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

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.

Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic steatohepatitis development in chimeric mice

“…Hepatocytes are central to lipid homeostasis, and humanized mice have plasma cholesterol profiles shifted toward lower density lipoproteins compared to wild type mice. 34 Similar to previous reports, 35–37 huFNRG on chow contained more LDL than HDL cholesterol particles compared to muFNRG mice ( Fig 2c ). Four weeks of WD feeding resulted in stark increases in VLDL and LDL cholesterol in huFNRG plasma.…”

“…Hepatocytes are central to systemic lipid and glucose regulation. Similar to previous reports 35–37 huFNRG on chow had starkly different lipid profiles than muFNRG, in part due to mice lacking cholesterol ester transfer protein. 37 In addition, we show that fasting glucose and possibly fasting insulin levels were higher in huFNRG mice than muFNRG mice on chow.…”

“…Similar to previous reports 35–37 huFNRG on chow had starkly different lipid profiles than muFNRG, in part due to mice lacking cholesterol ester transfer protein. 37 In addition, we show that fasting glucose and possibly fasting insulin levels were higher in huFNRG mice than muFNRG mice on chow. Species incompatibilities may contribute to the elevated fasting glucose of huFNRG mice on chow, as was illustrated by studies in the uPA liver chimeric model.…”

Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

“…Similar to previous reports [38][39][40] huFNRG on chow had starkly different lipid profiles than muFNRG, in part due to mice lacking cholesterol ester transfer protein. 40 In addition, we show that fasting glucose and possibly fasting insulin levels were higher in huFNRG mice than muFNRG mice on chow. Species incompatibilities may contribute to the elevated fasting glucose of huFNRG mice on chow, as was illustrated by studies in the uPA liver chimeric model.…”

“…Hepatocytes are central to lipid homeostasis, and humanized mice have plasma cholesterol profiles shifted toward lower density lipoproteins compared to wild type mice. 37 Similar to previous reports, [38][39][40] huFNRG on chow contained more LDL than HDL cholesterol particles compared to muFNRG mice (Fig 2c). Four weeks of WD feeding resulted in stark increases in VLDL and LDL cholesterol in huFNRG plasma.…”