Hepatology : official journal of the American Association for the Study of Liver Diseases
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Adaptive responses to sepsis are necessary to prevent organ failure and death. Cellular signaling responses that limit cell death and structural damage allow a cell to withstand insult from sepsis to prevent irreversible organ dysfunction. One such protective pathway to reduce hepatocellular injury is the up-regulation of heme oxygenase-1 (HO-1) signaling. HO-1 is up-regulated in the liver in response to multiple stressors, including sepsis and lipopolysaccharide (LPS), and has been shown to limit cell death. Another recently recognized rudimentary cellular response to injury is autophagy. The aim of these investigations was to test the hypothesis that HO-1 protects against hepatocyte cell death in experimental sepsis in vivo or LPS in vitro via induction of autophagy. These data demonstrate that both HO-1 and autophagy are up-regulated in the liver after cecal ligation and puncture (CLP) in C57BL/6 mice or in primary mouse hepatocytes after treatment with LPS (100 ng/mL). CLP or LPS results in minimal hepatocyte cell death. Pharmacological inhibition of HO-1 activity using tin protoporphyrin or knockdown of HO-1 prevents the induction of autophagic signaling in these models and results in increased hepatocellular injury, apoptosis, and death. Furthermore, inhibition of autophagy using 3-methyladenine or small interfering RNA specific to VPS34, a class III phosphoinositide 3-kinase that is an upstream regulator of autophagy, resulted in hepatocyte apoptosis in vivo or in vitro. LPS induced phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), in part, via HO-dependent signaling. Moreover, inhibition of p38 MAPK prevented CLP- or LPS-induced autophagy. ⋯ Sepsis or LPS-induced autophagy protects against hepatocellular death, in part via an HO-1 p38 MAPK-dependent signaling. Further investigations are needed to elucidate how autophagic signaling prevents apoptosis and cell death.
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Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a multicomponent enzyme that mediates electron transfer from nicotinamide adenine dinucleotide phosphate to molecular oxygen, which leads to the production of superoxide. NOX2/gp91(phox) is a catalytic subunit of NOX expressed in phagocytic cells. Several homologues of NOX2, including NOX1, have been identified in nonphagocytic cells. We investigated the contributory role of NOX1 and NOX2 in hepatic fibrosis. Hepatic fibrosis was induced in wild-type (WT) mice, NOX1 knockout (NOX1KO) mice, and NOX2 knockout (NOX2KO) mice by way of either carbon tetrachloride (CCl(4) ) injection or bile duct ligation (BDL). The functional contribution of NOX1 and NOX2 in endogenous liver cells, including hepatic stellate cells (HSCs), and bone marrow (BM)-derived cells, including Kupffer cells (KCs), to hepatic reactive oxygen species (ROS) generation and hepatic fibrosis was assessed in vitro and in vivo using NOX1 or NOX2 BM chimeric mice. Hepatic NOX1 and NOX2 messenger RNA expression was increased in the two experimental mouse models of hepatic fibrosis. Whereas NOX1 was expressed in HSCs but not in KCs, NOX2 was expressed in both HSCs and KCs. Hepatic fibrosis and ROS generation were attenuated in both NOX1KO and NOX2KO mice after CCl(4) or BDL. Liver fibrosis in chimeric mice indicated that NOX1 mediates the profibrogenic effects in endogenous liver cells, whereas NOX2 mediates the profibrogenic effects in both endogenous liver cells and BM-derived cells. Multiple NOX1 and NOX2 components were up-regulated in activated HSCs. Both NOX1- and NOX2-deficient HSCs had decreased ROS generation and failed to up-regulate collagen α1(I) and transforming growth factor β in response to angiotensin II. ⋯ Both NOX1 and NOX2 have an important role in hepatic fibrosis in endogenous liver cells, including HSCs, whereas NOX2 has a lesser role in BM-derived cells.
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Randomized Controlled Trial Comparative Study
Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects.
Obesity-related hepatic steatosis is a major risk factor for metabolic and cardiovascular disease. Fat reduced hypocaloric diets are able to relieve the liver from ectopically stored lipids. We hypothesized that the widely used low carbohydrate hypocaloric diets are similarly effective in this regard. A total of 170 overweight and obese, otherwise healthy subjects were randomized to either reduced carbohydrate (n = 84) or reduced fat (n = 86), total energy restricted diet (-30% of energy intake before diet) for 6 months. Body composition was estimated by bioimpedance analyses and abdominal fat distribution by magnetic resonance tomography. Subjects were also submitted to fat spectroscopy of liver and oral glucose tolerance testing. In all, 102 subjects completed the diet intervention with measurements of intrahepatic lipid content. Both hypocaloric diets decreased body weight, total body fat, visceral fat, and intrahepatic lipid content. Subjects with high baseline intrahepatic lipids (>5.56%) lost ≈7-fold more intrahepatic lipids compared with those with low baseline values (<5.56%) irrespective of diet composition. In contrast, changes in visceral fat mass and insulin sensitivity were similar between subgroups, with low and high baseline intrahepatic lipids. ⋯ A prolonged hypocaloric diet low in carbohydrates and high in fat has the same beneficial effects on intrahepatic lipid accumulation as the traditional low-fat hypocaloric diet. The decrease in intrahepatic lipids appears to be independent of visceral fat loss and is not tightly coupled with changes in whole body insulin sensitivity during 6 months of an energy restricted diet.
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In cohort studies of atomic bomb survivors and Mayak nuclear facility workers, radiation-associated increases in liver cancer risk were observed, but hepatitis B virus (HBV) and hepatitis C virus (HCV) infections were not taken strictly into account. We identified 359 hepatocellular carcinoma (HCC) cases between 1970 and 2002 in the cohort of atomic bomb survivors and estimated cumulative incidence of HCC by radiation dose. To investigate contributions of radiation exposure and hepatitis virus infection to HCC risk, we conducted a nested case-control study using sera stored before HCC diagnosis in the longitudinal cohort of atomic bomb survivors. The study included 224 HCC cases and 644 controls that were matched to the cases on gender, age, city, and time and method of serum storage, and countermatched on radiation dose. The cumulative incidence of HCC by follow-up time and age increased significantly with radiation dose. The relative risk (RR) of HCC for radiation at 1 Gy was 1.67 (95% confidence interval: 1.22-2.35) with adjustment for alcohol consumption, body mass index (BMI), and smoking habit, whereas the RRs for HBV or HCV infection alone were 63 (20-241) and 83 (36-231) with such adjustment, respectively. Those estimates changed little when radiation and hepatitis virus infection were fit simultaneously. The RR of non-B, non-C HCC at 1 Gy was 1.90 (1.02-3.92) without adjustment for alcohol consumption, BMI, or smoking habit and 2.74 (1.26-7.04) with such adjustment. ⋯ These results indicate that radiation exposure and HBV and HCV infection are associated independently with increased HCC risk. In particular, radiation exposure was a significant risk factor for non-B, non-C HCC with no apparent confounding by alcohol consumption, BMI, or smoking habit.
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In Taiwan, a screening system using an infant stool color card to promote the early diagnosis of biliary atresia (BA) was established in 2002. This study aimed to investigate the 5-year outcome of BA before and after using the screening program. BA patients were divided into three cohorts according to their birth dates. The patients in cohort A (n = 89) were born before the stool card screening program (1990-2000); those in cohort B (n = 28) were screened by the stool card regional screening program (2002-2003); and those in cohort C (n = 74) were screened by the stool card universal screening program (2004-2005). The relative odds ratios were computed using logistic regression to compare the different factors affecting survival time. The rate of age at Kasai operation <60 days was 49.4% and 65.7% in cohorts A and B+C, respectively (P = 0.02). The jaundice-free (total serum bilirubin <2.0 mg/dL) rate 3 months after surgery was 34.8% and 60.8% in cohorts A and B+C, respectively (P < 0.001). The 3-year jaundice-free survival rate with native liver was 31.5% in cohort A and 56.9% in cohort B+C (P < 0.001), whereas the 3-year overall survival rates were 64.0% and 89.2%, respectively (P < 0.001). The 5-year jaundice-free survival rate with native liver was 27.3% in cohort A and 64.3% in cohort B (P < 0.001), and the 5-year overall survival rates were 55.7% and 89.3%, respectively (P < 0.001). ⋯ The stool color card screening program for BA allows for earlier Kasai operation, which increases the jaundice-free rate at 3 months postsurgery. With higher surgical success rates, the 3- and 5-year outcome of BA patients in Taiwan improves remarkably.