Insights From Liver‐Humanized Mice on Cholesterol Lipoprotein Metabolism and LXR‐Agonist Pharmacodynamics in Humans

• Published in: Hepatology (Baltimore, Md.) Vol. 72; no. 2; pp. 656 - 670
• Main Authors: Minniti, Mirko E., Pedrelli, Matteo, Vedin, Lise‐Lotte, Delbès, Anne‐Sophie, Denis, Raphaël G.P., Öörni, Katariina, Sala, Claudia, Pirazzini, Chiara, Thiagarajan, Divya, Nurmi, Harri J., Grompe, Markus, Mills, Kevin, Garagnani, Paolo, Ellis, Ewa C.S., Strom, Stephen C., Luquet, Serge H., Wilson, Elizabeth M., Bial, John, Steffensen, Knut R., Parini, Paolo
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer Health, Inc 01.08.2020; Wiley-Blackwell; John Wiley and Sons Inc
• Subjects: Agonists; Animals; Aorta; Benzoates - pharmacokinetics; Benzylamines - pharmacokinetics; Cholesterol; Cholesterol - metabolism; Cholesteryl ester transfer protein; Diabetes mellitus; Endocrinology and metabolism; Hepatocytes; Hepatocytes - metabolism; Hepatocytes - transplantation; Hepatology; Human health and pathology; Humans; Hépatology and Gastroenterology; Kexin; Life Sciences; Lipid metabolism; Lipoproteins; Lipoproteins - metabolism; Liver - metabolism; Liver - surgery; Liver X receptors; Liver X Receptors - agonists; Male; Metabolism; Mice; Mice, Knockout; mRNA; Original; Pharmacodynamics; Precision medicine; Proprotein convertases; Proteoglycans; RAG2 protein; Receptor density; RNA editing; Subtilisin; Triglycerides
• ISSN: 0270-9139; 1527-3350; 1527-3350
• DOI: 10.1002/hep.31052

Background and Aims Genetically modified mice have been used extensively 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. Approach and Results Fah−/−, Rag2−/−, and Il2rg−/− knockout mice on the nonobese diabetic (FRGN) background were repopulated with primary human hepatocytes from different donors. Cholesterol lipoprotein profiles of LHM showed a human‐like pattern, characterized by a high ratio of low‐density lipoprotein to high‐density lipoprotein, and dependency on the human donor. This pattern was determined by a higher level of apolipoprotein B100 in circulation, as a result of lower hepatic mRNA editing and low‐density lipoprotein receptor expression, and higher levels of circulating proprotein convertase subtilisin/kexin type 9. As a consequence, LHM lipoproteins bind to human aortic proteoglycans in a pattern similar to human lipoproteins. Unexpectedly, cholesteryl ester transfer protein 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 stimulation (i.e., a dramatic increase of cholesterol and triglycerides in circulation). Innovatively, LHM allowed the characterization of these effects at a molecular level. Conclusions LHM represent an interesting translatable model of human hepatic and lipoprotein metabolism. Because several metabolic parameters displayed donor dependency, LHM may also be used in studies for personalized medicine.