Cholesterol induces lipoprotein lipase expression in a tree shrew (Tupaia belangeri chinensis) model of non-alcoholic fatty liver disease.

Linqiang Zhang,Bin Liang,Qing Chang,Yunhai Li,Xiaoyun Wu,Zhiguo Zhang,Shasha Liao

doi:10.1038/srep15970

Abstract

Animal models are indispensible to investigate the pathogenesis and treatments of non-alcoholic fatty liver diseases (NAFLD). Altered cholesterol metabolism has been implicated into the pathogenesis of NAFLD. Here, using high fat, cholesterol and cholate diet (HFHC), we generated a novel tree shrew (Tupaia belangeri chinensis) model of NAFLD, which displayed dyslipidemia with increased levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-c) and high density lipoprotein-cholesterol (HDL-c), but decreased level of triglycerides (TG). Liver histopathology and genes expression indicated that HFHC diet successfully induced liver steatosis to inflammation and fibrosis progressively within 10 weeks. Moreover, HFHC induced the transcriptional expression of lipoprotein lipase (lpl) in the liver, but repressed the expression of LDL receptor, and the endogenous synthesis pathway and excretion of cholesterol. Notably, Poloxamer 407 (P-407) inhibition of LPL improved the severity of steatosis and reduced inflammation. These results illustrated that LPL plays an important role in cholesterol metabolism in NAFLD, and the tree shrew may be a valuable animal model for further research into NAFLD.

Highlights

Animal models are indispensible to investigate the pathogenesis and treatments of non-alcoholic fatty liver diseases (NAFLD)
Over the course of the experiment, neither diets of HFLC nor HFHC changed the level of fast blood glucose (FBG), but HFHC decreased the level of hemoglobin A1c (HbA1c) at 10 weeks (Table 1)
The HFHC diet did not exhibit any impairment of oral glucose tolerance test (OGTT) at 3 and 6 weeks, though glucose levels among this group showed a significant difference at 120 minutes (Figure S1D,E)

Summary

Introduction

Animal models are indispensible to investigate the pathogenesis and treatments of non-alcoholic fatty liver diseases (NAFLD). Poloxamer 407 (P-407) inhibition of LPL improved the severity of steatosis and reduced inflammation These results illustrated that LPL plays an important role in cholesterol metabolism in NAFLD, and the tree shrew may be a valuable animal model for further research into NAFLD. Researchers were successful in creating a viable model by supplying a diet supplemented with cholesterol, due to its important role in the pathogenesis of NAFLD In these models, an atherogenic diet (1.25% cholesterol and 0.5% cholate) or with the addition of high fat was successful in forcing the progression from steatosis to inflammation and fibrosis in a time-dependent manner among mice[16], as did a combination diet of high fat (15%) and high cholesterol (1%)[18]. Given the successes of previous studies in generating other models using a combination diet of fat, cholesterol, and cholate to partially replicate the histological features of human NAFLD in animals, it seems feasible that a similar approach could be used to develop a tree shrew NAFLD model

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