The pathogenesis of hepatitis C virus (HCV)-associated insulin resistance remains unclear. Therefore, we investigated mechanisms for HCV-associated insulin resistance. Homeostasis model assessment ...for insulin resistance was increased in patients with HCV infection. An increase in fasting insulin levels was associated with the presence of serum HCV core, the severity of hepatic fibrosis and a decrease in expression of insulin receptor substrate (IRS) 1 and IRS2, central molecules of the insulin-signaling cascade, in patients with HCV infection. Down-regulation of IRS1 and IRS2 was also seen in HCV core-transgenic mice livers and HCV core-transfected human hepatoma cells. Carbobenzoxy-
l-leucyl-
l-leucyl-
l-leucinal, a potent proteosomal proteolysis inhibitor, blocked down-regulation of IRS1 and IRS2 in HCV core-transfected hepatoma cells. In human hepatoma cells, HCV core up-regulated suppressor of cytokine signaling (SOCS) 3 and caused ubiquitination of IRS1 and IRS2. HCV core-induced down-regulation of IRS1 and IRS2 was not seen in SOCS3
−/− mouse embryonic fibroblast cells. Furthermore, HCV core suppressed insulin-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase and Akt, activation of 6-phosphofructo-2-kinase, and glucose uptake. In conclusion, HCV infection changes a subset of hepatic molecules regulating glucose metabolism. A possible mechanism is that HCV core-induced SOCS3 promotes proteosomal degradation of IRS1 and IRS2 through ubiquitination.
Hepatitis C virus (HCV) infection is linked to greater insulin resistance. Although HCV itself is a candidate for the development of insulin resistance, the effects of antiviral treatment on impaired ...glucose metabolism remain unclear. The aim of this study is to examine the effects of clearance of HCV on insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate (IRS)1/2, central molecules for insulin signaling.
We analyzed 89 biopsy-proven patients with chronic HCV infection. Patients received interferon-alpha or interferon-alpha plus ribavirin for 6 months and were classified into three groups at 6 months after the conclusion of antiviral therapy according to their response to antiviral therapy: sustained responders (N = 29), relapsers (N = 12), and nonresponders (N = 48). Insulin resistance and beta-cell function were assessed by the homeostasis model assessment method (HOMA-IR and HOMA-%B, respectively). Hepatic expression of IRS1/2 was evaluated by immunoblotting and immunostaining in 14 sustained responders.
In nonresponders and relapsers, there were no significant changes in HOMA-IR and HOMA-%B values after antiviral therapy. On the other hand, in sustained responders, HOMA-IR values significantly decreased to 1.7 +/- 0.8 from 3.1 +/- 1.1 (P < 0.05) after antiviral therapy. Similarly, HOMA-%B values significantly decreased to 90.6 +/- 10.0 from 113.7 +/- 15.3 (P < 0.05). Immunoblotting showed a threefold increase in IRS1/2 expression after clearance of HCV. Immunostaining revealed that greater IRS1/2 expression was seen in hepatocytes.
We showed that clearance of HCV improves insulin resistance, beta-cell function, and hepatic IRS1/2 expression.
Background & Aims: We investigated whether endothelial progenitor cell (EPC) transplantation could reduce established liver fibrosis and promote hepatic regeneration by isolating rat EPCs from bone ...marrow cells. Methods: Recipient rats were injected intraperitoneally with carbon tetrachloride (CCl4 ) twice weekly for 6 weeks before initial administration of EPCs. CCl4 was then readministered twice weekly for 4 more weeks, and EPC transplantation was carried out for these same 4 weeks. Results: At 7 days in culture, the cells expressed Thy-1, CD31, CD133, Flt-1, Flk-1, and Tie-2, suggesting an immature endothelial lineage. Immunohistochemical analyses showed fluorescent-labeled, transplantation EPCs were incorporated into the portal tracts and fibrous septa. Single and multiple EPC transplantation rats had reduced liver fibrosis, with decreased α2-(I)-procollagen, fibronectin, transforming growth factor-β, and α-smooth muscle actin-positive cells. Film in situ zymographic analysis revealed strong gelatinolytic activity in the periportal area, in accordance with EPC location. Real-time polymerase chain reaction analysis of multiple EPC-transplantation livers showed significantly increased messenger RNA levels of matrix metalloproteinase (MMP)-2, -9 and -13, whereas tissue inhibitor of metalloproteinase-1 expression was significantly reduced. Expression of hepatocyte growth factor, transforming growth factor-α, epidermal growth factor, and vascular endothelial growth factor was increased in multiple EPC-transplantation livers, while hepatocyte proliferation increased. Transaminase, total bilirubin, total protein, and albumin levels were maintained in EPC-transplantation rats, significantly improving survival rates. Conclusions: We conclude that single or repeated EPC transplantation halts established liver fibrosis in rats by suppressing activated hepatic stellate cells, increasing matrix metalloproteinase activity, and regulating hepatocyte proliferation.
Increased insulin resistance is frequently associated with chronic liver disease and is a pathophysiological feature of hepatogenous diabetes.Distinctive factors including hepatic parenchymal cell ...damage,portalsystemic shunting and hepatitis C virus are responsible for the development of hepatogenous insulin resistance/diabetes.Although it remains unclear whether insulin secretion from pancreatic beta cells is impaired as it is in type 2 diabetes,retinopathic and cardiovascular risk is low and major causes of death in cirrhotic patients with diabetes are liver failure,hepatocellular carcinoma and gastrointestinal hemorrhage.Hemoglobin A1c is an inaccurate marker for the assessment and management of hepatogenous diabetes.Moreover,exogenous insulin or sulfonylureas may be harmful because these agents may promote hepatocarcinogenesis.Thus,pathogenesis,cause of death,assessment and therapeutic strategy for hepatogenous insulin resistance/diabetes differ from those for lifestyle-related type 2 diabetes.In this article,we review features of insulin resistance in relationship to chronic liver disease.We also discuss the impact of anti-diabetic agents on interferon treatment and hepatocarcinogenesis.
Aim: In patients with chronic liver disease who are at risk of malnutrition, simple and useful assessments for nutritional status should be established for ordinary medical care. The prognostic ...nutritional index (PNI) and controlling nutritional status (CONUT) are simple assessments constructed of only two or three laboratory data. We aimed to describe the potential of PNI and CONUT as a nutritional assessment tool in patients with chronic liver disease.
Methods: We enrolled 165 patients, aged 18–85 years, with chronic liver disease. These patients were nutritionally assessed by PNI or CONUT, demonstrating the association with the severity of chronic liver disease or anthropometric values.
Results: The value of PNI or CONUT was significantly associated with the severity of chronic liver disease (P < 0.001, respectively). In addition, the value of CONUT was significantly associated with all the anthropometric values such as body mass index (BMI, P < 0.05), mid‐arm circumference (AC, P < 0.001), mid‐arm muscle circumference (AMC, P < 0.001), and triceps skinfold thickness (TSF, P < 0.001), whereas the value of PNI was significantly associated with the values of AC (P < 0.01), AMC (P < 0.05) and TSF (P < 0.05). Approximately 80% of cirrhotic patients were assessed by PNI or CONUT to have obvious malnutrition.
Conclusion: PNI and CONUT are potential tools for nutritional assessment in patients with chronic liver disease, especially for ordinary medical care, because of their simplicity.
Motor vehicle accidents （MVAs） are serious social issues worldwide and driver illness is an important cause of MVAs. Minimal hepatic encephalopathy （MHE） is a com- plex cognitive dysfunction with ...attention deficit, which frequently occurs in cirrhotic patients independent of severity of liver disease. Although MHE is known as a risk factor for MVAs, the impact of diagnosis and treatment of MHE on MVA-related societal costs is largely unknown. Recently, Bajaj et al demonstrated valuable findings that the diagnosis of MHE by rapid screening using the inhibitory control test （ICT）, and subsequent treatment with lactulose could substantially reduce the societal costs by preventing MVAs. Besides the ICT and lactulose, there are various diagnostic tools and therapeutic strategies for MHE. In this commentary, we discussed a current issue of diagnostic tools for MHE, including neuropsychological tests. We also discussed the advantages of the other therapeutic strategies for MHE, such as intake of a regular breakfast and coffee, and supplementation with zinc and branched chain amino acids, on the MVA-related societal costs.
Aim: Cognitive dysfunction (CD) is frequently observed in cirrhotic patients. However, the biochemical profiles associated with CD remain unclear. We investigated the biochemical profiles associated ...with the incidence of CD in cirrhotic patients by using multivariate analyses, including a decision‐tree algorithm.
Methods: In this study, 27 viral cirrhotic patients were enrolled. All subjects underwent neuropsychiatric tests; two or more abnormal results were defined as CD. A logistic regression model was used for multivariate stepwise analysis. A decision‐tree algorithm was constructed, and the categorical differences based on the decision‐tree model were analyzed by χ2‐tests.
Results: Multivariate stepwise analysis showed the levels of total bilirubin, triglycerides and free fatty acids (FFA) as independent bioparameters associated with the incidence of CD in cirrhotic patients. The decision‐tree algorithm showed that among patients with FFA of 514 mEq/L or more, 77.8% had CD. Meanwhile, among patients with FFA of less than 514 mEq/L and triglycerides of 106 mg/dL or more, 20.0% had CD. The sensitivity, specificity and accuracy for the incidence of CD using the lipid profile (FFA >514 mEq/L or triglycerides <106 mg/dL) were 85.7% (12/14), 61.5% (8/13) and 74.1% (20/27), respectively.
Conclusion: The levels of total bilirubin, FFA and triglycerides are independently associated with the incidence of CD in cirrhotic patients. In addition, a decision‐tree algorithm revealed that FFA of more than 514 mEq/L or triglycerides of less than 106 mg/dL is a profile associated with the incidence of CD. Thus, this lipid profile could be a possible screening bioparameter for CD in cirrhotic patients.
Aim: Hepatitis C virus (HCV) core protein critically contributes to hepatocarcinogenesis, which is often observed in liver cirrhosis. Since the liver cirrhosis microenvironment is affected by ...hypoxia, we focused on the possible driving force of HCV core protein on signal relay from hypoxia‐inducible factor (HIF)‐1α to vascular endothelial growth factor (VEGF).
Methods: Human hepatocellular carcinoma cells stably overexpressing HCV core (Core cells) and NS5A (NS5A cells) were established; empty vector‐transfected (EV) cells were used as controls. Hypoxia was induced by oxygen deprivation or by using cobalt chloride (CoCl2). YC‐1 was used to inhibit HIF‐1α expression. Protein analyses for cultured cells and liver tissues obtained from CoCl2‐treated HCV core‐transgenic (Core‐Tg) mice were performed by western blot and/or immunocytochemistry. Cellular mRNA levels were evaluated by quantitative real‐time reverse transcription‐polymerase chain reaction.
Results: Under hypoxia, the sustained expression of HIF‐1α, but not HIF‐2α, was profoundly observed in Core cells but, was faint in EV and NS5A cells. Immunocytochemistry revealed increased HIF‐1α in the nucleus. HIF‐1α mRNA levels were significantly higher in Core cells than in EV cells under both normoxia and hypoxia. The HIF‐1α‐targeted VEGF and Bcl‐xL expressions were increased in Core cells under hypoxia and abolished by YC‐1 treatment. Hypoxic liver samples of Core‐Tg mice indicated significant increases in both HIF‐1α and VEGF expression compared with the wild type.
Conclusions: Hepatitis C virus core protein has the distinct potential to transcriptionally upregulate and sustain HIF‐1α expression under hypoxia, thereby contributing to increased VEGF expression, a key regulator in the hypoxic milieu of liver cirrhosis.
Background
Glucose intolerance in patients with liver cirrhosis (LC), known as hepatogenous diabetes, is thought to be distinct from type 2 diabetes (T2DM) in some aspects. Hyperinsulinemia and/or ...insulin resistance in liver disease is associated with hepatocarcinogenesis, growth of hepatocellular carcinoma, and poor prognosis. However, the pathophysiological processes in islets that are responsible for hyperinsulinemia in LC are still not precisely known. Therefore, we investigated the histopathological differences in islets of Langerhans cells between LC and T2DM.
Methods
A total of 35 human autopsy pancreatic tissue samples were used in this study (control,
n
= 18; T2DM,
n
= 6; LC,
n
= 11). The expression of insulin, glucagon, somatostatin, pancreatic duodenal homeobox-1 (PDX-1), proliferating cell nuclear antigen (PCNA), and Ki-67 was examined using immunohistochemistry and quantitated by image analysis.
Results
Islet hypertrophy and a significant increase in PCNA-positive cells in islets were observed in the tissues from LC cases. The insulin-positive areas in islets were significantly decreased in LC cases compared with control and T2DM cases (
P
= 0.001,
P
= 0.035, respectively), whereas the PDX-1-positive area was significantly increased in LC cases (
P
= 0.001) compared with the control. Furthermore, disorganization of pancreatic endocrine cells and nucleocytoplasmic translocation of PDX-1 were both seen in the LC subjects.
Conclusions
In LC, islets undergo hypertrophy and exhibit paradoxical expression of insulin and PDX-1. In the subjects autopsied, insulin expression was decreased, whereas expression of the pancreatic transcription factor PDX-1 was increased in LC. These results point to important distinctions between LC and T2DM.
The drug delivery system to tumors is a critical factor in upregulating the effect of anticancer drugs and reducing adverse events. Recent studies indicated selective migration of bone marrow‐derived ...endothelial progenitor cells (EPC) into tumor tissues. Cytosine deaminase (CD) transforms nontoxic 5‐fluorocytosine (5‐FC) into the highly toxic 5‐fluorouracil (5‐FU). We investigated the antitumor effect of a new CD/5‐FC system with CD cDNA transfected EPC for hepatocellular carcinoma (HCC) in mice. We used human hepatoma cell lines (HuH‐7, HLF, HAK1‐B, KYN‐2, KIM‐1) and a rat EPC cell line (TR‐BME‐2). Escherichia coli CD cDNA was transfected into TR‐BME‐2 (CD‐TR‐BME). The inhibitory effect of 5‐FU on the proliferation of hepatoma cell lines and the inhibitory effect of 5‐FU secreted by CD‐TR‐BME and 5‐FC on the proliferation of co‐cultured hepatoma cells were evaluated by a tetrazolium‐based assay. In mouse subcutaneous xenograft models of KYN‐2 and HuH‐7, CD‐TR‐BME was transplanted intravenously followed by 5‐FC injection intraperitoneally. HuH‐7 cells were the most sensitive to 5‐FU and KYN‐2 cells were the most resistant. CD‐TR‐BME secreted 5‐FU and inhibited HuH‐7 proliferation in a 5‐FC dose‐dependent manner. CD‐TR‐BME were recruited into the tumor tissues and some were incorporated into tumor vessels. Tumor growth of HuH‐7 was significantly suppressed during 5‐FC administration. No bodyweight loss, ALT abnormality or bone marrow suppression was observed. These findings suggest that our new CD/5‐FC system with CD cDNA transfected EPC could be an effective and safe treatment for suppression of 5‐FU‐sensitive HCC growth. (Cancer Sci 2012; 103: 542–548)
PDF
