{"title":"对肝脏硬度的纵向评估显示,肝脏胆固醇是小鼠肝纤维化进展的决定因素。","authors":"Na Young Lee , Ja Hyun Koo","doi":"10.1016/j.lfs.2024.123201","DOIUrl":null,"url":null,"abstract":"<div><h3>Aims</h3><div>The metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30 % of the global population. While excessive consumption of dietary fat induces steatosis, it does not develop fibrosis, indicating that additional factors are required as “second hits” for further progression of MASLD. Here, based on shear wave elastography, we compared the longitudinal patterns of fibrogenesis induced by different diets and show the crucial role of cholesterol accumulation in fibrosis progression.</div></div><div><h3>Materials and methods</h3><div>Mice were fed chow, high-fat (HFD), high-fat high-cholesterol (HFHCD), choline-deficient, L-amino acid-defined high-fat (CDAHFD), or 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine diets over 12 weeks.</div></div><div><h3>Key findings</h3><div>Mice fed with HFD gained significant amounts of body weight but did not show an increase in liver stiffness. In contrast, the addition of cholesterol in the same diet robustly induced liver stiffening starting from the first week, which was comparable to the CDAHFD-induced fibrosis model. Longitudinal tracking of liver stiffness revealed a two-step progression of fibrosis after prolonged feeding of HFHCD and CDAHFD, likely due to cellular cholesterol accumulation over a certain threshold after the transition point. Biochemical analyses suggested the critical role of both total and hepatic cholesterol accumulation in liver fibrosis development.</div></div><div><h3>Significance</h3><div>Collectively, our results underscore the significance of cholesterol in liver fibrosis development, also highlighting the benefit of monitoring liver stiffness to understand the pathogenesis of liver fibrosis.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"358 ","pages":"Article 123201"},"PeriodicalIF":5.2000,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Longitudinal evaluation of liver stiffness reveals hepatic cholesterol as the determinant of fibrosis progression in mice\",\"authors\":\"Na Young Lee , Ja Hyun Koo\",\"doi\":\"10.1016/j.lfs.2024.123201\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Aims</h3><div>The metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30 % of the global population. While excessive consumption of dietary fat induces steatosis, it does not develop fibrosis, indicating that additional factors are required as “second hits” for further progression of MASLD. Here, based on shear wave elastography, we compared the longitudinal patterns of fibrogenesis induced by different diets and show the crucial role of cholesterol accumulation in fibrosis progression.</div></div><div><h3>Materials and methods</h3><div>Mice were fed chow, high-fat (HFD), high-fat high-cholesterol (HFHCD), choline-deficient, L-amino acid-defined high-fat (CDAHFD), or 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine diets over 12 weeks.</div></div><div><h3>Key findings</h3><div>Mice fed with HFD gained significant amounts of body weight but did not show an increase in liver stiffness. In contrast, the addition of cholesterol in the same diet robustly induced liver stiffening starting from the first week, which was comparable to the CDAHFD-induced fibrosis model. Longitudinal tracking of liver stiffness revealed a two-step progression of fibrosis after prolonged feeding of HFHCD and CDAHFD, likely due to cellular cholesterol accumulation over a certain threshold after the transition point. Biochemical analyses suggested the critical role of both total and hepatic cholesterol accumulation in liver fibrosis development.</div></div><div><h3>Significance</h3><div>Collectively, our results underscore the significance of cholesterol in liver fibrosis development, also highlighting the benefit of monitoring liver stiffness to understand the pathogenesis of liver fibrosis.</div></div>\",\"PeriodicalId\":18122,\"journal\":{\"name\":\"Life sciences\",\"volume\":\"358 \",\"pages\":\"Article 123201\"},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2024-10-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Life sciences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0024320524007914\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0024320524007914","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Longitudinal evaluation of liver stiffness reveals hepatic cholesterol as the determinant of fibrosis progression in mice
Aims
The metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30 % of the global population. While excessive consumption of dietary fat induces steatosis, it does not develop fibrosis, indicating that additional factors are required as “second hits” for further progression of MASLD. Here, based on shear wave elastography, we compared the longitudinal patterns of fibrogenesis induced by different diets and show the crucial role of cholesterol accumulation in fibrosis progression.
Materials and methods
Mice were fed chow, high-fat (HFD), high-fat high-cholesterol (HFHCD), choline-deficient, L-amino acid-defined high-fat (CDAHFD), or 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine diets over 12 weeks.
Key findings
Mice fed with HFD gained significant amounts of body weight but did not show an increase in liver stiffness. In contrast, the addition of cholesterol in the same diet robustly induced liver stiffening starting from the first week, which was comparable to the CDAHFD-induced fibrosis model. Longitudinal tracking of liver stiffness revealed a two-step progression of fibrosis after prolonged feeding of HFHCD and CDAHFD, likely due to cellular cholesterol accumulation over a certain threshold after the transition point. Biochemical analyses suggested the critical role of both total and hepatic cholesterol accumulation in liver fibrosis development.
Significance
Collectively, our results underscore the significance of cholesterol in liver fibrosis development, also highlighting the benefit of monitoring liver stiffness to understand the pathogenesis of liver fibrosis.
期刊介绍:
Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed.
The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.