LDL and apoB
Liver-humanized mice show a human-like cholesterol lipoprotein profile without needing CETP (Hepatology 2020)
Original title: Insights From Liver-Humanized Mice on Cholesterol Lipoprotein Metabolism and LXR-Agonist Pharmacodynamics in Humans
Mice with a knockout background repopulated with primary human hepatocytes (liver-humanized mice) were characterized for lipoprotein metabolism to assess their translatability as a human hepatic and systemic metabolism model. These mice showed a human-like cholesterol lipoprotein pattern, with a high ratio of LDL to HDL driven by higher circulating apolipoprotein B100, lower hepatic LDL receptor expression, and higher circulating PCSK9, causing their lipoproteins to bind human aortic proteoglycans similarly to human lipoproteins. Unexpectedly, cholesteryl ester transfer protein was not required to produce this human-like lipoprotein profile. The mice also reproduced the negative lipid outcomes seen in the first human trial of the LXR agonist GW3965 (a dramatic rise in circulating cholesterol and triglycerides), allowing molecular-level characterization of that liver X receptor toxicity.
Original abstract
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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.