Dataset Information

A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology.

ABSTRACT: Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disorder that is associated with an increased incidence of cardiovascular disease and type 2 diabetes. Animal models adequately mimicking this condition are scarce. We herein investigate whether Ldlr-/-. Leiden mice on different high-fat diets represent a suitable NASH model. Ldlr-/-. Leiden mice were fed a healthy chow diet or fed a high-fat diet (HFD) containing lard or a fast food diet (FFD) containing milk fat. Additionally, the response to treatment with obeticholic acid (OCA) was evaluated. Both high-fat diets induced obesity, hyperlipidemia, hyperinsulinemia, and increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Mice on both diets developed progressive macro- and microvesicular steatosis, hepatic inflammation, and fibrosis, along with atherosclerosis. HFD induced more severe hyperinsulinemia, while FFD induced more severe hepatic inflammation with advanced (F3) bridging fibrosis, as well as more severe atherosclerosis. OCA treatment significantly reduced hepatic inflammation and fibrosis, and it did not affect atherosclerosis. Hepatic transcriptome analysis was compared with human NASH and illustrated similarity. The present study defines a translational model of NASH with progressive liver fibrosis and simultaneous atherosclerosis development. By adaptation of the fat content of the diet, either insulin resistance (HFD) or hepatic inflammation and fibrosis (FFD) can be aggravated.

SUBMITTER: van den Hoek AM

PROVIDER: S-EPMC7565967 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology.

van den Hoek Anita M AM Verschuren Lars L Worms Nicole N van Nieuwkoop Anita A de Ruiter Christa C Attema Joline J Menke Aswin L AL Caspers Martien P M MPM Radhakrishnan Sridhar S Salic Kanita K Kleemann Robert R

Cells 20200901 9

Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disorder that is associated with an increased incidence of cardiovascular disease and type 2 diabetes. Animal models adequately mimicking this condition are scarce. We herein investigate whether Ldlr-/-. Leiden mice on different high-fat diets represent a suitable NASH model. Ldlr-/-. Leiden mice were fed a healthy chow diet or fed a high-fat diet (HFD) containing lard or a fast food diet (FFD) containing milk fat. Additionally, the re ...[more]

PMID: 32883049

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Project description:The prevalence of sarcopenia is increasing while it is often challenging, expensive and time-consuming to test the effectiveness of interventions against sarcopenia. Translational mouse models that adequately mimic underlying physiological pathways could accelerate research but are scarce. Here, we investigated the translational value of three potential mouse models for sarcopenia, namely partial immobilized (to mimic sedentary lifestyle), caloric restricted (CR; to mimic malnutrition) and a combination (immobilized & CR) model. C57BL/6J mice were calorically restricted (-40%) and/or one hindleg was immobilized for two weeks to induce loss of muscle mass and function. Muscle parameters were compared to those of young control (4 months) and old reference mice (21 months). Transcriptome analysis of quadriceps muscle was performed to identify underlying pathways and were compared with those being expressed in aged human vastus lateralis muscle-biopsies using a meta-analysis of five different human studies. Caloric restriction induced overall loss of lean body mass (-15%, p<0.001), whereas immobilization decreased muscle strength (-28%, p<0.001) and muscle mass of hindleg muscles specifically (on average -25%, p<0.001). The proportion of slow myofibers increased with aging in mice (+5%, p<0.05), and this was not recapitulated by the CR and/or immobilization models. The diameter of fast myofibers decreased with aging (-7%, p<0.05), and this was mimicked by all models. Transcriptome analysis revealed that the combination of CR and immobilization recapitulated more pathways characteristic for human muscle-aging (73%) than naturally aged (21 months old) mice (45%). In conclusion, the combination model exhibits loss of both muscle mass (due to CR) and function (due to immobilization) and has a remarkable similarity with pathways underlying human sarcopenia. These findings underline that external factors such as sedentary behavior and malnutrition are key elements of a translational mouse model and favor the combination model as a rapid model for testing the treatments against sarcopenia.

Project description:Abstract Background: The prevalence of sarcopenia is increasing and effective interventions are required to prevent or reverse age-related muscle loss. However it is often challenging expensive and time-consuming to develop and test the effectiveness of such interventions. Furthermore translational animal models that adequately mimic underlying physiological pathways are scarce. Strong predictors for the incidence of sarcopenia include a sedentary life-style and malnutrition. Therefore our objective was to investigate the translational value of three potential mouse models for sarcopenia namely partial immobilized caloric restricted (CR) and a combination (immobilized & CR) model. Methods: C57BL/6J mice were calorically restricted (-40%) and/or one hindleg was immobilized for two weeks to induce loss of muscle mass and function. Muscle mass function and diameter and distribution of slow (type 1) and fast ( type 2) myofibers were compared to those of young control (4 months) and old reference mice (21 months). Transcriptome analysis of quadriceps muscle was performed to identify underlying pathways and were compared with those being expressed in aged human vastus lateralis muscle-biopsies using a meta-analysis of five different human studies. Results: Caloric restriction induced overall loss of lean body mass (-15% p<0.001) whereas immobilization decreased muscle strength (-28% p<0.001) and muscle mass of hindleg muscles specifically (on average -25% p<0.001). The proportion of slow myofibers increased with aging in mice (+5% p<0.05) and this was not recapitulated by the CR and/or immobilization models. The diameter of fast myofibers decreased with aging (-7% p<0.05) and this was mimicked by all models. Transcriptome analysis revealed that the combination of CR and immobilization recapitulated more pathways characteristic for human muscle-aging (73%) than naturally aged (21 months old) mice (45%). These pathways included critical pathways relevant for protein synthesis/ breakdown (mitochondrial) metabolism neurology and the vascular system. Conclusions: The combination model exhibits loss of both muscle mass (due to CR) and function (due to immobilization) and has a remarkable similarity with pathways underlying human sarcopenia. Our results demonstrate that naturally aging up to 21 months in mice only partially recapitulates the human pathology with fewer overlapping pathways than the combination model. These findings underline that external factors such as sedentary behavior and malnutrition are key elements of a translational mouse model and favor the combination model as a rapid model for testing the treatments against sarcopenia.

Project description:SUMMARY: This article presents a predictive molecular signature that marks the early onset of fibrosis in a translational nonalcoholic steatohepatitis mouse model. Overlap of genes and processes with human nonalcoholic steatohepatitis and a list of top candidate biomarkers for early fibrosis are described. BACKGROUND & AIMS: The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. METHODS: A time-course study in low-density lipoprotein–receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. RESULTS: High-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. CONCLUSIONS: An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames. Keywords: Systems Biology; Metabolic Syndrome; Liver Disease; Diagnosis.

Dataset Information

A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology.

Publications

A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology.

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