**5. CYP7A1**

Our previous study showed that dysregulated expression of enzymes involved in BA synthesis led to the accumulation of BA in the livers of SHRSP5/Dmcr rats fed an HFC diet [36]. We further investigate the role of CYP7A1 in the pathogenesis of hypertension-associated NASH, and evaluated its hepatic levels in hypertensive SHR and SHRSP5/Dmcr rats, and the normotensive WKY strain [28]. Constitutive CYP7A1 levels were markedly higher (over 300-fold) in the hypertensive strains compared with those in the normotensive WKY strain. Upregulation of CYP7A1 may result in an excessive accumulation of toxic BAs, such as hydrophobic BAs, which may lead to oxidative stress and liver damage. In addition, Kamisako et al. showed that the Nrf2 pathway may regulate the expression of genes associated with BA synthesis and fatty acid metabolism, including CYP7A1 [57]. Our study showed increased activation of Nrf2 signaling in the livers of hypertensive rats fed a control diet compared with the normotensive WKY, which might be the responsible for the overexpression of CYP7A1 in the hypertensive strains [28].

**7. Treatment of NAFLD/NASH**

regression of hepatic fibrosis.

NAFLD/NASH is related to poor lifestyle, including unhealthy diet habit and lack of exercise, which may, in turn, lead to excessive weight gain. Therefore, dietary intervention and exercise, targeted at weight loss, are the primary therapies for obesity-related NAFLD/NASH [63]. Vilar-Gomezet al. evaluated the effect of weight loss through lifestyle modifications on the improvement of NASH-related histologic features [64]. The study included 293 patients with NASH who followed a recommended lifestyle over 52 weeks to reduce body weight, including a low-fat, hypocaloric diet (750 kcal per day) and walking (200 min per week). Among these patients, 30% lost ≥5% of their weight at 52 weeks, 25% showed resolution of steatohepatitis, and 47% showed reduced nonalcoholic fatty liver disease activity score (NAS). This study also reported that the extent of weight loss was associated with histologic improvement. A higher proportion of patients with ≥5% weight loss had NASH resolution compared with those with ≤5% weight loss. Furthermore, 45% of patients with ≥10% weight loss showed

The Role of Cholesterol in the Pathogenesis of Hypertension-Associated Nonalcoholic…

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Although NAFLD/NASH is closely linked with obesity and diabetes, it may also occur in the absence of these diseases [65]. As described before, the hypertensive SHRSP5/Dmcr rat represents a good model of NAFLD/NASH without obesity and diabetes [20]. We used this model to investigate the efficacy of dietary intervention for improving HFC-induced NASH [66]. Rats were fed an HFC diet for 2 weeks (before the appearance of hepatic fibrosis) or 8 weeks (after the appearance of fibrosis), then subsequently fed a control diet for 6 or 12 weeks. We found that dietary intervention prior to the appearance of fibrosis markedly improved steatosis and suppressed the HFC-induced increase in serum AST, ALT, and TC. On the other hand, dietary intervention after the appearance of fibrosis was unable to suppress the increase in serum ALT and hepatic TC. Although the dietary intervention (in both cases) reset the increased expression of fibrosis-relative proteins, TGF-β1 and α-SMA, it only slightly reduced the fibrotic area compared with continuous HFC feeding. Taken together, dietary intervention was able to completely or partially improve steatosis, inflammation, and cholesterol accumulation in the livers of rats fed an HFC diet, although this was not enough to improve hepatic fibrosis.

In addition, several pharmacological agents use in the treatment of NASH, including vitamin E and pioglitazone, have been tested [67, 68]. Oxidative stress and insulin resistance are considered as key factors implicated in the progression of NASH, and are, therefore, attractive targets for the treatment of NASH [69]. Sanyal et al. tested the efficacy of vitamin E, a lipid-soluble antioxidant, and pioglitazone, an insulin sensitizer, in NASH patients without diabetes [69]. The 247 patients included in this study received 800 IU vitamin E (84 subjects), 30 mg pioglitazone (80 subjects), or placebo (83 subjects) daily for 96 weeks. Both vitamin E and pioglitazone were associated with improvements in hepatic steatosis and lobular inflammation, as well as a reduction of serum AST and ALT, compared with the placebo. However, neither drug had a significant effect on hepatic fibrosis. In conclusion, lifestyle intervention (controlled dietary intake as well as exercise) may be the first choice for NAFLD/NASH treatment and should be optimized, while pharmacological management can be used as an auxil-

iary method, and should be further tested in large studies with long-term outcomes.
