title: LDL receptor knock-out mice are a physiological model particularly vulnerable to study the onset of inflammation in non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  Non-alcoholic steatohepatitis (NASH) involves steatosis combined with inflammation, which can progress into fibrosis and cirrhosis. Exploring the molecular mechanisms of NASH is highly dependent on the availability of animal models. Currently, the most commonly used animal models for NASH imitate particularly late stages of human disease. Thus, there is a need for an animal model that can be used for investigating the factors that potentiate the inflammatory response within NASH. We have previously shown that 7-day high-fat-high-cholesterol (HFC) feeding induces steatosis and inflammation in both APOE2ki and Ldlr(-/-) mice. However, it is not known whether the early inflammatory response observed in these mice will sustain over time and lead to liver damage. We hypothesized that the inflammatory response in both models is sufficient to induce liver damage over time.
  
  
  METHODS
  APOE2ki and Ldlr(-/-) mice were fed a chow or HFC diet for 3 months. C57Bl6/J mice were used as control.
  
  
  RESULTS
  Surprisingly, hepatic inflammation was abolished in APOE2ki mice, while it was sustained in Ldlr(-/-) mice. In addition, increased apoptosis and hepatic fibrosis was only demonstrated in Ldlr(-/-) mice. Finally, bone-marrow-derived-macrophages of Ldlr(-/-) mice showed an increased inflammatory response after oxidized LDL (oxLDL) loading compared to APOE2ki mice.
  
  
  CONCLUSIONS
  Ldlr(-/-) mice, but not APOE2ki mice, developed sustained hepatic inflammation and liver damage upon long term HFC feeding due to increased sensitivity for oxLDL uptake. Therefore, the Ldlr(-/-) mice are a promising physiological model particularly vulnerable for investigating the onset of hepatic inflammation in non-alcoholic steatohepatitis.
authors.affiliation: Department of Molecular Genetics, Pathology, Physiology and Clinical Genetics of Nutrition and Toxicology Research (NUTRIM) Institute of Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Veerle
authors.initials: V
authors.lastname: Bieghs
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Van Gorp
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Wouters
authors.forename: Tim
authors.initials: T
authors.lastname: Hendrikx
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Marc
authors.initials: M
authors.lastname: van Bilsen
authors.forename: Jaap
authors.initials: J
authors.lastname: Bakker
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
mesh_terms: D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D055786:Gene Knockout Techniques; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications; D007249:Inflammation / Q000150:complications; D007728:Kupffer Cells / Q000166:cytology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics*; D013997:Time Factors
chemical_list: D053329:Apolipoprotein E2; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol