Insulin Resistance, Steatohepatitis, and Hepatocellular Carcinoma in a New Congenic Strain of Fatty Liver Shionogi (FLS) Mice with the Lepob Gene

Soga, Masahiko; Hashimoto, Satomi; Kishimoto, Yoshio; Hirasawa, Tsutomu; Makino, Susumu; Inagaki, Soichi

doi:10.1538/expanim.59.407

Cited by 17 publications

(17 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The features of FLS-ob/ob mice are hyperphagia, obesity, hyperlipidemia and diabetes mellitus (15). They exhibit histologically severe steatosis, hepatocellular ballooning and advanced hepatic fibrosis, increased oxidative stress, elevated inflammatory, as well as pro-fibrotic cytokine production, increased apoptosis of hepatocytes and the mice also develop cirrhosis and liver tumors (16,17). FLS-ob/ob mice are the closest animal model to metabolic syndrome-associated NASH in humans and possess targets of DPP-IV inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob/ob male mice

Onoyama¹,

Koda²,

Okamoto³

et al. 2015

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Non-alcoholic steatohepatitis is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The dipeptidyl peptidase-IV enzyme is important in glucose metabolism, as well as lipid accumulation, extracellular matrix metabolism and immune stimulation. Furthermore, the enzyme activity of dipeptidyl peptidase-IV is known to be increased in non-alcoholic steatohepatitis. Therefore, dipeptidyl peptidase-IV inhibitors are potential therapeutic agents for non-alcoholic steatohepatitis. The present study assessed the therapeutic effects of sitagliptin, a dipeptidyl peptidase-IV inhibitor, on non-alcoholic steatohepatitis using fatty liver Shionogi-ob/ob male mice. Sitagliptin (2 mg/kg/day; n=10) or placebo (control; n=10) was orally administered to fatty liver Shionogi-ob/ob mice for 12 weeks, and hepatic steatosis, fibrosis, inflammation and oxidative stress were assessed in comparison with the controls. Sitagliptin administration reduced body weight and blood glucose levels, and improved hepatic fibrosis. It also inhibited the gene expression levels of fatty acid synthase, transforming growth factor-β1, tissue inhibitor of metalloproteinases-1, procollagen-type 1, tumor necrosis factor-α, monocyte chemoattractant protein-1 and enhanced peroxisome proliferator activated receptor-α. Furthermore, a marked attenuation of hepatic stellate cell activation and Kupffer cells was observed in the sitagliptin group. A decrease in oxidative stress and apoptosis was also observed. Sitagliptin attenuated the progression of hepatic fibrosis by improving lipid metabolism, inflammation and oxidative stress in non-alcoholic steatohepatitis. IntroductionNon-alcoholic steatohepatitis (NASH) is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The central pathophysiological issue in patients afflicted with NASH is insulin resistance. Improvement of insulin resistance has therapeutic potential in preventing the progression of NASH (1). Previously, dipeptidyl peptidase (DPP)-IV inhibitors have been used as novel oral drugs for the treatment of type 2 diabetes. DPP-IV is an enzyme, which inactivates incretins, including glucagon-like peptide-1 and gastric inhibitory polypeptide, which regulates blood glucose primarily via stimulation of glucose-dependent insulin release. As a result, the activation of DPP-IV leads to the development of glucose intolerance and hepatic steatosis (2). DPP-IV enzyme has widespread organ distribution throughout the body and has pleiotropic biological functions (3-5). DPP-IV is involved in glucose metabolism and lipid accumulation, degradation of the extracellular matrix, appetite regulation and immune stimulation via its peptidase activities (6-10). The liver is one of the organs expressing DPP-IV to a high degree (11). The mRNA expression of DPP-IV is also increased in the liver of non-alcoholic fatty liver disease (NAFLD) (12). Serum DPP-IV activity and the expression of hepatic DPP-IV are correlated with hepatic steatosis and NAFLD s...

show abstract

Section: Introductionmentioning

confidence: 99%

Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob/ob male mice

Onoyama¹,

Koda²,

Okamoto³

et al. 2015

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…The reasons why DEN-treated Zucker fatty rats developed tumors more easily than other models are not clear, but the difference may correlate with the higher concentration of plasma insulin in Zucker Fatty rats than in FLS 19 or db/db mice. 20 Ours could be a good model of obesity-induced hepatocellular carcinoma, because the high frequency of carcinogenesis reduces the number of experimental animals required for experimentation.…”

Section: In Vivo Evaluation Of Diethylnitrosamineinduced Liver Tumorsmentioning

confidence: 99%

Long-term Branched Chain Amino Acid Supplementation Ameliorates Diethylnitrosamine-induced Liver Glutathione S-transferase-p Positivity in Zucker Fatty Rats

Ishizaki

Nishiyama

Hagiwara

2013

Journal of Clinical and Experimental Hepatology

View full text Add to dashboard Cite

Background: Obesity increases the risk of fatty liver disease and liver cancer. There are several models of obesityassociated hepatocellular carcinoma, but tumor development in these models is slow. Materials and methods: We investigated Zucker fatty rats, a model of obesity and insulin resistance, to discover if diethylnitrosamine (DEN), a potent liver carcinogen, might enhance liver carcinogenesis. We also investigated the effect of branched chain amino acids (BCAA) against the development of liver cancer. Results: Incidence and number of hepatocellular carcinomas and adenomas were significantly greater in DEN-treated Zucker fatty rats than in DEN-treated lean rats. All treated Zucker fatty rats developed hepatocellular carcinoma within 16 weeks. Long-term BCAA supplementation significantly reduced expression of CyclinD1, PCNA, thymidine kinase, Bcl-2, and GST-p and increased expression of p21 in the liver. Furthermore, BCAA treatment significantly reduced the area of GST-p positive foci. Conclusion: Long-term BCAA treatment may induces cell cycle arrest and apoptotic induction, thus suppressing pre-neoplastic lesions. ( J CLIN EXP HEPATOL 2013;3:192-197)

show abstract

“…NASH may been accelerated by a second “hit” of inflammatory/oxidative stress, using, for example, intraperitoneal injection of lipopolysaccharide (LPS) (79), dietary stressors such as a MCD diet (80), or crossing with another NASH-prone strain, such as the fatty liver Shionogi (FLS) mice, which are discussed later (81). Notably, however, leptin is required for normal immune function, and its deficiency dampens down both innate and acquired immune responses in humans (82, 83), though it seems to play a pro-inflammatory and pro-fibrogenic role in mice (78).…”

Section: Murine “Pre-hepatic” Nafldmentioning

confidence: 99%

“…Precisely, why this model is so susceptible to HCC is not known. Crossing of FLS mice with ob/ob mice results in a model with the full metabolic syndrome and progressive fibrosis (81, 98); this model most closely recapitulates the whole human spectrum of NAFLD in a practical, experimental timeframe.…”

Section: Hepatocyte-autonomous Murine Nafldmentioning

confidence: 99%

How Useful Are Monogenic Rodent Models for the Study of Human Non-Alcoholic Fatty Liver Disease?

2016

View full text Add to dashboard Cite

Improving understanding of the genetic basis of human non-alcoholic fatty liver disease (NAFLD) has the potential to facilitate risk stratification of affected patients, permit personalized treatment, and inform development of new therapeutic strategies. Animal models have been widely used to interrogate the pathophysiology of, and genetic predisposition to, NAFLD. Nevertheless, considerable interspecies differences in intermediary metabolism potentially limit the extent to which results can be extrapolated to humans. For example, human genome-wide association studies have identified polymorphisms in PNPLA3 and TM6SF2 as the two most prevalent determinants of susceptibility to NAFLD and its inflammatory component (NASH), but animal models of these mutations have had only variable success in recapitulating this link. In this review, we critically appraise selected murine monogenic models of NAFLD, NASH, and hepatocellular carcinoma (HCC) with a focus on how closely they mirror human disease.

show abstract

Insulin Resistance, Steatohepatitis, and Hepatocellular Carcinoma in a New Congenic Strain of Fatty Liver Shionogi (FLS) Mice with the Lepob Gene

Abstract: Abstract:In order to examine the influence of obesity on metabolic disorder and liver pathogenesis of the Fatty Liver Shionogi (FLS)

Cited by 17 publications

References 29 publications

Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob/ob male mice

Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob/ob male mice

Long-term Branched Chain Amino Acid Supplementation Ameliorates Diethylnitrosamine-induced Liver Glutathione S-transferase-p Positivity in Zucker Fatty Rats

How Useful Are Monogenic Rodent Models for the Study of Human Non-Alcoholic Fatty Liver Disease?

Contact Info

Product

Resources

About