an advisor to Glaxo Smith Kline, Celsius, and is the recipient of a grant from Genetech/Roche.

Titel:	Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions.
Autor/in / Beteiligte Person:	Kaffe, E ; Roulis, M ; Zhao, J ; Qu, R ; Sefik, E ; Mirza, H ; Zhou, J ; Zheng, Y ; Charkoftaki, G ; Vasiliou, V ; Vatner, DF ; Mehal, WZ ; Kluger, Yuval ; Flavell, RA
Zeitschrift:	Cell, Jg. 186 (2023-08-31), Heft 18, S. 3793-3809.e26
Veröffentlichung:	Cambridge, Ma : Cell Press ; <i>Original Publication</i>: Cambridge, MIT Press., 2023
Medientyp:	academicJournal
ISSN:	1097-4172 (electronic)
DOI:	10.1016/j.cell.2023.07.017
Schlagwort:	Animals Humans Mice Hepatocytes metabolism Kupffer Cells metabolism Non-alcoholic Fatty Liver Disease metabolism Fibrosis metabolism Endothelial Cells metabolism Liver cytology Liver metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Corporate Authors: AlcHepNet ; NIAAA Alcoholic Hepatitis Consortia, USA. Publication Type: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Cell] 2023 Aug 31; Vol. 186 (18), pp. 3793-3809.e26. <i>Date of Electronic Publication: </i>2023 Aug 09. MeSH Terms: Endothelial Cells* / metabolism ; Liver* / cytology ; Liver* / metabolism ; Animals ; Humans ; Mice ; Hepatocytes / metabolism ; Kupffer Cells / metabolism ; Non-alcoholic Fatty Liver Disease / metabolism ; Fibrosis / metabolism Comments: Comment in: Cell Res. 2024 Jan;34(1):9-10. (PMID: 37730939) References: JHEP Rep. 2021 Mar 21;3(3):100278. (PMID: 34027339) ; Comp Biochem Physiol B Biochem Mol Biol. 2003 Jun;135(2):219-29. (PMID: 12798933) ; Cells Tissues Organs. 2017;203(4):243-257. (PMID: 27889769) ; Nutr Rev. 2009 Nov;67(11):615-23. (PMID: 19906248) ; Gastroenterology. 1967 Apr;52(4):638-46. (PMID: 6021786) ; Science. 2021 Feb 26;371(6532):887-888. (PMID: 33632834) ; Clin Gastroenterol Hepatol. 2020 Nov;18(12):2650-2666. (PMID: 31401364) ; Nat Commun. 2022 Jan 11;13(1):192. (PMID: 35017482) ; Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):160-7. (PMID: 12588754) ; Compr Physiol. 2013 Jul;3(3):1191-212. (PMID: 23897684) ; PLoS One. 2008 Aug 13;3(8):e2930. (PMID: 18698373) ; Curr Biol. 2017 Nov 6;27(21):R1147-R1151. (PMID: 29112863) ; Nat Commun. 2013;4:2823. (PMID: 24264436) ; Science. 2001 Oct 19;294(5542):559-63. (PMID: 11577199) ; Diabetes Obes Metab. 2016 Sep;18(9):936-40. (PMID: 27109453) ; Redox Biol. 2017 Apr;11:622-630. (PMID: 28126520) ; J Gastroenterol Hepatol. 2022 Jan;37(1):208-215. (PMID: 34655465) ; J Lipid Res. 2017 Feb;58(2):350-363. (PMID: 27940481) ; Nat Biotechnol. 2014 Apr;32(4):364-72. (PMID: 24633240) ; Dig Liver Dis. 2005 May;37(5):349-56. (PMID: 15843085) ; Hepatology. 2016 Oct;64(4):1072-85. (PMID: 27359351) ; Blood. 2000 Feb 1;95(3):952-8. (PMID: 10648408) ; Nat Biotechnol. 2007 Aug;25(8):903-10. (PMID: 17664939) ; J Lipid Res. 2020 Apr;61(4):480-491. (PMID: 32086245) ; Int J Mol Med. 2013 Mar;31(3):547-54. (PMID: 23337955) ; Blood. 2016 Jul 7;128(1):104-9. (PMID: 27207787) ; J Biol Chem. 1997 Jan 17;272(3):1456-60. (PMID: 8999814) ; Blood. 2017 Feb 23;129(8):959-969. (PMID: 28077418) ; Lancet Gastroenterol Hepatol. 2020 Mar;5(3):245-266. (PMID: 31981519) ; ACS Chem Biol. 2018 Aug 17;13(8):2280-2287. (PMID: 29963848) ; World J Gastroenterol. 2014 Nov 14;20(42):15539-48. (PMID: 25400438) ; J Biol Chem. 2002 Jul 19;277(29):25963-9. (PMID: 12004058) ; Cell. 2022 Jan 20;185(2):379-396.e38. (PMID: 35021063) ; J Hepatol. 2004 Feb;40(2):261-8. (PMID: 14739097) ; Hepatology. 2019 Jun;69(6):2623-2635. (PMID: 30762896) ; Am J Surg Pathol. 1995 Dec;19(12):1409-17. (PMID: 7503362) ; Am J Physiol Gastrointest Liver Physiol. 2010 Nov;299(5):G1204-10. (PMID: 20813915) ; Hepatology. 2007 Jan;45(1):195-204. (PMID: 17187422) ; Proc Natl Acad Sci U S A. 2020 Jan 21;117(3):1678-1688. (PMID: 31915293) ; Biomedicines. 2021 May 27;9(6):. (PMID: 34072125) ; Cell Rep Med. 2022 Oct 18;3(10):100754. (PMID: 36220068) ; Arch Toxicol. 2021 Jan;95(1):117-133. (PMID: 33150952) ; J Biol Chem. 1994 Jul 29;269(30):19375-9. (PMID: 8034703) ; J Hepatol. 1998 Sep;29(3):450-4. (PMID: 9764993) ; Cell. 2019 Jun 13;177(7):1888-1902.e21. (PMID: 31178118) ; Nat Commun. 2018 Oct 22;9(1):4383. (PMID: 30348985) ; Front Microbiol. 2018 May 08;9:908. (PMID: 29867819) ; Sci Rep. 2017 Mar 13;7:44356. (PMID: 28287163) ; Bone Marrow Transplant. 2000 Sep;26(6):667-71. (PMID: 11035373) ; Science. 2021 Mar 5;371(6533):1019-1025. (PMID: 33674488) ; Elife. 2020 Mar 10;9:. (PMID: 32154783) ; Nature. 2019 Aug;572(7768):199-204. (PMID: 31292543) ; Gastroenterology. 2013 Sep;145(3):574-82.e1. (PMID: 23727264) ; J Lipid Res. 2016 Dec;57(12):2130-2137. (PMID: 27638959) ; PLoS One. 2013 Nov 04;8(11):e78550. (PMID: 24223822) Grant Information: United States HHMI Howard Hughes Medical Institute; P30 DK045735 United States DK NIDDK NIH HHS; I01 BX003259 United States BX BLRD VA; R21 AA029206 United States AA NIAAA NIH HHS; R24 AA022057 United States AA NIAAA NIH HHS; R01 DK124272 United States DK NIDDK NIH HHS; UL1 TR001863 United States TR NCATS NIH HHS; U01 AA026962 United States AA NIAAA NIH HHS; U54 DK106857 United States DK NIDDK NIH HHS; R03 AI159275 United States AI NIAID NIH HHS Contributed Indexing: Keywords: FZD5; WNT2; bile acid conjugation; cholesterol; fibrosis; humanized liver; lipidomics; liver sinusoidal endothelial cells; non-alcoholic fatty liver disease; stellate cells Entry Date(s): Date Created: 20230810 Date Completed: 20231004 Latest Revision: 20240321 Update Code: 20240321 PubMed Central ID: PMC10544749

Klicken Sie ein Format an und speichern Sie dann die Daten oder geben Sie eine Empfänger-Adresse ein und lassen Sie sich per Email zusenden.

BibTeX Citavi, JabRef, u.a.
(Literaturverwaltung)

PDF kein Volltext!
(Merkzettel, Notizen)

RIS Endnote, Citavi u.a.
(Literaturverwaltung)

MODS
(XML zur Weiterverarbeitung)

oder

Wählen Sie das für Sie passende Zitationsformat und kopieren Sie es dann in die Zwischenablage, lassen es sich per Mail zusenden oder speichern es als PDF-Datei.

Gewünschter Zitations-Stil:

oder

Bitte prüfen Sie, ob die Zitation formal korrekt ist, bevor Sie sie in einer Arbeit verwenden. Benutzen Sie gegebenenfalls den "Exportieren"-Dialog, wenn Sie ein Literaturverwaltungsprogramm verwenden und die Zitat-Angaben selbst formatieren wollen.

Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions.