GH and IGF-I Ameliorate Liver Steatosis and Fibrosis in Nonalcoholic Steatohepatitis Mouse Model

2011 ◽  
pp. P1-139-P1-139
Author(s):  
Hitoshi Nishizawa ◽  
Genzo Iguchi ◽  
Michiko Takahashi ◽  
Masaaki Yamamoto ◽  
Kentaro Suda ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nonalcoholic Steatohepatitis ◽  
Liver Steatosis ◽  
Igf I

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 Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis

2015 ◽  
Vol 21 (1) ◽  
pp. 453-465 ◽  
Author(s):  
Ilija Jeftic ◽  
Nemanja Jovicic ◽  
Jelena Pantic ◽  
Nebojsa Arsenijevic ◽  
Miodrag L. Lukic ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nonalcoholic Steatohepatitis ◽  
Liver Steatosis ◽  
Galectin 3

scholarly journals Atorvastatin Modulates Bile Acid Homeostasis in Mice with Diet-Induced Nonalcoholic Steatohepatitis

2021 ◽  
Vol 22 (12) ◽  
pp. 6468
Author(s):  
Hana Lastuvkova ◽  
Fatemeh Alaei Faradonbeh ◽  
Jolana Schreiberova ◽  
Milos Hroch ◽  
Jaroslav Mokry ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nonalcoholic Steatohepatitis ◽  
Plasma Concentrations ◽  
Liver Steatosis ◽  
Saturated Fat ◽  
Cardiovascular Complications ◽  
Biliary Secretion ◽  
Fecal Excretion ◽  
High Cholesterol Diet ◽  
Chow Diet

Bile acids (BA) play a significant role in the pathophysiology of nonalcoholic steatohepatitis (NASH). The present study evaluates the modulation of bile acid metabolomics by atorvastatin, a cholesterol-lowering agent commonly used to treat cardiovascular complications accompanying NASH. NASH was induced in mice by 24 weeks of consuming a high–saturated fat, high-fructose, and high-cholesterol diet (F), with atorvastatin administered orally (20 mg/kg/day) during the last three weeks. Biochemical and histological analyses confirmed the effectiveness of the F diet in inducing NASH. Untreated NASH animals had significantly reduced biliary secretion of BA and increased fecal excretion of BA via decreased apical sodium-dependent bile salt transporter (Asbt)-mediated reabsorption. Atorvastatin decreased liver steatosis and inflammation in NASH animals consistently with a reduction in crucial lipogenic enzyme stearoyl–coenzyme A (CoA) desaturase-1 and nuclear factor kappa light chain enhancer of activated B-cell pro-inflammatory signaling, respectively. In this group, atorvastatin also uniformly enhanced plasma concentration, biliary secretion and fecal excretion of the secondary BA, deoxycholic acid (DCA). However, in the chow diet–fed animals, atorvastatin decreased plasma concentrations of BA, and reduced BA biliary secretions. These changes stemmed primarily from the increased fecal excretion of BA resulting from the reduced Asbt-mediated BA reabsorption in the ileum and suppression of synthesis in the liver. In conclusion, our results reveal that atorvastatin significantly modulates BA metabolomics by altering their intestinal processing and liver synthesis in control and NASH mice.

scholarly journals Empagliflozin Improves Metabolic and Hepatic Outcomes in a Non-Diabetic Obese Biopsy-Proven Mouse Model of Advanced NASH

2021 ◽  
Vol 22 (12) ◽  
pp. 6332
Author(s):  
Nikolaos Perakakis ◽  
Pavlina Chrysafi ◽  
Michael Feigh ◽  
Sanne Skovgard Veidal ◽  
Christos S. Mantzoros
Keyword(s):  
Mouse Model ◽  
Cell Activation ◽  
Stellate Cell ◽  
Liver Steatosis ◽  
Tolerance Test ◽  
The Body ◽  
Oral Glucose ◽  
Alcoholic Fatty Liver ◽  
Metabolic Outcomes ◽  
Anti Inflammatory

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.

scholarly journals Berberine Prevents Disease Progression of Nonalcoholic Steatohepatitis through Modulating Multiple Pathways

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 210
Author(s):  
Yanyan Wang ◽  
Yun-Ling Tai ◽  
Derrick Zhao ◽  
Yuan Zhang ◽  
Junkai Yan ◽  
...  
Keyword(s):  
Bile Acid ◽  
Mouse Model ◽  
Disease Progression ◽  
Nonalcoholic Steatohepatitis ◽  
Noncoding Rna ◽  
Metabolic Diseases ◽  
Immune Cell ◽  
Stellate Cell ◽  
Clinical Investigation ◽  
Beneficial Effects

Background and Aims: The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC–MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR’s beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.

scholarly journals Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Takaomi Kessoku ◽  
Kento Imajo ◽  
Yasushi Honda ◽  
Takayuki Kato ◽  
Yuji Ogawa ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nonalcoholic Steatohepatitis
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