Pioglitazone upregulates hepatic angiotensin converting enzyme 2 expression in rats with steatohepatitis.

OBJECTIVE: Angiotensin II, one component of renin-angiotensin system (RAS), is formed from Ang I by the catalysing of angiotensin converting enzyme (ACE). Angiotensin II plays an important role in the development of insulin resistance. ACE2, a homologue of ACE, couterregulate the actions of angiotensin II by facilitating its breakdown to angiotensin-(1-7). RAS has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH). Earlier demonstration that thiazolidinediones (TZDs) improve steatohepatitis promoted us to evaluate the change of hepatic ACE2 expression in rats with high fat diet (HFD)-induced NASH and the effects of TZDs on the hepatic ACE2 expression. MATERIAL AND METHODS: Rats were divided into normal control group, high fat diet (HFD) group, and pioglitazone group. After 24 weeks of treatment with pioglitazone, a TZD, we evaluated changes in liver histology, insulin sensitivity, lipid metabolism, circulating RAS levels and hepatic ACE2 expression. RESULTS: Compared with normal controls, the concentrations of serum lipid, aminotransaminase, glucose, insulin, ACE, angiotensin II, ACE2, angiotensin-(1-7) and the degree of hepatic ACE2 expression were significantly higher in rats with HFD-induced NASH. Pioglitazone significantly reduced the concentrations of serum lipid, aminotransaminase, glucose, insulin, ACE, angiotensin II while markedly raised the concentrations of serum ACE2, angiotensin-(1-7) and the degree of hepatic ACE2 expression. CONCLUSION: Hepatic ACE2 expression markedly increased in rats with HFD-induced NASH and was further upregulated by pioglitazone. Hepatic ACE2 may be a new target of pioglitazone treatment for NASH.

Probucol ameliorates the development of nonalcoholic steatohepatitis in rats fed high-fat diets.

AIMS: We sought to evaluate the effects of probucol on steatohepatitis and associated molecular mechanisms in a rat model of nonalcoholic steatohepatitis (NASH) induced by high-fat diet (HFD). METHODS: Forty male rats weighing 100-120 g were randomly assigned to the following treatments (n = 10 for each treatment): standard diet + normal saline (NC group), standard diet + 500 mg/kg/day probucol (NP group), HFD + normal saline (HD group), and HFD + 500 mg/kg/day probucol (HP group). All animals received the above treatments for 15 weeks. Lipid metabolism and steatohepatitis were assessed. Systemic insulin resistance, oxidative stress status, serum tumor necrosis factor-alpha (TNF-α) and adiponectin levels, and gene expression were examined. RESULTS: High-fat feeding resulted in macrovesicular steatosis, lobular inflammation, and hepatocellular ballooning degeneration in the liver, coupled with increased concentrations of serum aspartate aminotransferase and alanine aminotransferase. Probucol exposure attenuated the biochemical and histological changes comparable with NASH. Moreover, probucol treatment significantly prevented the elevations of serum total cholesterol, low-density lipoprotein, and high-density lipoprotein and the increase in the expression of numerous lipid metabolism-related genes in HFD-fed rats. There were increased insulin sensitivity and serum adiponectin levels and enhanced hepatic AMP-activated protein kinase phosphorylation in the HP group. Probucol lessened the HFD-induced elevation of serum TNF-α and hepatic malondialdehyde and reduced antioxidant enzymatic activities. CONCLUSIONS: Probucol shows beneficial effects on HFD-induced steatohepatitis by improving insulin resistance and attenuating oxidative stress and systemic inflammation.