A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma

Fujisawa, Masato; Shibazaki, Yuichiro; Wakamatsu, Kazumasa; Honda, Yutaka; Kawauchi, Yusuke; Suzuki, Kenji; Arumugam, Somasundaram; Watanabe, Kenichi; Ichida, Takafumi; Asakura, Hitoshi; Yoneyama, Hiroyuki

doi:10.1007/s00795-013-0016-1

Cited by 289 publications

(363 citation statements)

References 41 publications

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“…To further evaluate the effect of miR-122 on hepatic steatosis in vivo , STZ-HFD-induced NASH mice were generated to induce insulin resistance and liver steatosis as observed in previous reports [22]. We adopted the ‘lentiviral tail vein injection’ method to deliver pre-mmu-miR-122 into mouse hepatocytes.…”

Section: Resultsmentioning

confidence: 99%

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MicroRNA-122 Inhibits Lipid Droplet Formation and Hepatic Triglyceride Accumulation via Yin Yang 1

Chen²,

Chen³

et al. 2017

Cell Physiol Biochem

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Background/Aims: An increase in intracellular lipid droplet formation and hepatic triglyceride (TG) content usually results in nonalcoholic fatty liver disease. However, the mechanisms underlying the regulation of hepatic TG homeostasis remain unclear. Methods: Oil red O staining and TG measurement were performed to determine the lipid content. miRNA expression was evaluated by quantitative PCR. A luciferase assay was performed to validate the regulation of Yin Yang 1 (YY1) by microRNA (miR)-122. The effects of miR-122 expression on YY1 and its mechanisms involving the farnesoid X receptor and small heterodimer partner (FXR-SHP) pathway were evaluated by quantitative PCR and Western blot analyses. Results: miR-122 was downregulated in free fatty acid (FFA)-induced steatotic hepatocytes, and streptozotocin and high-fat diet (STZ-HFD) induced nonalcoholic steatohepatitis (NASH) in mice. Transfection of hepatocytes with miR-122 mimics before FFA induction inhibited lipid droplet formation and TG accumulation in vitro. These results were verified by overexpressing miR-122 in the livers of STZ-HFD-induced NASH mice. The 3’-untranslated region (3’UTR) of YY1 mRNA is predicted to contain an evolutionarily conserved miR-122 binding site. In silico searches, a luciferase reporter assay and quantitative PCR analysis confirmed that miR-122 directly bound to the YY1 3’UTR to negatively regulate YY1 mRNA in HepG2 and Huh7 cells. The (FXR-SHP) signaling axis, which is downstream of YY1, may play a key role in the mechanism of miR-122-regulated lipid homeostasis. YY1-FXR-SHP signaling, which is negatively regulated by FFA, was enhanced by miR-122 overexpression. This finding was also confirmed by overexpression of miR-122 in the livers of NASH mice. Conclusions: The present results indicate that miR-122 plays an important role in lipid (particularly TG) accumulation in the liver by reducing YY1 mRNA stability to upregulate FXR-SHP signaling.

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Section: Resultsmentioning

confidence: 99%

“…Normal control mice were housed without any treatment and fed a normal diet (composed of 12 kcal% fat). NASH model mice were generated as previously described [22]. Briefly, pregnant C57BL/6J mice were purchased from the Laboratory Animal Center of Shanghai, Academy of Science.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-122 Inhibits Lipid Droplet Formation and Hepatic Triglyceride Accumulation via Yin Yang 1

Chen²,

Chen³

et al. 2017

Cell Physiol Biochem

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“…The STAM mouse model has been developed as a small animal model that recapitulates important features of the human disease (33). Nearly 100% of STAM mice follow disease progression from steatosis to NASH to fibrosis to HCC, making this a model that is well suited to evaluate the ability of compounds to prevent disease progression.…”

Section: Ir-snas Demonstrate Enhanced Antifibrotic Activity In a Mousementioning

confidence: 99%

Immunomodulatory spherical nucleic acids

Radovic‐Moreno

Chernyak

Mader

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

214

233

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Immunomodulatory nucleic acids have extraordinary promise for treating disease, yet clinical progress has been limited by a lack of tools to safely increase activity in patients. Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate (immunostimulatory, IS-SNA) or regulate (immunoregulatory, IR-SNA) immunity by engaging TLRs have been designed, synthesized, and characterized. Compared with free oligonucleotides, IS-SNAs exhibit up to 80-fold increases in potency, 700-fold higher antibody titers, 400-fold higher cellular responses to a model antigen, and improved treatment of mice with lymphomas. IR-SNAs exhibit up to eightfold increases in potency and 30% greater reduction in fibrosis score in mice with nonalcoholic steatohepatitis (NASH). Given the clinical potential of SNAs due to their potency, defined chemical nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies.

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“…Animals and experimental design, and sample preparation STAM mice were used to model NASH and were obtained according to the method described by Fujii et al (2013). Pathogenfree, 14-day pregnant female C57BL/6J mice were purchased from Charles River Laboratories (Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Dietary D-Allose Ameliorates Hepatic Inflammation in Mice with Non-alcoholic Steatohepatitis

Yamamoto

Iida

Tanikawa

et al. 2017

FSTR

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Nonalcoholic steatohepatitis (NASH) is characterized by excess lipid accumulation and inflammation inhepatocytes. In this study, to provide insight into the preventive effects of d-allose, a rare sugar, on the onset of NASH, we designed animal experiments using male STAM mice treated with streptozotocin and fed a high-fat diet (HFD). Experiments were initiated when the mice reached 5 weeks of age and lasted 3 weeks. After the 3-week protocol, mice fed the HFD containing d-allose exhibited significantly decreased serum alanine aminotransferase levels, hepatic lipid accumulation and inflammation, and improved nonalcoholic fatty liver disease activity score compared to mice fed HFD without d-allose ( p < 0.05). Further, hepatic mRNA expression of sterol regulatory element binding protein-1 (Srebp-1) and monocyte chemotactic protein-1 (Mcp-1) was lower in mice fed d-allose.These results suggested that d-allose prevented NASH by blocking hepatic lipid accumulation and progressive inflammation.Keywords: nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, rare sugar, d-allose IntroductionNonalcoholic fatty liver disease (NAFLD) is an increasingly common hepatic phenotype of metabolic syndrome not caused by chronic alcohol consumption and is characterized by lipid accumulation in hepatocytes (Williams et al., 2011). Nonalcoholic steatohepatitis (NASH), a type of NAFLD, is a significant risk factor for the development of cirrhosis and hepatocellular carcinoma (Feldstein et al., 2009;Cohen et al., 2011). The two-hit theory (Day and James, 1998) and multiple parallel hits hypothesis (Tilg et al., 2010) have been used to explain the progression of simple steatosis to NASH via lipid accumulation, inflammation, and oxidative stress in the liver, although the exact mechanisms R. Yamamoto et al. 320 have not yet been elucidated.In the alternative medicinal food sciences, recent reports have claimed that excessive sugar intake (e.g., d-fructose and highfructose corn syrup) is a high risk factor in the progression of NAFLD/NASH (Abdelmalek et al., 2010;Nseir et al., 2010).Meanwhile, the physiological effects of rare sugars, such as shown to protect against inflammatory and oxidative ischemia/ reperfusion (I/R) injury in liver, retinal, and cerebral injuries in rodent models (Hossain et al., 2003;Hirooka et al., 2006;Gao et al., 2013). Previous studies have revealed the physiological benefits Materials and MethodsAnimals and experimental design, and sample preparation STAM mice were used to model NASH and were obtained according to the method described by Fujii et al. (2013). Pathogenfree, 14-day pregnant female C57BL/6J mice were purchased from Charles River Laboratories (Tokyo, Japan). To induce NASH, STAM mice were primarily obtained by treating C57BL/6J mice with a single subcutaneous injection of 200 µg STZ (SigmaAldrich, St. Louis, MO, USA) 2 days after birth. At 4 weeks of age, the mice were fed a HFD (HFD32; CLEA Japan, Tokyo, Japan) ad libitum for 1 week (the experimental scheme is shown in Fig. 1). At 5 ...

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A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma

Cited by 289 publications

References 41 publications

MicroRNA-122 Inhibits Lipid Droplet Formation and Hepatic Triglyceride Accumulation via Yin Yang 1

MicroRNA-122 Inhibits Lipid Droplet Formation and Hepatic Triglyceride Accumulation via Yin Yang 1

Immunomodulatory spherical nucleic acids

Dietary D-Allose Ameliorates Hepatic Inflammation in Mice with Non-alcoholic Steatohepatitis

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