Mice with chimeric livers are an improved model for human lipoprotein metabolism.
OBJECTIVE
Rodents are poor model for human hyperlipidemias because total cholesterol and low density lipoprotein levels are very low on a normal diet. Lipoprotein metabolism is primarily regulated by hepatocytes and we therefore assessed whether chimeric mice extensively repopulated with human cells can model human lipid and bile acid metabolism.


METHODS
FRG [ F ah(-/-) R ag2(-/-)Il2r g (-/-)]) mice were repopulated with primary human hepatocytes. Serum lipoprotein lipid composition and distribution (VLDL, LDL, and HDL) was analyzed by size exclusion chromatography. Bile was analyzed by LC-MS or by GC-MS. RNA expression levels were measured by quantitative RT-PCR.


RESULTS
Chimeric mice displayed increased LDL and VLDL fractions and a lower HDL fraction compared to wild type, thus significantly shifting the ratio of LDL/HDL towards a human profile. Bile acid analysis revealed a human-like pattern with high amounts of cholic acid and deoxycholic acid (DCA). Control mice had only taurine-conjugated bile acids as expcted, but highly repopulated mice had glycine-conjugated cholic acid as found in human bile. RNA levels of human genes involved in bile acid synthesis including CYP7A1, and CYP27A1 were significantly upregulated as compared to human control liver. However, administration of recombinant hFGF19 restored human CYP7A1 levels to normal.


CONCLUSIONS
Humanized-liver mice showed a typical human lipoprotein profile with LDL as the predominant lipoprotein fraction even on a normal diet. The bile acid profile confirmed presence of an intact enterohepatic circulation. Although bile acid synthesis was deregulated in this model, this could be fully normalized by FGF19 administration. Taken together these data indicate that chimeric FRG-mice are a useful new model for human lipoprotein and bile-acid metabolism.
Department of Clinical Science, Intervention and Technology (CLINTEC) Division of Transplantation Surgery, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Ewa C S
EC
Ellis
Willscott Edward
WE
Naugler
Scott
S
Nauglers
Paolo
P
Parini
Lisa-Mari
LM
Mörk
Carl
C
Jorns
Helen
H
Zemack
Anita Lövgren
AL
Sandblom
Ingemar
I
Björkhem
Bo-Göran
BG
Ericzon
Elizabeth M
EM
Wilson
Stephen C
SC
Strom
Markus
M
Grompe
D000818:Animals; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000378:metabolism*; D002678:Chimera / Q000235:genetics / Q000378:metabolism*; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D002850:Chromatography, Gel; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D018703:Founder Effect; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
D001647:Bile Acids and Salts; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; C117476:FGF19 protein, human; D005346:Fibroblast Growth Factors; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase