scholarly journals Liraglutide improves hepatic steatosis and metabolic dysfunctions in a 3-week dietary mouse model of non-alcoholic steatohepatitis

2019 ◽  
Author(s):  
Thibaut Duparc ◽  
François Briand ◽  
Charlotte Trenteseaux ◽  
Jules Mérian ◽  
Guillaume Combes ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hepatic Steatosis ◽  
Dietary Intervention ◽  
Liver Steatosis ◽  
Alcoholic Steatohepatitis ◽  
Stress Markers ◽  
Preclinical Drug Development ◽  
Dietary Period ◽  
Metabolic Dysfunctions ◽  
Liver Insulin Resistance

ABSTRACTAimNon-alcoholic steatohepatitis (NASH) is an emerging health problem worldwide. However, efficacious pharmacological treatment for NASH is lacking. A major issue for preclinical evaluation of potential therapeutics for NASH is the limited number of appropriate animal models, i.e., models that do not require long-term dietary intervention and adequately mimic disease progression in humans. The present study aimed to evaluate a 3-week dietary mouse model of NASH and to validate it by studying the effects of liraglutide, a compound in advanced clinical development for NASH.MethodsC57BL6/J mice were fed a diet high in fat (60%), cholesterol (1.25%) and cholic acid (0.5%) along with 2% hydroxypropyl-β-cyclodextrin in drinking water (HFCC-CDX diet). Histological and biological parameters were measured at 1 and 3 weeks. Following 1-week diet induction, liraglutide was administrated daily for 2 weeks, and then NASH-associated phenotypic aspects were evaluated in comparison with control mice.ResultsPrior to treatment with liraglutide, mice fed the HFCC-CDX diet for 1 week developed liver steatosis and had increased levels of oxidative-stress markers and hepatic and systemic inflammation. For mice not treated with liraglutide, these aspects were even more pronounced after 3 weeks of the dietary period, with additional liver insulin resistance and fibrosis. Liraglutide treatment corrected the diet-induced alterations in glucose metabolism and significantly reduced hepatic steatosis and inflammation.ConclusionThis study provides a novel 3-week dietary model of mice that rapidly develop NASH features, and this model will be suitable for evaluating the therapeutic efficacy of compounds in preclinical drug development for NASH.

scholarly journals Liraglutide improves hepatic steatosis and metabolic dysfunctions in a 3-week dietary mouse model of nonalcoholic steatohepatitis

2019 ◽  
Vol 317 (4) ◽  
pp. G508-G517
Author(s):  
Thibaut Duparc ◽  
François Briand ◽  
Charlotte Trenteseaux ◽  
Jules Merian ◽  
Guillaume Combes ◽  
...  
Keyword(s):  
Drinking Water ◽  
Mouse Model ◽  
Hepatic Steatosis ◽  
Cholic Acid ◽  
Nonalcoholic Steatohepatitis ◽  
Dietary Intervention ◽  
Liver Steatosis ◽  
Rapid Screening ◽  
Drug Candidates ◽  
Stress Markers

Nonalcoholic steatohepatitis (NASH) is an emerging health problem worldwide. However, efficacious pharmacological treatment for NASH is lacking. A major issue for preclinical evaluation of potential therapeutics for NASH is the limited number of appropriate animal models, i.e., models that do not require long-term dietary intervention and adequately mimic disease progression in humans. The present study aimed to evaluate a 3-wk dietary mouse model of NASH and validate it by studying the effects of liraglutide, a compound in advanced clinical development for NASH. C57BL6/J mice were fed a diet high in fat (60%), cholesterol (1.25%), and cholic acid (0.5%), along with 2% hydroxypropyl-β-cyclodextrin in drinking water (HFCC-CDX diet). Histological and biological parameters were measured at 1 and 3 wk. After 1-wk diet induction, liraglutide was administrated daily for 2 wk and then NASH-associated phenotypic aspects were evaluated in comparison with control mice. Prior to treatment with liraglutide, mice fed the HFCC-CDX diet for 1 wk developed liver steatosis and had increased levels of oxidative-stress markers and hepatic and systemic inflammation. For mice not treated with liraglutide, these aspects were even more pronounced after 3 wk of the dietary period, with additional liver insulin resistance and fibrosis. Liraglutide treatment corrected the diet-induced alterations in glucose metabolism and significantly reduced hepatic steatosis and inflammation. This study provides a novel 3-wk dietary model of mice that rapidly develop NASH features, and this model will be suitable for evaluating the therapeutic efficacy of compounds in preclinical drug development for NASH. NEW & NOTEWORTHY We propose a diet high in fat (60%), cholesterol (1.25%), and cholic acid (0.5%) along with 2% hydroxypropyl-β-cyclodextrin in drinking water (HFCC-CDX diet) as a new dietary model of nonalcoholic steatohepatitis. We used the HFCC-CDX model to reproduce the main features of disease development in humans for the purpose of facilitating the rapid screening of drug candidates and prioritizing the more promising candidates for advanced preclinical assessment and subsequent clinical trials.

scholarly journals Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention

2011 ◽  
Vol 43 (8) ◽  
pp. 408-416 ◽  
Author(s):  
Isabel Rubio-Aliaga ◽  
Baukje de Roos ◽  
Manuela Sailer ◽  
Gerard A. McLoughlin ◽  
Mark V. Boekschoten ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Carbon Metabolism ◽  
Dietary Intervention ◽  
Liver Steatosis ◽  
Oxidative Capacity ◽  
Blood Cholesterol ◽  
High Fat ◽  
One Carbon Metabolism ◽  
Fat Feeding

Obesity frequently leads to insulin resistance and the development of hepatic steatosis. To characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from C57BL/6J mice obtained from two independent intervention trials. After 12 wk of high-fat feeding the animals became obese, hyperglycemic, and insulin resistant, had elevated levels of blood cholesterol and VLDL, and developed hepatic steatosis. Nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. The hepatic oxidative capacity and the lipid milieu were significantly altered, which may play a key role in the development of insulin resistance. Additionally, high choline levels were observed after the high-fat diet. Previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of one-carbon metabolism. The present results suggest that the coupling of high levels of choline and low levels of methionine plays an important role in the development of insulin resistance and liver steatosis. In conclusion, the complexities of the alterations induced by high-fat feeding are multifactorial, indicating that the interplay between several metabolic pathways is responsible for the pathological consequences.

scholarly journals Periostin antisense oligonucleotide prevents hepatic steatosis and fibrosis in a mouse model of non‐alcoholic steatohepatitis

2020 ◽  
Vol 35 (12) ◽  
pp. 2140-2150 ◽  
Author(s):  
Tomoki Kobayashi ◽  
Keishi Kanno ◽  
Phuong Thao Nguyen ◽  
Akiko Sugiyama ◽  
Akihiro Kawahara ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hepatic Steatosis ◽  
Antisense Oligonucleotide ◽  
Alcoholic Steatohepatitis

scholarly journals Quantitative, noninvasive MRI characterization of disease progression in a mouse model of non-alcoholic steatohepatitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Philip A. Waghorn ◽  
Diego S. Ferreira ◽  
Derek J. Erstad ◽  
Nicholas J. Rotile ◽  
Ricard Masia ◽  
...  
Keyword(s):  
Mouse Model ◽  
Disease Progression ◽  
Lysyl Oxidase ◽  
Liver Steatosis ◽  
Liver Fat ◽  
Advanced Fibrosis ◽  
Fibrotic Disease ◽  
Noninvasive Methods ◽  
Alcoholic Steatohepatitis ◽  
Normal Chow

AbstractNon-alcoholic steatohepatitis (NASH) is an increasing cause of chronic liver disease characterized by steatosis, inflammation, and fibrosis which can lead to cirrhosis, hepatocellular carcinoma, and mortality. Quantitative, noninvasive methods for characterizing the pathophysiology of NASH at both the preclinical and clinical level are sorely needed. We report here a multiparametric magnetic resonance imaging (MRI) protocol with the fibrogenesis probe Gd-Hyd to characterize fibrotic disease activity and steatosis in a common mouse model of NASH. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) to induce NASH with advanced fibrosis. Mice fed normal chow and CDAHFD underwent MRI after 2, 6, 10 and 14 weeks to measure liver T1, T2*, fat fraction, and dynamic T1-weighted Gd-Hyd enhanced imaging of the liver. Steatosis, inflammation, and fibrosis were then quantified by histology. NASH and fibrosis developed quickly in CDAHFD fed mice with strong correlation between morphometric steatosis quantification and liver fat estimated by MRI (r = 0.90). Sirius red histology and collagen quantification confirmed increasing fibrosis over time (r = 0.82). Though baseline T1 and T2* measurements did not correlate with fibrosis, Gd-Hyd signal enhancement provided a measure of the extent of active fibrotic disease progression and correlated strongly with lysyl oxidase expression. Gd-Hyd MRI accurately detects fibrogenesis in a mouse model of NASH with advanced fibrosis and can be combined with other MR measures, like fat imaging, to more accurately assess disease burden.

Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis

2013 ◽  
Vol 47 (3) ◽  
pp. 137-149 ◽  
Author(s):  
Thomas Klein ◽  
Masato Fujii ◽  
Jan Sandel ◽  
Yuichiro Shibazaki ◽  
Kyoko Wakamatsu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hepatic Steatosis ◽  
Alcoholic Steatohepatitis

scholarly journals The Role of Tryptophan-Nicotinamide (TRP-NAM) Pathway in Malnutrition Induced Liver Dysfunction

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 688-688
Author(s):  
Guanlan Hu ◽  
Catriona Ling ◽  
Lijun Chi ◽  
Samuel Furse ◽  
Albert Koulman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hepatic Steatosis ◽  
Target Genes ◽  
Dietary Intervention ◽  
Control Diet ◽  
Severe Malnutrition ◽  
Mtdna Copy Number ◽  
Metabolic Disturbances ◽  
Atp Levels ◽  
Protein Group

Abstract Objectives Malnutrition contributes to 45% of the deaths of children < 5. Mortality in severe malnutrition is often related to metabolic disturbances, including hypoglycemia, indicating hepatic metabolic dysfunction. Children with severe malnutrition have been found to have significantly lower circulating tryptophan (TRP) levels in their blood. Disturbances in TRP-NAM pathway have been implicated in liver and intestine diseases, potentially mediated by NAD-dependent deacetylase SIRT1. This study aim to evaluate the effect of modulating TRP-NAM pathway on hepatic metabolism dysfunction in a mouse model of severe malnutrition. Methods Weanling male C57BL/6J mice were randomized into different groups fed with a control diet (18% protein), or a malnourished diet (1% protein) with or without supplementation of modulators of the TRP-NAM pathway (NAM, NR and TRP). Supplementation therapies were given from days 7–14 after start of the dietary intervention. In addition, SIRT1 modulators treatment including resveratrol, EX-527 and vehicle were tested. Comprehensive metabolic, histological and molecular analyses were performed. Results After diet treatment, the mice in the 1% protein group had significantly lower body weight and body length compared to the 18% protein group, without any effect of modulators of the TRP-NAM pathway. Feeding mice a 1% protein diet led to severe hepatic steatosis, mitochondrial structural alterations, lower ATP levels, disrupted TRP-NAM pathway metabolites, and a decrease of phospholipids to triglycerides ratio. NAM, NR and TRP treatment all led to a partial reversal of the hepatic steatosis in the 1% protein-fed mice. ATP levels, mtDNA copy number, and PPARα target genes in the β-oxidation pathway were also recovered in treatment group. We postulate that the effect is mediated through changes in levels of NAD+, which is critical in redox reactions and is a substrate for SIRT1, important for mitochondrial function. Conclusions Modulating TRP-NAM pathway can partially improve liver metabolic function in a mouse model of severe malnutrition. This study improves our understanding of the cellular pathophysiology of severe malnutrition. The results of this project could lead to the development of new interventions which could then be taken to clinical trials. Funding Sources Bill & Melinda Gates Foundation.

scholarly journals The endothelial dysfunction blocker CU06-1004 ameliorates choline-deficient L-amino acid diet-induced non-alcoholic steatohepatitis in mice

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243497
Author(s):  
Cho-Rong Bae ◽  
Haiying Zhang ◽  
Young-Guen Kwon
Keyword(s):  
Amino Acid ◽  
Endothelial Dysfunction ◽  
Mouse Model ◽  
Hepatic Steatosis ◽  
Hepatic Fibrosis ◽  
Liver Sinusoidal Endothelial Cell ◽  
Alcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Alcoholic Steatohepatitis ◽  
Expression Of Genes

Non-alcoholic steatohepatitis (NASH) is a severe, advanced form of non-alcoholic fatty liver disease (NAFLD) that is associated with features of metabolic syndrome and characterized by hepatic steatosis, inflammation, and fibrosis. In addition, NASH is associated with endothelial dysfunction within the hepatic vasculature. Treatment with CU06-1004 (previously called Sac-1004) ameliorates endothelial dysfunction by inhibiting hyperpermeability and inflammation. In this study, we investigated the protective effects of CU06-1004 in a choline-deficient L-amino acid (CDAA)-induced mouse model of NASH for 3 or 6 weeks. Specifically, we evaluated the effects of CU06-1004 on lipid accumulation, inflammation, hepatic fibrosis, and liver sinusoidal endothelial cell (LSEC) capillarization through biochemical analysis, immunohistochemistry, and real-time PCR. We found that the administration of CU06-1004 to mice improved liver triglyceride (TG) and serum alanine aminotransferase (ALT) in this CDAA-induced model of NASH for 6 weeks. In groups of NASH induced mice for both 3 and 6 weeks, CU06-1004 significantly reduced the hepatic expression of genes related to lipogenesis, inflammation, and cell adhesion. However, expression of genes related to hepatic fibrosis and vascular endothelial changes were only decreased in animals with mild NASH. These results suggest that the administration of CU06-1004 suppresses hepatic steatosis, inflammation, fibrosis, and LSEC capillarization in a CDAA-induced mouse model of NASH. This suggests that CU06-1004 has therapeutic potential for the treatment of mild NASH.

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