Effect of intermittent fasting on non-alcoholic steatohepatitis in mice
- 주제(키워드) 도움말 비알코올성 지방간염 , 간헐적단식 , 천연물
- 발행기관 강릉원주국립대학교
- 지도교수 도움말 유기연
- 발행년도 2022
- 학위수여년월 2023. 2
- 학위명 석사
- 학과 및 전공 도움말 일반대학원 치의학과
- 세부분야 바이오-제약
- 실제URI http://www.dcollection.net/handler/kangnung/000000011312
- UCI I804:42001-000000011312
- 본문언어 영어
초록/요약 도움말
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic hepatic diseases worldwide, its more severe progressive form is Nonalcoholic steatohepatitis (NASH). The gradual increase in the prevalence of NASH poses an increasing burden on global healthcare systems and the economies, but there are currently no FDA approved therapeutics for NASH. The objective of this study was to investigate the hepatoprotective effect and mechanism of intermittent fasting (IF) and our newly developed natural product (BS012) in the development of NASH. Treated the C57BL/6N mice with fructose, palmitate, and cholesterol (FPC) diet along with 42g/L fructose water to induce a NASH model with human-like metabolic characteristics. Within 6 months, FPC group mice showed a remarkable increase in body weight, accompanied by significantly elevated levels of hepatocellular injury, steatosis, apoptosis, inflammation, and fibrosis. IF as a nutritional intervention, shows promise as an effective approach in the prevention of multi metabolic diseases. In the current study, an every-other-day fasting method was performed on the mice. Compared with their ad libitum group, mice underwent IF exhibited decreased growth rate of body weight, improved blood glucose metabolism, and the level of serum biochemical markers. IF management also improved hepatic steatosis, and inhibited the expression of inflammation and fibrotic factors in the liver. Meanwhile, the autophagy pathway was also significantly activated under IF treatment. While in some special cases, such as diabetic patients who need to keep stable blood glucose levels, IF practice is not suitable for them. Therefore, pharmacological interventions are still needed, natural products are widely welcomed in disease research. The newly developed natural product BS012 used in the current study is a mixture of Platycodon grandiflorum (PG); Cinnamomum cassia (CC) and Asiasarum sieboldii (AS) in a radio of 2:2:1, using 70% ethanol to make the extract. The results showed that 200 and 300 mg/kg BS012 administration demonstrated a better effect in controlling the body weight gain caused by FPC diet, inhibiting hepatic lipid accumulation, improving liver injury, decreasing inflammation and apoptosis levels, and also reducing the progression of fibrosis. Taken together, the current experiment provided evidence that IF management and BS012 administration attenuates the pathological features of NASH, and thus may provide a possible novel treatment method for NASH.
more목차 도움말
List of figures 8
Acknowledgment 10
Ⅰ. Introduction 11
1. Epidemiology and clinical aspects of NAFLD and NASH 11
2. Pathophysiology of NASH 13
3. Autophagy in liver disease 15
4. Intermittent fasting and NASH 17
5. Natural products in liver diseases and NASH 19
6. Experimental models of NASH research 22
Ⅱ. Materials and methods 26
1. Preparation of BS012 26
2. Animal model design 26
3. Body weight and food intake 28
4. Fasting glucose and ketone levels 28
5. Sacrifice 30
6. Serum analysis 30
7. Liver histological analysis 30
8. Liver tissue western blot analysis 30
9. Statistical Analysis 32
Ⅲ. Results 33
1. IF shows the ability to control the body weight increase; regulate blood glucose and ketone levels, without affecting the calorie consumption 33
2. BS012 treatment was able to control weight gain without affecting calorie consumption, with little effect on regulating blood glucose and ketone levels 37
3. IF and BS012 treatment can effectively control the abdominal fat and liver weight gain due to the FPC diet 41
4. Changes in serum TC and TG content with IF/BS012 treatment 45
5. IF/BS012 treatment reduced the progression of steatosis in NASH development with the evidence of Oil-Red-O staining 49
6. Treatment with IF/BS012 improved the expression of lipid metabolism-related proteins in the liver of mice induced by FPC diet 50
7. The effect of IF/BS012 on biochemical indicators of liver damage 54
8. Histological observation from Hematoxylin and Eosin staining showed that IF/BS012 treatment had a protective effect on the liver 58
9. Treatment with IF/BS012 partially reverse hepatocyte apoptosis induced by the NASH 60
10. Treatment of IF/BS012 inhibits the TLR4-mediated activation of pro-inflammatory factors 64
11. Masson's trichrome staining showed that IF/BS012 treatment improved liver fibrosis in NASH mice 68
12. Treatment of IF/BS012 effectively inhibited the activated TGF-β/Smad signaling pathway in NASH 70
13. Effect of IF and BS012 on autophagy activation in the liver of NASH mice 72
Ⅳ. Discussion 75
Ⅴ. Conclusion 82
References 83
Abstract 100
