Abstract
Dietary cholesterol is a crucial risk factor for nonalcoholic steatohepatitis (NASH). Our recent studies indicated that high cholesterol intake was associated with the pathogenesis of hypertension-associated NASH. We developed a novel hypertensive rat model of NASH by feeding stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr) a high fat and cholesterol (HFC) diet. Histological features resembling human NASH were observed in this model. Furthermore, we investigated the kinetics of cholesterol in the rats fed an HFC diet and determined that suppression of bile acid (BA) detoxification led by HFC feeding results in cytotoxic BA accumulation in hepatocytes, which induces inflammatory response and liver damage. Sex differences in fibrogenesis were also observed in this model, and we found this was associated with a different ability in BA detoxification. Since SHRSP5/Dmcr rats are hypertensive, we investigated the role of hypertension in NASH progression by comparing NASH development among SHRSP5/Dmcr rats, spontaneously hypertensive rats and their original strain, Wistar Kyoto, with normal blood pressure. HFC diet induced more severe hepatic fibrosis in the hypertensive strains compared with the normotensive one. In conclusion, dietary cholesterol plays an essential role in the pathogenesis of NASH, and the combined action of cholesterol and hypertension further aggravates its progression.
Highlights
High dietary cholesterol intake may lead to increased risk of diseases such as cardiovascular disease and diabetes [1, 2]
In order to investigate the kinetics of cholesterol during the development of high fat and cholesterol (HFC)-induced nonalcoholic steatohepatitis (NASH) in our hypertensive SHRSP5/Dmcr rat model, we evaluated the expression of proteins involved in de novo cholesterol synthesis, cholesterol uptake from bloodstream in the form of LDL, cholesterol secretion into blood in the form of very-low-density lipoprotein, and bile acid (BA) synthesis and detoxification [36]
Histological features resembling human NASH were observed in the rats, suggesting that this model is useful for studying hypertension-associated NASH
Summary
High dietary cholesterol intake may lead to increased risk of diseases such as cardiovascular disease and diabetes [1, 2]. We previously developed a novel animal model of hypertension-associated NASH by feeding stroke-prone spontaneously hypertensive5/Dmcr (SHRSP5/Dmcr) rats a high fat and cholesterol (HFC) diet [20]. The SHRSP5/Dmcr rats, formally known as arteriolipidosis-prone rats, were developed as an animal model of arteriosclerosis, marked enlargement and an abnormal whitish color of the liver were noted in the 47th generation These findings prompted our studies on HFC diet-induced liver damage in this strain. In order to investigate the role of dietary cholesterol in the pathogenesis of HFC diet-induced NASH in SHRSP5/Dmcr rats, we compared hepatic histological changes induced by a high fat (HF) diet and those by an HFC diet (unpublished). It was suggested that dietary cholesterol may play a key role in the transition from simple steatosis to fibrotic steatohepatitis, the progressive stage, during the progression of NAFLD/NASH
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