Minniti, ME;
Pedrelli, M;
Vedin, L-L;
Delbès, A-S;
Denis, RGP;
Öörni, K;
Sala, C;
... Parini, P; + view all
(2020)
New insights from liver-humanized mice on cholesterol lipoprotein metabolism and LXR-agonist pharmacodynamics in humans.
Hepatology
10.1002/hep.31052.
(In press).
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Abstract
Genetically modified mice have been extensively used to study human disease. However, the data gained are not always translatable to humans because of major species differences. Liver-humanized mice (LHM) are considered a promising model to study human hepatic and systemic metabolism. Therefore, we aimed to further explore their lipoprotein metabolism and to characterize key hepatic species-related, physiological differences. Fah-/- , Rag2-/- , Il2rg-/- (FRG® -KO) mice on the non-obese diabetic (NOD) background (FRGN) were repopulated with primary human hepatocytes from different donors. Cholesterol lipoprotein profiles of LHM showed a human-like pattern, characterized by high ratio of low-density lipoprotein (LDL) to high-density lipoprotein (HDL), and dependency on the human donor. This pattern was determined by a higher level of apolipoprotein (APO) B100 in circulation, as a result of lower hepatic APOB mRNA editing and LDL receptor (LDLR) expression, and higher levels of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9). As a consequence, LHM lipoproteins bound to human aortic proteoglycans in a pattern similar to human lipoproteins. Unexpectedly, cholesteryl ester transfer protein (CETP) was not required to determine the human-like cholesterol lipoprotein profile. Moreover, LHM treated with GW3965 mimicked the negative lipid outcomes of the first human trial of liver X receptor (LXR) stimulation, i.e. a dramatic increase of cholesterol and triglycerides in circulation. Innovatively, LHM allowed the characterization of these effects at molecular level. CONCLUSIONS: LHM represent an interesting translatable model of human hepatic and lipoprotein metabolism. Since several metabolic parameters displayed donor-dependency, LHM may also be employed in studies for personalized medicine.
| Type: | Article |
|---|---|
| Title: | New insights from liver-humanized mice on cholesterol lipoprotein metabolism and LXR-agonist pharmacodynamics in humans |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/hep.31052 |
| Publisher version: | https://doi.org/10.1002/hep.31052 |
| Language: | English |
| Additional information: | This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | APOB, CETP, LDL, LDLR, hepatocytes, translatability |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10088333 |
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