Pathophysiological Characteristics of Non-Alcoholic Steatohepatitis-Like Changes in Cholesterol-Loaded Type 2 Diabetic Rats

Toriniwa, Yasufumi; Muramatsu, Makoto; Ishii, Yoshiharu; Riya, E; Miyajima, Katsuhiro; Ohshida, S; Kitatani, Kanae; Takekoshi, Susumu; Matsui, Tohru; Kume, Shinji; Yamada, Takahisa; Ohta, Takeshi

doi:10.33549/physiolres.933784

Cited by 11 publications

(10 citation statements)

References 31 publications

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“…In either of these theories, lipid synthesis/accumulation and inflammation are important for the development of NAFLD/NASH, and insulin resistance is a basic factor [ 2 ]. The female SDT fatty rat used in this study showed NASH-like lesions with insulin resistance, and the rat is expected to be useful as a NASH model [ 8 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…The female SDT fatty rat exhibits obesity, hyperinsulinemia, hyperglycemia and dyslipidemia at approximately 6 weeks of age, and hepatic NASH-like lesions are observed at 32–40 weeks of age [ 8 , 9 , 23 ]. Moreover, the NASH-like lesions in female SDT fatty rats are observed at 20 weeks of age with a cholesterol-enriched diet [ 29 ]. The female SDT fatty rat is expected to be useful for NASH research.…”

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confidence: 99%

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Investigation of pharmacological responses to anti-diabetic drugs in female Spontaneously Diabetic Torii (SDT) fatty rats, a new nonalcoholic steatohepatitis (NASH) model

Toriniwa

Saito

Miyajima

et al. 2018

The Journal of Veterinary Medical Science

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Nonalcoholic steatohepatitis (NASH) is a progressive liver disease, and some patients develop hepatic cirrhosis/carcinoma. Animal models play key roles in the development of new therapies for NASH. In this study, the pharmacological effects of metformin and pioglitazone were investigated in female Spontaneously Diabetic Torii (SDT) fatty rats to verify the utility of this model. The anti-diabetic drugs were administered to SDT fatty rats fed a cholesterol-enriched diet from 4 to 25 weeks, and changes in food intake, body weight, and blood chemistry parameters were evaluated every 4 weeks. The hepatic lipid content, mRNA expression in relation to lipid synthesis, inflammation, and fibrosis, and histopathological analyses were performed at 25 weeks. Pioglitazone improved hyperglycemia, hyperlipidemia, and abnormalities in hepatic parameters. The insulin levels were lower than those in the control rats before 16 weeks. Plasma glucose levels in the metformin-treated rats were lower than those in the control rats, and plasma alanine aminotransferase levels temporarily decreased. The lipid content and some mRNA expression in relation to fibrosis in the liver decreased with pioglitazone treatment, and the mRNA expression of microsomal triglyceride transfer protein increased. Hepatic fibrosis observed in the SDT fatty rats improved with pioglitazone treatment; however, the effect with metformin treatment was partial. These results in both drugs are in line with results in the human study, suggesting that the SDT fatty rat is useful for developing new anti-NASH drugs that show potential to regulate glucose/lipid metabolism.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Investigation of pharmacological responses to anti-diabetic drugs in female Spontaneously Diabetic Torii (SDT) fatty rats, a new nonalcoholic steatohepatitis (NASH) model

Toriniwa

Saito

Miyajima

et al. 2018

The Journal of Veterinary Medical Science

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“…The pathogenesis of NAFLD/NASH is initiated by systemic dysmetabolism, leading to lipid accumulation, hepatosteatosis, hepatocyte ballooning [4], in ammatory cell in ltration, increased oxidative stress [6,7], hepatocyte injury, brosis, etc. [8][9][10] . CCl 4 is a known liver toxin causing direct hepatocyte injury, leading to liver brosis, cirrhosis and carcinoma, which often requires relatively high doses from 0.2 to 5 mL/kg [23].…”

Section: Discussionmentioning

confidence: 99%

“…While simple steatosis with minimal in ammation has no clinical implications, nonalcoholic steatohepatitis (NASH) with lobular in ammation has serious consequences as it progresses to liver brosis in 10-20% of cases, leading to cirrhosis and possible hepatocellular carcinoma (HCC) [3]. A sequential two-or multiple hit model of pathogenesis was proposed for the progression of liver steatosis to NASH; rst, hepatic fat accumulation results in both macrovesicular (adipocyte accumulation) and microvesicular (hepatocyte ballooning) steatosis [4,5], followed by exposure of the accumulated hepatic lipids to hepatic oxidative stress (lipid peroxidation to release lipid peroxides) [6,7], which causes in ammatory in ltration, nally, hepatocyte damage, repairment and brosis [8][9][10]. In addition, insulin resistance, adipose tissue-derived factors, nutritional factors, gut microbiota, and genetic and epigenetic factors, work together and contribute to the pathogenesis of NAFLD/NASH [5].…”

Section: Introductionmentioning

confidence: 99%

Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

Zhang

Wang

Chung

et al. 2020

Preprint

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Background: Multiple murine models of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) have been established by using obesogenic diets and/or chemical induction. MS-NASH mouse (formally FATZO) is a spontaneously developed dysmetabolic strain that can progress from hepatosteatosis to moderate fibrosis when fed a western diet supplemented with 5% fructose (WDF). This study aimed to use carbon tetrachloride (CCl4) to accelerate and aggravate progression of NAFLD/NASH in MS-NASH mouse. Methods: Male MS-NASH mice at 8 weeks of age were fed WDF for the entire study. Starting at 16 weeks of age, CCl4 was intraperitoneally administered twice weekly at a dose of 0.2 mL/kg for 3 weeks or 0.08 mL/kg for 8 weeks. Obeticholic acid (OCA, 30 mg/kg, QD) was administered in both MS-NASH and C57Bl/6 mice fed WDF and treated with CCl4 (0.08 mL/kg).Results: WDF enhanced obesity and hepatosteatosis, as well as induced moderate fibrosis in MS-NASH mice similar to previous reports. Administration of CCl4 accelerated liver fibrosis with increased bridging and liver hydroxyproline contents, but had no significant impact on liver steatosis and lipid contents. High dose CCl4 caused high mortality and dramatic elevation of ALT and ASL, while low dose CCl4 resulted in a moderate elevation of ALT and AST with low mortality. Compared to C57BI/6 mice with WDF and CCl4 (0.08 mL/kg), MS-NASH mice had more prominent hepatosteatosis and fibrosis. OCA treatment significantly lowered liver triglycerides, steatosis and fibrosis in both MS-NASH and C57Bl/6 mice fed WDF with CCl4 treatment. Conclusions: CCl4 reduced induction time and exacerbated liver fibrosis in MS-NASH mice on WDF, proving a superior NASH model with more prominent liver pathology, which has been used favorably in pharmaceutical industry for testing novel NASH therapeutics.

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“…While simple steatosis with minimal in ammation has no clinical implications, nonalcoholic steatohepatitis (NASH) with lobular in ammation has serious consequences as it progresses to liver brosis in 10-20% of cases, leading to cirrhosis and possible hepatocellular carcinoma (HCC) [3]. A two-hit model of pathogenesis has been widely accepted for the development of NASH from liver steatosis that requires 2 sequential events; rst, hepatic fat accumulation results in both macrovesicular (adipocytes accumulation) and microvesicular (hepatocyte ballooning) steatosis [4], followed by exposure the accumulated hepatic lipids to hepatic oxidative stress [5,6] causing lipid peroxidation to release lipid peroxides, which then leads to hepatocyte damage [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

Zhang

Wang

Chung

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Multiple NAFLD/NASH murine models have been developed by obesogenic diets and/or chemical induction. MS-NASH (formally FATZO) mouse is a spontaneously developed dysmetabolic strain that can progress from hepatosteatosis to moderate fibrosis when fed western diet supplemented with 5% fructose (WDF). This study aimed to use carbon tetrachloride (CCl4) to accelerate and aggravate progression of NAFLD/NASH in MS-NASH mouse. Methods Male MS-NASH mice at 8 weeks of age were fed WDF for the entire study. Starting at 16 weeks of age, CCl4 was intraperitoneally administrated twice weekly at a dose of 0.2 mL/kg for 3 weeks or 0.08 mL/kg for 8 weeks. Obeticholic acid (OCA, 30 mg/kg, QD) was administered in both MS-NASH and C57Bl/6 mice fed WDF and treated with CCl4 (0.08 mL/kg). Results WDF enhanced obesity and hepatosteatosis, as well as induced moderate fibrosis in MS-NASH mice similar to that reported previously. Administration of CCl4 accelerated liver fibrosis with increased bridging, but no significant impact on liver steatosis and lipid contents. Compared to the high dose CCl4 at 0.2 mL/kg, the lower dose of 0.08 mL/kg caused less death and smaller elevation of ALT and AST. Compared to MS-NASH mice, C57BI/6 mice with WDF and CCl4 (0.08 mL/kg) resulted in milder hepatosteatosis and fibrosis. OCA treatment significantly lowered liver triglycerides, steatosis and fibrosis in both MS-NASH and C57Bl/6 mice treated with WDF and CCl4. Conclusions CCl4 reduced induction time and exacerbated the fibrosis in MS-NASH mice on WDF, which, thus, becomes a superior NASH model with more prominent liver pathology used favorably in pharmaceutical industry for testing novel therapeutics targeting NASH.

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Pathophysiological Characteristics of Non-Alcoholic Steatohepatitis-Like Changes in Cholesterol-Loaded Type 2 Diabetic Rats

Cited by 11 publications

References 31 publications

Investigation of pharmacological responses to anti-diabetic drugs in female Spontaneously Diabetic Torii (SDT) fatty rats, a new nonalcoholic steatohepatitis (NASH) model

Investigation of pharmacological responses to anti-diabetic drugs in female Spontaneously Diabetic Torii (SDT) fatty rats, a new nonalcoholic steatohepatitis (NASH) model

Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

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