The therapeutic efficacy of angiotensin II receptor antagonist, losartan, was studied in patients with nonalcoholic steatohepatitis (NASH). Seven patients with both NASH and hypertension were treated with losartan (50 mg/d) for 48 weeks. Treatment with losartan resulted in a significant decrease in blood markers of hepatic fibrosis, plasma TGF-␤1 and serum ferritin concentration concurrently with an improvement in serum aminotransferase levels. Histological assessment showed improvement of hepatic necroinflammation in five patients, reduction of hepatic fibrosis in four patients, and disappearance of iron deposition in two patients. No side effect of treatment was noted at any time during the study. In conclusion, the present data raise the possibility that an angiotensin II receptor antagonist may be therapeutically efficacious for NASH. (HEPATOLOGY 2004;40:1222-1225 N onalcoholic steatohepatitis (NASH) is a distinct clinical entity characterized by varying degrees of progressive steatosis, lobular inflammation and fibrosis of the liver. 1,2 Although the causes of NASH are not well defined and several therapies including diet, 3 antioxidants, 4 and approaches that improve insulin resistance 5 have been tried, no commonly accepted therapeutic protocol has yet been established. Recent studies have demonstrated a crucial role of angiotensin II in the pathogenesis of hepatic fibrosis, 6 and this peptide has been shown to enhance insulin resistance and tissue iron deposition. 7,8 Administration of an antagonist of angiotensin II type 1 receptor has been shown to decrease hepatic fibrosis in rats. 6 In the present study, the effects of losartan, a selective angiotensin II type I receptor antagonist, were investigated in patients with NASH. Patients and MethodsEight patients (two men and six women), aged 41-65 (median 57) years, with both NASH and hypertension, were entered into this study. All patients consumed less than 40 g of alcohol per week. Four patients were obese (body mass index Ͻ 25), four had diabetes mellitus, four had hyperlipidemia, and one had hyperuricemia. At the time of the study, some of the patients had already been on medication, including benzodiazepines, calcium antagonists or anticoagulants for at least 12 months. These therapeutic regimens were not changed after the start of the study. None of the patients were taking any angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists before the study.Baseline laboratory assessment revealed abnormally high serum transaminase and ␥-glutamyl transpeptidase concentrations in all patients. Five patients showed high serum ferritin concentrations. Homeostasis model assessment (HOMA)-R was abnormally high in all patients. Liver biopsies were performed prior to entry the study, and revealed moderate to severe lobular steatosis, and various degrees of hepatic necroinflammation and fibrosis in all patients. In two patients, iron deposition in hepatocytes was noted (Table 1).

Hypoxia-inducible factor 1 (HIF-1) is involved in tumor progression/metastasis and activated in various cancers. Here we show that HIF-1A, which plays a major role in HIF-1 activation, is overexpressed in preneoplastic hepatocytic lesions from a very early stage during hepatocarcinogenesis in mice and man. Transcriptional targets of HIF-1, such as vascular endothelial growth factor, glut-1, c-met, and insulinlike growth factor II (IGF-II), were also overexpressed in mouse lesions. Oxygen tension within the lesions was not different from that of the normal hepatic tissues, indicating that HIF-1A expression was independent of hypoxia. On the other hand, Akt, the pathway of which can up-regulate HIF-1A expression, was activated in the mouse lesions, whereas HIF-1A was markedly down-regulated in the mouse hepatocellular carcinoma (HCC) cell lines after treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, indicating that HIF-1A expression is dependent on PI3K/Akt signaling. Conversely, HIF-1A knockdown by short interfering RNA in the HCC cell line resulted in decreased expression of activated Akt together with the HIF-1 target genes, indicating that Akt activation is reversely dependent on HIF-1 activation. Treating the HCC cells with IGF-II or epidermal growth factor (EGF) up-regulated both phospho-Akt and HIF-1A, whereas inhibition of IGF-II or EGF signaling down-regulated them both, suggesting that IGF-II and EGF can, at least in part, mediate the activation of Akt and HIF-1A. However, Akt was not activated by IGF-II or EGF in the HIF-1A knockdown cells, indicating that expression of the HIF-1 target genes is necessary for the Akt activation. These findings suggest that the reciprocal activation of PI3K/Akt signaling and HIF-1A may be important in the progression of hepatocarcinogenesis.

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http://dx.doi.org/10.1016/j.surg.2009.03.01

Our data suggest the crucial involvement of HSCs in anti-fibrotic effect of angiotensin II receptor antagonist on patients with NASH.