2020-P: Comparable Disease Progression in GAN and AMLN Diet-Induced Obese Mouse Models of Biopsy-Confirmed Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is a rising chronic liver disease and comprises a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to end-stage cirrhosis and risk of hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is multifactorial, but inflammation is considered the key element of disease progression. The liver harbors an abundance of resident immune cells, that in concert with recruited immune cells, orchestrate steatohepatitis. While inflammatory processes drive fibrosis and disease progression in NASH, fueling the ground for HCC development, immunity also exerts antitumor activities. Furthermore, immunotherapy is a promising new treatment of HCC, warranting a more detailed understanding of inflammatory mechanisms underlying the progression of NASH and transition to HCC. Novel methodologies such as single-cell sequencing, genetic fate mapping, and intravital microscopy have unraveled complex mechanisms behind immune-mediated liver injury. In this review, we highlight some of the emerging paradigms, including macrophage heterogeneity, contributions of nonclassical immune cells, the role of the adaptive immune system, interorgan crosstalk with adipose tissue and gut microbiota. Furthermore, we summarize recent advances in preclinical and clinical studies aimed at modulating the inflammatory cascade and discuss how these novel therapeutic avenues may help in preventing or combating NAFLD-associated HCC.

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Reduced Expression of Urokinase Plasminogen Activator in Brown Adipose Tissue of Obese Mouse Models

International Journal of Molecular Sciences ◽

10.3390/ijms22073407 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3407

Author(s):

Chung-Ze Wu ◽

Li-Chien Chang ◽

Chao-Wen Cheng ◽

Te-Chao Fang ◽

Yuh-Feng Lin ◽

...

Keyword(s):

Adipose Tissue ◽

Glomerular Filtration Rate ◽

Brown Adipose Tissue ◽

Glomerular Filtration ◽

Plasminogen Activator ◽

Mouse Models ◽

Filtration Rate ◽

Obese Mouse ◽

Adipose Tissues ◽

Brown Adipose

In recent decades, the obesity epidemic has resulted in morbidity and mortality rates increasing globally. In this study, using obese mouse models, we investigated the relationship among urokinase plasminogen activator (uPA), metabolic disorders, glomerular filtration rate, and adipose tissues. Two groups, each comprised of C57BL/6J and BALB/c male mice, were fed a chow diet (CD) and a high fat diet (HFD), respectively. Within the two HFD groups, half of each group were euthanized at 8 weeks (W8) or 16 weeks (W16). Blood, urine and adipose tissues were collected and harvested for evaluation of the effects of obesity. In both mouse models, triglyceride with insulin resistance and body weight increased with duration when fed a HFD in comparison to those in the groups on a CD. In both C57BL/6J and BALB/c HFD mice, levels of serum uPA initially increased significantly in the W8 group, and then the increment decreased in the W16 group. The glomerular filtration rate declined in both HFD groups. The expression of uPA significantly decreased in brown adipose tissue (BAT), but not in white adipose tissue, when compared with that in the CD group. The results suggest a decline in the expression of uPA in BAT in obese m models as the serum uPA increases. There is possibly an association with BAT fibrosis and dysfunction, which may need further study.

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Berberine Prevents Disease Progression of Nonalcoholic Steatohepatitis through Modulating Multiple Pathways

Cells ◽

10.3390/cells10020210 ◽

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.

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45 Mouse models of Gaucher disease: Insights into visceral and CNS disease progression

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2007.08.050 ◽

2007 ◽

Vol 92 (4) ◽

pp. 21

Author(s):

Greg Grabowski

Keyword(s):

Disease Progression ◽

Mouse Models ◽

Gaucher Disease ◽

Cns Disease

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An Overview of Mouse Models of Nonalcoholic Steatohepatitis: From Past to Present

Current Protocols in Mouse Biology ◽

10.1002/cpmo.3 ◽

2016 ◽

Vol 6 (2) ◽

pp. 185-200 ◽

Cited By ~ 22

Author(s):

Ans Jacobs ◽

Anne‐Sophie Warda ◽

Jef Verbeek ◽

David Cassiman ◽

Pieter Spincemaille

Keyword(s):

Mouse Models ◽

Nonalcoholic Steatohepatitis

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Abstract PO-060: Gna13 delays disease progression in mouse models of pancreatitis and pancreatic cancer

10.1158/1538-7445.panca20-po-060 ◽

2020 ◽

Author(s):

Mario A. Shields ◽

Christina Spaulding ◽

Mahmoud G. Khalafalla ◽

Thao D.N. Pham ◽

Hidayatullah G. Munshi

Keyword(s):

Pancreatic Cancer ◽

Disease Progression ◽

Mouse Models

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Mouse Models of Nonalcoholic Steatohepatitis: Head-to-Head Comparison of Dietary Models and Impact on Inflammation and Animal Welfare

Gastroenterology Research and Practice ◽

10.1155/2020/7347068 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Andreas Kroh ◽

Vanina Ivanova ◽

Hannah Drescher ◽

Julia Andruszkow ◽

Thomas Longerich ◽

...

Keyword(s):

Mouse Model ◽

Animal Welfare ◽

Mouse Models ◽

Nonalcoholic Steatohepatitis ◽

Cell Sorting ◽

High Fat Diet ◽

Histopathological Examination ◽

Clinical Status ◽

Nonalcoholic Fatty Liver ◽

The Impact

A variety of dietary nonalcoholic steatohepatitis (NASH) mouse models are available, and choosing the appropriate mouse model is one of the most important steps in the design of NASH studies. In addition to the histopathological and metabolic findings of NASH, a sufficient mouse model should guarantee a robust clinical status and good animal welfare. Three different NASH diets, a high-fat diet (HFD60), a western diet (WD), and a cafeteria diet (CAFD), were fed for 12 or 16 weeks. Metabolic assessment was conducted at baseline and before scheduled sacrifice, and liver inflammation was analyzed via fluorescence-associated cell sorting and histopathological examination. Clinical health conditions were scored weekly to assess the impact on animal welfare. The HFD60 and WD were identified as suitable NASH mouse models without a significant strain on animal welfare. Furthermore, the progression of inflammation and liver fibrosis was associated with a decreased proportion of CD3+ NK1.1+ cells. The WD represents a model of advanced-stage NASH, and the HFD60 is a strong model of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. However, the CAFD should not be considered a NASH model.

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