Abstract
ObjectiveRodents 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.DesignFRG [ 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.ResultsChimeric 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.ConclusionHumanized-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.
Highlights
The use of experimental animals in scientific research has enabled some of the most important breakthroughs in medical research [1]
RNA levels of human genes involved in bile acid synthesis including CYP7A1, and CYP27A1 were significantly upregulated as compared to human control liver
Bile acid synthesis was deregulated in this model, this could be fully normalized by fibroblast growth factor 19 (FGF19) administration
Summary
The use of experimental animals in scientific research has enabled some of the most important breakthroughs in medical research [1]. Mice and human differ greatly in many aspects of cholesterol metabolism ranging from lipoprotein processing to cholesterol catabolism through bile acid synthesis. Modified mouse strains have been developed for atherosclerosis research, but the information gained has been limited because of the major species differences and the complex nature of cholesterol and lipid metabolism [6,7,8]. Catabolism of cholesterol via bile acid synthesis differs in mice and humans. Regulation of the rate limiting enzyme in bile acids synthesis, cholesterol 7alpha-hydroxylase is dissimilar, and frequently opposite in rodents and man [10]. Stimulation of LXR by cholesterol leads to a feed-forward regulation that increases the synthesis of bile acids in mice, but not in humans
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