LDL Receptor Knock-Out Mice Are a Physiological Model Particularly Vulnerable to Study the Onset of Inflammation in Non-Alcoholic Fatty Liver Disease

Abstract

Background & AimsNon-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.ResultsSurprisingly, 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.Conclusion 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.

Low-Density Lipoprotein Receptor–Dependent and Low-Density Lipoprotein Receptor–Independent Mechanisms of Cyclosporin A–Induced Dyslipidemia

“…15 This was supported by our histological studies ( Figure I in the online-only Data Supplement). Hepatic cholesterol, cholesteryl ester (CE), and triglyceride contents were higher in Ldlr −/− mice compared with wt mice, most marked in triglyceride content (115 versus 30 nmol/mg; P<0.05; Table 1).…”

Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis

“…22,23 LDLR or ApoE single-knockout mice developed some of the NAFLD characteristics [24][25][26] but generally failed to broadly reflect the whole spectrum of NAFLD key features. As such, ApoE À / À mice on a fat-and cholesterol-enriched diet developed hepatic inflammation but only mild steatosis.…”

Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH

“…Recent experimental studies suggest that FC is an important lipotoxic molecule that promotes the development of NASH (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Thus, using diverse animal models [dietary with cholesterolcontaining atherogenic (Ath) diets ( 4,5,7 ), LDLR knockout and ApoE knock-in mice ( 9-12 ), appetite-defective Alms1 mutant ( foz/foz ) ( 6,8 ), or melanocortin 4 receptor-defi cient ( Mc4r-ko ) ( 13 ) mice fed an Ath diet, and ABCB4 mutant opossums with defective hepatic cholesterol excretion in bile ( 14 )], there is support for a consistent association between hepatic FC content and NASH pathology.…”