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 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.

Inhibition of Transcriptional Regulator Taz (Wwtr1) by Antisense Oligonucleotide (ASO) Treatment Improves Obesity and Hepatic Steatosis in a Mouse Model of NASH

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 2439-PUB
Author(s):  
RAECHEL PERALTA ◽  
AUDREY K. LOW ◽  
JOANNA SCHMIDT ◽  
ANNIE FERNG ◽  
SUE MURRAY ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hepatic Steatosis ◽  
Antisense Oligonucleotide ◽  
Transcriptional Regulator

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 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.

Elafibranor and liraglutide improve differentially liver health and metabolism in a mouse model of non‐alcoholic steatohepatitis

2021 ◽  
Author(s):  
Nikolaos Perakakis ◽  
Konstantinos Stefanakis ◽  
Michael Feigh ◽  
Sanne Skovgard Veidal ◽  
Christos S. Mantzoros
Keyword(s):  
Mouse Model ◽  
Alcoholic Steatohepatitis ◽  
Liver Health

scholarly journals Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1515
Author(s):  
Keiichiro Okuda ◽  
Atsushi Umemura ◽  
Shiori Umemura ◽  
Seita Kataoka ◽  
Hiroyoshi Taketani ◽  
...  
Keyword(s):  
Mouse Model ◽  
Glucocorticoid Receptor ◽  
Nuclear Translocation ◽  
Growth Factor Receptor ◽  
Public Health Problem ◽  
Egfr Signaling ◽  
Alcoholic Steatohepatitis ◽  
Genetic Mouse Model ◽  
Treatment And Prevention ◽  
Egfr Expression

Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. We used a genetic mouse model in which HCC was induced via high-fat diet feeding. This mouse model strongly resembles human NASH-induced HCC. The natural product honokiol (HNK) was tested for its preventative effects against NASH progression to HCC. Then, to clarify the mechanisms underlying HCC development, human HCC cells were treated with HNK. Human clinical specimens were also analyzed to explore this study’s clinical relevance. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH and human HCC specimens. Inhibition of EGFR signaling by HNK drastically attenuated HCC development in the mouse model. Mechanistically, HNK accelerated the nuclear translocation of glucocorticoid receptor (GR) and promoted mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, leading to EGFR degradation and thereby resulting in robust tumor suppression. In human samples, EGFR-positive HCC tissues and their corresponding non-tumor tissues exhibited decreased ERRFI1 mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased ERRFI1 expression. EGFR degradation or inactivation represents a novel approach for NASH–HCC treatment and prevention, and the GR–MIG6 axis is a newly defined target that can be activated by HNK and related compounds.

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