**8. Conclusions**

In our previous study, we established a novel model of fibrotic steatohepatitis by feeding hypertensive SHRSP5/Dmcr rats an HFC diet. Histological features resembling human NASH were observed in the rats, suggesting that this model is useful for studying hypertension-associated NASH. We compared NASH development among hypertensive strains (SHRSP5/Dmcr and SHR) and the normotensive WKY strain, and showed that hypertension accelerates progression of HFC-induced NASH by elevating BA synthesis (CYP7A1), inducing increased activation of inflammatory signaling (MAPK and NF-κB), and suppressing signaling associated with antioxidant defense (Nrf2/Keap1). To elucidate the role of cholesterol in NASH development, we investigated the kinetics of cholesterol in this model, and found that the HFC diet induced dysregulation of BA synthesis and suppression of BA detoxification, therefore resulting in cytotoxic BA accumulation in hepatocytes, which further induced oxidative stress, followed by activation of signaling involved in hepatic inflammation and fibrosis (**Figure 1**). Sex differences in fibrogenesis were also observed in this model and were associated with a different sensitivity to BA toxicity. More sustained expression of nuclear receptors, CAR and PXR, and the enzymes involved in BA detoxification, UGT and SULT, contributed to the stronger resistance to HFC-induced liver damage in female rats compared with males. In conclusion, our studies demonstrate that dietary cholesterol may play a crucial role in the progression of NASH-associated hypertension and provide a basis for NAFLD/NASH treatment involving restriction of cholesterol intake.
