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Hepatology. 2019 Nov 30. doi: 10.1002/hep.31052. [Epub ahead of print]

New insights from liver-humanized mice on cholesterol lipoprotein metabolism and LXR-agonist pharmacodynamics in humans.

Author information

1
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
2
Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS, UMR 8251, F-75205, (Paris, France.
3
Atherosclerosis Research Laboratory, Wihuri Research Institute (Helsinki, Finland.
4
Department of Physics and Astronomy, University of Bologna, 40126, Bologna, Italy.
5
IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
6
Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
7
The Centre of Excellence in Translational Cancer Biology, University of Helsinki, Biomedicum Helsinki, Helsinki, Finland.
8
Oregon Stem Cell Center, Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.
9
Yecuris Corporation, Tualatin, OR, USA.
10
UCL Centre for Inborn Errors of Metabolism, University College London, London, UK.
11
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), and Interdepartmental Centre "L. Galvani" (CIG), University of Bologna, Bologna, Italy.
12
Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
13
Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
14
Metabolism Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
15
Patient Area Nephrology and Endocrinology, Inflammation and Infection Theme, Karolinska University Hospital, Stockholm, Sweden.

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.

KEYWORDS:

APOB; CETP; LDL; LDLR; hepatocytes; translatability

PMID:
31785104
DOI:
10.1002/hep.31052

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