Masahito Minami

Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease.

BackgroundHyperlipidemia, insulin resistance, and oxidative stress can heavily contribute to the initiation and progression of nonalcoholic fatty liver disease (NAFLD). Currently, there is no established treatment for this disease. Recently, several studies have shown that ezetimibe (EZ), a lipid-lowering drug, attenuates liver steatosis in an experimental NAFLD model. This study was designed to assess the efficacy of long-term EZ monotherapy in patients with NAFLD.MethodsA total of 45 patients with newly diagnosed liver biopsy-proven NAFLD were treated with EZ (10xa0mg/day) for 24xa0months. NAFLD-related biochemical parameters, imaging by computerized tomography, and liver biopsy were studied before and after treatment.ResultsEzetimibe therapy significantly improved NAFLD-related metabolic parameters including visceral fat area, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-R), triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-Ch), oxidative-LDL, the net electronegative charge modified-LDL, profiles of lipoprotein particle size and fatty acids component, and estimated desaturase activity. EZ therapy also significantly lowered serum alanine aminotransferase and high-sensitivity C-reactive protein levels, whereas no significant changes were found in serum type IV collagen 7S, adiponectin, leptin, and resistin levels. Histological features of steatosis grade (Pxa0=xa00.0003), necroinflammatory grade (Pxa0=xa00.0456), ballooning score (Pxa0=xa00.0253), and NAFLD activity score (NAS) (Pxa0=xa00.0007) were significantly improved from baseline. However, the fibrosis stage was not significantly (Pxa0=xa00.6547) changed.ConclusionThe results in this study suggest that the long-term EZ therapy can lead to improvement in metabolic, biochemical, and histological abnormalities of NAFLD. Therefore, EZ may be a promising agent for treatment of NAFLD.

Analysis of hepatic genes involved in the metabolism of fatty acids and iron in nonalcoholic fatty liver disease

Aims:u2002 Hepatic steatosis and iron cause oxidative stress, thereby progressing steatosis to steatohepatitis. We quantified the expression of genes involved in the metabolism of fatty acids and iron in patients with nonalcoholic fatty liver disease (NAFLD).

Predictive values of amino acid sequences of the core and NS5A regions in antiviral therapy for hepatitis C: a Japanese multi-center study

BackgroundChronic hepatitis C (CHC) genotype 1b patients with high viral load are resistant to peginterferon (PEG-IFN) and ribavirin (RBV) combination therapy, especially older and female patients.MethodsTo elucidate the factors affecting early and sustained viral responses (EVR and SVR), 409 genotype 1b patients CHC with high viral loads who had received 48xa0weeks of PEG-IFN/RBV therapy were enrolled. The amino acid (aa) sequences of the HCV core at positions 70 and 91 and of the interferon sensitivity determining region (ISDR) were analyzed. Host factors, viral factors, and treatment-related factors were subjected to multivariate analysis.ResultsMale gender, low HCV RNA load, high platelet count, two or more aa mutations of ISDR, and wild type of core aa 70 were independent predictive factors for SVR. In patients with over 80% adherences to both PEG-IFN and RBV, male gender, mild fibrosis stage, and wild type of core aa 70 were independent predictors for SVR.Conclusions Independent predictive factors for SVR were: no aa substitution at core aa 70, two or more aa mutations in the ISDR, low viral load, high values of platelet count, mild liver fibrosis and male gender.

Nonalcoholic steatohepatitis and increased risk of chronic kidney disease.

Nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) share common features. Both are associated with visceral obesity, type 2 diabetes mellitus, metabolic syndrome, and insulin resistance. However, the relationship between NAFLD and CKD is poorly understood. We examined the prevalence of and risk factors for CKD in patients with NAFLD. We analyzed 174 Japanese patients with liver biopsy-proven NAFLD using a cross-sectional design. Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min per 1.73 m(2) and/or overt proteinuria. Of 174 NAFLD patients, 92 (53%) exhibited histologic characteristics of nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD; and 82 (47%) had non-NASH NAFLD. Chronic kidney disease was present in 24 (14%) of 174 NAFLD patients. The prevalence of CKD was significantly higher in NASH patients (19 of 92; 21%) than non-NASH patients (5 of 82; 6%). The presence of CKD was associated with a higher body mass index and the presence of hypertension and NASH. Our results demonstrated a high prevalence of CKD among patients with NASH.

Evidence of oxidative stress as a cofactor in the development of insulin resistance in patients with chronic hepatitis C

Aim:u2002 The mechanisms by which metabolic disorders develop in patients with chronic hepatitis C are unknown. Our study aimed to test whether oxidative stress contributes to these mechanisms.

ERK5 is a target for gene amplification at 17p11 and promotes cell growth in hepatocellular carcinoma by regulating mitotic entry

Using high‐density oligonucleotide microarrays, we investigated DNA copy‐number aberrations in cell lines derived from hepatocellular carcinomas (HCCs) and detected a novel amplification at 17p11. To identify the target of amplification at 17p11, we defined the extent of the amplicon and examined HCC cell lines for expression of all seven genes in the 750‐kb commonly amplified region. Mitogen‐activated protein kinase (MAPK) 7, which encodes extracellular‐regulated protein kinase (ERK) 5, was overexpressed in cell lines in which the gene was amplified. An increase in MAPK7 copy number was detected in 35 of 66 primary HCC tumors. Downregulation of MAPK7 by small interfering RNA suppressed the growth of SNU449 cells, the HCC cell line with the greatest amplification and overexpression of MAPK7. ERK5, phosphorylated during the G2/M phases of the cell cycle, regulated entry into mitosis in SNU449 cells. In conclusion, our results suggest that MAPK7 is likely the target of 17p11 amplification and that the ERK5 protein product of MAPK7 promotes the growth of HCC cells by regulating mitotic entry.

Hepatic senescence marker protein-30 is involved in the progression of nonalcoholic fatty liver disease

BackgroundBoth insulin resistance and increased oxidative stress in the liver are associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Senescence marker protein-30 (SMP30) was initially identified as a novel protein in the rat liver, and acts as an antioxidant and antiapoptotic protein. Our aim was to determine whether hepatic SMP30 levels are associated with the development and progression of NAFLD.MethodsLiver biopsies and blood samples were obtained from patients with an NAFLD activity score (NAS)xa0≤xa02 (nxa0=xa018), NAS of 3–4 (nxa0=xa014), and NASxa0≥xa05 (nxa0=xa066).ResultsPatients with NASxa0≥xa05 had significantly lower hepatic SMP30 levels (12.5xa0±xa08.4xa0ng/mg protein) than patients with NASxa0≤xa02 (30.5xa0±xa014.2xa0ng/mg protein) and patients with NASxa0=xa03–4 (24.6xa0±xa012.2xa0ng/mg protein). Hepatic SMP30 decreased in a fibrosis stage-dependent manner. Hepatic SMP30 levels were correlated positively with the platelet count (rxa0=xa00.291) and negatively with the homeostasis model assessment of insulin resistance (rxa0=xa0−0.298), the net electronegative charge modified-low-density lipoprotein (rxa0=xa0−0.442), and type IV collagen 7S (rxa0=xa0−0.350). The immunostaining intensity levels of 4-hydroxynonenal in the liver were significantly and inversely correlated with hepatic SMP30 levels. Both serum large very low-density lipoprotein (VLDL) and very small low-density lipoprotein (LDL) levels in patients with NASxa0≥xa05 were significantly higher than those seen in patients with NASxa0≤xa02, and these lipoprotein fractions were significantly and inversely correlated with hepatic SMP30.ConclusionThese results suggest that hepatic SMP30 is closely associated with the pathogenesis of NAFLD, although it is not known whether decreased hepatic SMP30 is a result or a cause of cirrhosis.

Activation of B-Myb by E2F1 in hepatocellular carcinoma

Aim:u2002 Deregulation of E2F1 transcriptional activity is observed in a variety of cancers, including hepatocellular carcinoma (HCC). The aim of the present study is to identify transcriptional target genes of E2F1 in HCC.

Guidelines for the antiviral therapy of hepatitis C virus carriers with normal serum aminotransferase based on platelet counts.

Aim:u2002 We aimed to identify the candidates for antiviral therapy, among patients who are hepatitis C virus (HCV) carriers with normal serum aminotransferase (ALT), focused on the inhibition of hepatocellular carcinoma (HCC).

A novel amplification target, ARHGAP5, promotes cell spreading and migration by negatively regulating RhoA in Huh-7 hepatocellular carcinoma cells

RhoA, a member of the Rho family of small GTPases, directs the organization of the actin cytoskeleton and is involved in regulating cell shape and movement. Its activity is negatively regulated by p190-B RhoGAP (GTPase-activating protein). We investigated DNA copy number aberrations in human hepatocellular carcinoma and esophageal squamous cell carcinoma cell lines using a high-density oligonucleotide microarray and found a novel amplification at chromosomal region 14q12. We identified ARHGAP5 (the gene encoding p190-B RhoGAP) as a probable target for the amplification at 14q12, and our results showed that p190-B RhoGAP promotes cells spreading and migration by negatively regulating RhoA activity in Huh-7 hepatocellular carcinoma cells.