Development of a novel mouse model of diet-induced nonalcoholic steatohepatitis–related progressive bridging fibrosis

ABSTRACT Nonalcoholic steatohepatitis (NASH) progresses to liver fibrosis and cirrhosis. Existing mouse models of NASH rarely develop diet-induced severe fibrosis. We aimed to establish a dietary model of NASH with rapid progression to fibrosis. Six-week-old male Tsumura-Suzuki obese diabetes (TSOD) mice (a model of spontaneous metabolic syndrome) and corresponding control Tsumura-Suzuki nonobese (TSNO) mice were fed a novel diet high in fat, cholesterol, and cholate (iHFC). Histologic steatohepatitis, including steatosis, inflammation, and fibrosis, were observed in both TSNO and TSOD iHFC diet–fed mice at 20 weeks of age. As compared with TSOD mice, TSNO mice developed much more severe fibrosis and reached stage 3 of bridging fibrosis within 14 weeks under the iHFC diet feeding. Perivenular/perisinusoidal pattern of fibrosis in TSNO mice resembled human NASH. Our model of NASH with advanced fibrosis by simple diet offers many advantages useful in studying the mechanism of liver fibrosis and preclinical drug testing.

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Sugar Kelp (Saccharina latissima) Inhibits Hepatic Inflammation and Fibrosis with Increased Metabolic Rates in a Mouse Model of Diet-induced Nonalcoholic Steatohepatitis (OR24-08-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.or24-08-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Mi-Bo Kim ◽

Yoojin Lee ◽

Minkyung Bae ◽

Hyunju Kang ◽

Siqi Hu ◽

...

Keyword(s):

Physical Activity ◽

Liver Fibrosis ◽

Energy Expenditure ◽

Mouse Model ◽

Total Cholesterol ◽

Nonalcoholic Steatohepatitis ◽

Metabolic Rates ◽

Metabolic Disturbances ◽

Macrophage Marker ◽

M1 Macrophage

Abstract Objectives We investigated whether consumption of sugar kelp, an edible brown seaweed, can attenuate metabolic disturbances and nonalcoholic steatohepatitis (NASH) in a mouse model of NASH with evident liver fibrosis. Methods Male C57BL/6 J mice were fed a low-fat control (LF; 6% fat by wt), a high-fat/high-sucrose/high-cholesterol control (HF; 34% fat, 34% sucrose, 2.0% cholesterol by wt), or a HF containing sugar kelp (HF-Kelp; 6.0% dried sugar kelp powder by wt) for 14 weeks. Blood chemistry as well as biochemical, molecular, and histological analyses were conducted in the liver and epididymal white adipose tissue (eWAT). Metabolic rates, energy expenditure, and physical activity of mice were determined using indirect calorimetry Results Body weight of mice fed HF-Kelp was significantly lower than that of HF group. Compared to LF, HF significantly increased serum total cholesterol and glucose, which were decreased by kelp. In the liver, HF-Kelp group showed decreases in weight, triglycerides, total cholesterol, and steatosis compared with HF-fed mice. Also, kelp decreased hepatic expression of a macrophage marker F4/80 and an M1 macrophage marker CD11c. Mice fed HF-Kelp also exhibited decreased liver fibrosis as evidenced by less expression of fibrogenic genes and collagen accumulation than those of HF group. In eWAT, HF-Kelp diet reduced weight and adipocyte size compared with HF control. While HF-Kelp diet increased mRNA abundance of peroxisome proliferator activated receptor γ, it decreased the expression of collagen type VI alpha 1 chain, F4/80, CD11c, and tumor necrosis factor α, in eWAT. Oxygen consumption, carbon dioxide production, energy expenditure, and physical activity were significantly higher in HF-Kelp group than HF. Conclusions Kelp consumption markedly prevented weight gain, fat accumulation, inflammation, and fibrosis in the liver and eWAT of mice with NASH. The health benefits of kelp were accompanied by increased metabolic rates, energy expenditure, and physical activity. Therefore, kelp may be consumed to prevent obesity-associated metabolic disturbances and NASH. Funding Sources This study was supported by USDA Hatch.

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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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