Wataru Tomeno

The Selective SGLT2 Inhibitor Ipragliflozin Has a Therapeutic Effect on Nonalcoholic Steatohepatitis in Mice

Background & Aims In recent years, nonalcoholic steatohepatitis (NASH) has become a considerable healthcare burden worldwide. Pathogenesis of NASH is associated with type 2 diabetes mellitus (T2DM) and insulin resistance. However, a specific drug to treat NASH is lacking. We investigated the effect of the selective sodium glucose cotransporter 2 inhibitor (SGLT2I) ipragliflozin on NASH in mice. Methods We used the Amylin liver NASH model (AMLN), which is a diet-induced model of NASH that results in obesity and T2DM. AMLN mice were fed an AMLN diet for 20 weeks. SGLT2I mice were fed an AMLN diet for 12 weeks and an AMLN diet with 40 mg ipragliflozin/kg for 8 weeks. Results AMLN mice showed steatosis, inflammation, and fibrosis in the liver as well as obesity and insulin resistance, features that are recognized in human NASH. Ipragliflozin improved insulin resistance and liver injury. Ipragliflozin decreased serum levels of free fatty acids, hepatic lipid content, the number of apoptotic cells, and areas of fibrosis; it also increased lipid outflow from the liver. Conclusions Ipragliflozin improved the pathogenesis of NASH by reducing insulin resistance and lipotoxicity in NASH-model mice. Our results suggest that ipragliflozin has a therapeutic effect on NASH with T2DM.

Unfolded protein response pathways regulate Hepatitis C virus replication via modulation of autophagy

Abstract Background Hepatitis C virus (HCV) induces endoplasmic reticulum (ER) stress which, in turn, activates the unfolding protein response (UPR). UPR activates three distinct signalling pathways. Additionally, UPR induces autophagy (UPR-autophagy pathways). On the other hand, it has become clear that some positive-single-strand RNA viruses utilize autophagy. Some groups have used the siRNA silencing approach to show that autophagy is required for HCV RNA replication. However, the mechanism of induction of the UPR-autophagy pathways remain unclear in the cells with HCV. Method and results: we used a genome-length HCV RNA (strain O of genotype 1b) replication system (OR6) in hepatoma cells (HuH-7-derived OR6 cells). As control, we used OR6c cells from which the HCV genome had been removed by treatment with interferon-α. The UPR-autophagy pathways were activated to a greater degree in the OR6 cells as compared to the OR6c cells. Rapamycin, mTOR-independent autophagy inducer, activated HCV replication in the OR6 cells. On the other hand, HCV replication in the cells was inhibited by 3-methyladenine (3-MA), which is an inhibitor of autophagy. Salubrinal (Eukaryotic Initiation Factor 2(eIF2)-alpha phosphatase inhibitor), 3-ethoxy-5, 6-dibromosalicylaldehyde (X-box binding protein-1 (XBP-1) splicing inhibitor) and sp600125 (c-Jun N-terminal kinases (JNK) inhibitor) inhibited HCV replication and autophagy. Additionally, HCV replication and autophagy were inhibited more strongly by combination of these inhibitors. Conclusion Our results suggest that UPR-autophagy pathways exert an influence on HCV replication. Therefore, control these pathways may serve as a novel therapeutic strategy against replication of HCV.

Risk factors for colonic diverticular hemorrhage: Japanese multicenter study.

Background and Aim: Diverticular hemorrhage is the common cause of lower gastrointestinal bleeding, and its incidence has been increasing in Japan. However, the exact cause of diverticular hemorrhage is not well understood. We investigated the risk factors for diverticular hemorrhage. Methods: We selected 103 patients with diverticular hemorrhage as cases and patients with colonic diverticulosis without a history of bleeding were selected as control subjects, exactly matched for age and gender. We collected the data from the medical records of each of the patients, such as those related to the comorbidities, medications and findings of colonoscopy, and conducted a matched case-control study to analyze the risk factors for diverticular hemorrhage. Results: Both groups were composed of 75 men and 28 women. The median age of the patients in both groups was 72.0 years (47.0–87.0). The body weight (p = 0.0065), body mass index (p = 0.006), prevalence of hypertension (p = 0.0242), prevalence of ischemic heart disease (p = 0.0015), and frequency of use of low-dose aspirin (p = 0.042) were significantly different between the two groups. The percentage of patients with bilateral diverticula, that is, diverticula on both the right and left hemicolon, was significantly higher in the diverticular hemorrhage group (p = 0.0011). Multiple regression analysis identified only the diverticular location as being significantly associated with the risk of diverticular hemorrhage (p = 0.0021). Conclusions: Only the diverticular location (bilateral) was found to be an independent risk factor for diverticular hemorrhage.

Influence of inducible nitric oxide synthase polymorphisms in Japanese patients with non-alcoholic fatty liver disease

Aim:  Genetic factors as well as environmental factors play an important role in the development of non‐alcoholic fatty liver disease (NAFLD). Recently, inducible nitric oxide synthase (iNOS) was significantly higher in the severest form of non‐alcoholic steatohepatitis (NASH), and nitric oxide (NO) has been determined to play an important role in the process of fibrosis in NASH. In this study, we investigated iNOS gene polymorphisms for associations with NAFLD.

Soluble CD14 Levels Reflect Liver Inflammation in Patients with Nonalcoholic Steatohepatitis

Background & Aims Liver inflammation is a risk factor for the progression of nonalcoholic fatty liver disease (NAFLD). However, the diagnosis of liver inflammation is very difficult and invasive liver biopsy is still the only method to reliably detect liver inflammation. We previously reported that overexpression of CD14 in Kupffer cells may trigger the progression to nonalcoholic steatohepatitis (NASH) via liver inflammation following hyper-reactivity to low-dose lipopolysaccharide. Therefore, the aim of this study was to investigate the relationship between soluble type of CD14 (sCD14) and histological features in patients with NAFLD. Methods Our cohort consisted of 113 patients with liver biopsy-confirmed NAFLD and 21 age-matched healthy controls. Serum sCD14 levels were measured by an enzyme-linked immunosorbent assay. Results Serum sCD14 levels were significantly associated with diagnosis of NASH and the area under the receiver operator characteristic curve (AUROC) to distinguish between not NASH and NASH was 0.802. Moreover, serum sCD14 levels were significantly associated with the disease activity based on NAFLD activity score and hepatic CD14 mRNA expression, which is correlated with membrane CD14 (mCD14) expression, in patients with NAFLD. In multiple regression analysis, the serum sCD14 levels were independently associated with liver inflammation. The AUROC to distinguish between mild and severe liver inflammation in patients with NAFLD was 0.752. Conclusions We found that serum sCD14 levels increased significantly with increasing liver inflammation grade in patients with NAFLD, reflecting increased hepatic CD14 expression. Serum sCD14 is a promising tool to predict the worsening of liver inflammation, and may offer a potential biomarker for evaluation of therapeutic effects in NAFLD.

Capsule endoscopy with flexible spectral imaging color enhancement reduces the bile pigment effect and improves the detectability of small bowel lesions

BackgroundCapsule endoscopy with flexible spectral imaging color enhancement (CE-FICE) has been reported to improve the visualization and detection of small-bowel lesions, however, its clinical usefulness is still not established. Therefore, we conducted a study to evaluate whether CE-FICE contributes to improve the detectability of small-bowel lesions by CE trainees.MethodsFour gastroenterology trainees without prior CE experience were asked to read and interpret 12 CE videos. Each of the videos was read by conventional visualization method and under three different FICE settings. To evaluate whether the lesion recognition ability of the CE trainees could be improved by the FICE technology, the lesion detection rate under each of the three FICE settings was compared with that by conventional CE. CE trainees tend to miss small-bowel lesions in bile-pigment-positive condition, therefore we evaluated whether CE-FICE contributes to reducing the bile-pigment effect. The bile-pigment condition was determined by the color values around the small-bowel lesions according to the results of the receiver-operating-characteristic analysis. Moreover, we also evaluated whether poor bowel preparion might affect the accuracy of lesion recognition by CE-FICE.ResultsOf a total of 60 angioectasias, CE trainees identified 26 by conventional CE, 40 under FICE setting 1, 38 under FICE setting 2, and 31 under FICE setting 3. Of a total of 82 erosions/ulcerations, CE trainees identified 38 by conventional CE, 62 under FICE setting 1, 60 under FICE setting 2, and 20 under FICE setting 3. Compared with conventional CE, FICE settings 1 and 2 significantly improved the detectability of angioectasia (P = 0.0017 and P = 0.014, respectively) and erosions/ulcerations (P = 0.0012 and P = 0.0094, respectively). Although the detectability of small-bowel lesions by conventional CE (P = 0.020) and under FICE setting 2 (P = 0.0023) was reduced by the presence of bile-pigments, that under FICE setting 1 was not affected (P = 0.59). Our results also revealed that in poor bowel visibility conditions, CE-FICE yielded a high rate of false-positive findings.ConclusionsCE-FICE may reduce the bile-pigment effect and improve the detectability of small-bowel lesions by CE trainees; the reliability of CE-FICE may be improved by good bowel preparation.

Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis

The natural polyphenol compound resveratrol (RSV) is considered to have a broad spectrum of beneficial biological activities upon human health. However, the exact effect of RSV on steatosis (a phenotype of non-alcoholic fatty liver [NAFL]) or fibrosis and inflammation (major phenotypes of non-alcoholic steatohepatitis [NASH]) is not known. Our data showed that administration of RSV (2 or 20 mg/kg/day) did not suppress steatosis in a high-fat diet-induced model of NAFL in mice. In contrast, identical concentrations of RSV dramatically inhibited inflammation and fibrosis in a low-dose lipopolysaccharide-induced model of NASH. These data suggested that RSV administration-mediated improvement of inflammation and fibrosis was due to the inhibition of LPS reactivity controlled by CD14 expression in Kupffer cells. These findings suggest that RSV could be a candidate agent for the treatment of NASH.

Evaluation of the Liver Fibrosis Index calculated by using real‐time tissue elastography for the non‐invasive assessment of liver fibrosis in chronic liver diseases

A rapid and non‐invasive method of detecting fibrosis in patients with chronic liver diseases is of major clinical interest. The purpose of this study was to comparatively investigate the effectiveness of the Liver Fibrosis Index (LF Index) calculated using real‐time tissue elastography (RTE) in patients with non‐alcoholic fatty liver disease (NAFLD) and patients with chronic hepatitis C (CHC).

Characteristics of non-obese non-alcoholic fatty liver disease: Effect of genetic and environmental factors

There are a considerable number of patients with non‐obese non‐alcoholic fatty liver disease (NAFLD). However, the clinical characteristics of non‐obese NAFLD is not fully understood. We investigated genetic and other clinical parameters in non‐obese and obese NAFLD.

LDL-migration index (LDL-MI), an indicator of small dense low-density lipoprotein (sdLDL), is higher in non-alcoholic steatohepatitis than in non-alcoholic fatty liver: a multicenter cross-sectional study.

Background Non-alcoholic fatty liver disease (NAFLD) is associated with increased risks of atherosclerotic diseases, including cardiovascular disease. However, the difference in risk between patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) has not yet been determined. Accumulating evidence has shown that high amounts of small dense low-density lipoprotein (sdLDL) are closely associated with atherosclerotic diseases. This study investigated differences in risk factors for atherosclerotic diseases, especially LDL-migration index (LDL-MI), an indicator of sdLDL, between patients with NAFL and NASH. Methods LDL-MI was analyzed in a primary cohort of 156 patients with NAFLD, including 53 with NAFL and 103 with NASH, and a validation cohort of 69 patients with NAFLD, including 25 with NAFL and 44 with NASH. Results In the primary cohort, NASH was associated with elevated LDL-MI (p = 0.039). Multiple regression analysis showed that NASH and the non-use of lipid lowering medications were independently correlated with higher LDL-MI in all patients with NAFLD. Among patients not on lipid lowering medications, those with NASH had significantly higher LDL-MI than those with NAFL (p = 0.001). These findings were confirmed in a validation cohort, in that LDL-MI was significantly higher in patients with NASH than with NAFL (p = 0.043). Conclusion This study is the first to show that LDL-MI, an indicator of sdLDL, was higher in patients with NASH than with NAFL, suggesting that the risk of atherosclerotic diseases may be higher in NASH than NAFL. Patients with NASH should be followed closely, especially for the progression of liver pathology and atherosclerotic diseases. Trial Registration UMIN000009614