289 - Metabolic characterization of the high-fat/high sucrose diet challenge in liver-humanized mice (ID 1321)
Abstract
Background and Aims
We have recently shown that liver-humanized mice (LHM), i.e. mice repopulated with human hepatocytes, are a translatable model to study human hepatic and lipoprotein metabolism. Moreover, conversely to regular mouse models, LHM could predict the negative lipid outcomes of the first human trial of liver X receptor (LXR) stimulation. High-fat/high-sucrose diet (HFHSD) is often used to induce cardiometabolic diseases in mouse models. Considering the different responses observed between LHM and mouse models, we aimed to characterize the effects of HFHSD on lipoprotein and intrahepatic metabolism in LHM.
Methods
FRGN mice receiving hepatocytes from 3 different human donors or NOD mouse (liver-murinized mice, LMM) were fed HFHSD for 8 weeks. Serum lipoproteins and lipids were separated by size-exclusion chromatography and quantified. Liver triglycerides, cholesterol composition, cholesterol and bile acid precursors, and biliary bile acids were assessed by colorimetry, GC-MS or LC-MS/MS. A multiomic approach was used to analyze gene and protein expression.
Results
Compared to LMM, LHM exhibited higher levels of plasma cholesterol and triglycerides, principally accumulated within VLDL and LDL. In liver, despite similar levels of total cholesterol, cholesteryl esters were higher in LMM, whereas free cholesterol was higher in LHM. Precursors of cholesterol and bile acid synthesis in liver were higher in LHM. LMM bile contained mainly tauromuricholic acids, whereas taurocholic acid was higher in LHM.
Conclusions
LHM challenged with HFHSD behaved more similarly to humans in regard to both plasma and hepatic lipid metabolism. These results corroborate LHM also as model to study diet-induced cardiometabolic diseases with higher relevance for humans.
