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

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.

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.

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.

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.