PXB-mouse and PXB-cells for non-alcoholic steatohepatitis NASH
Image credits to D. Zhalmuratova

International NASH DayJune 12 – is aimed to increase public awareness about non-alcoholic steatohepatitis (NASH). NASH is characterized by the presence of an abnormal accumulation of fat in the liver which can progress to liver cell injury (hepatocellular ballooning) and inflammation.

NASH and NAFLD facts for USA

Did you know that more than 75 million people in the US may have NAFLD (non-alcoholic fatty liver disease)? Up to 30% of them will develop NASH and up to 20% of people with NASH will develop liver cirrhosis. Our joint responsibility is to help in fighting with this life-threatening disease.

PhoenixBio technology platform of chimeric mouse with humanized liver is used to develop a treatment to cure those in need. Both PXB-mouse®  and PXB-cells®  are used in NASH-related translational research. A novel NASH model can be established based on PXB-mice fed with various disease-related diets, taking into the account that PXB-mice show humanized lipoprotein metabolism even on the regular mice diet.

PXB-mouse® has up to 95% human hepatocyte engraftment in the liver and displays human-like circulating lipoprotein cholesterol profile. The LDL/HDL ratio in PXB-mice is similar to that reported in humans (LDL – low density lipoprotein, HDL – high density lipoprotein). The publication by the Intercept team in the Journal of Lipid Research found that Obeticholic acid (OCA) induced human-like changes in cholesterol profile in PXB-mice. Thus, PXB-mouse® reproduces the effects of farnesoid X receptor (FXR) activation seen in clinical trials.

Human-like lipoprotein profile in PXB-mouse
Humanized lipoprotein profile of PXB-mouse® compared to C57 mice

PhoenixBio Group’s research and development team reported the development of humanized NASH liver mouse model with pathophysiological features commonly observed in human NASH liver using PXB-mouse®. For this disease model two types of diets have been used: choline deficient, L-amino acid defined (CDA) high-fat diet and Gubra AMLN NASH (GAN) diet. PXB-mice on these diets develop inflammation,  fibrosis and ballooning of human hepatocytes. With the CDA high fat diet, the changes in total ALT associated with the diet were compared with the change of human-specific ALT-1 (this assay can be performed at PhoenixBio).

PXB-cells® (fresh human hepatocytes, often referred to as PHH) also shown their usability in metabolic disease studies as shown in the recent publication “Lipoprotein profile and lipid metabolism of PXB-cells®, human primary hepatocytes from liver-humanized mice: proposal of novel in vitro system for screening anti-lipidemic drugs”.

Humanized lipoprotein profile of PXB-cells – human hepatocytes
Lipoprotein profile of PXB-cells compared to other hepatoma cell lines. Image modified from Hata et al., Biomed Res. 2020 Feb 1;41(1):33.

The paper discusses lipoprotein profile and lipid metabolism of PXB-cells®, showing their suitability to screen anti-lipidemic agents. The authors show that PXB-cells® mainly release triglycerides and cholesterol as VLDL (similar to primary human hepatocytes) in contrast to two other hepatoma cell lines, which mainly release LDL (VLDL – very low density lipoprotein). Fenofibrate (PPARα ligand) suppressed lipoprotein production from PXB-cells® in a dose-dependent manner as shown by triglycerides and cholesterol profiles.