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Non-alcoholic steatohepatitis

Dongxia Fu, Haibin Cui, Yunna Zhang
BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. This study aims to investigate whether chloride channel 2 (ClC-2) is involved in high fat diet (HFD)-induced NAFLD and possible molecular mechanisms. METHODS: ClC-2 expression was liver-specifically downregulated using adeno-associated virus in C57BL/6 mice treated with a chow diet or HFD for 12 weeks. Peripheral blood and liver tissues were collected for biochemical and pathological estimation respectively...
March 10, 2018: Cellular Physiology and Biochemistry
Melissa Palmer, Lee Jennings, Debra G Silberg, Caleb Bliss, Patrick Martin
BACKGROUND: Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat...
March 16, 2018: BMC Pharmacology & Toxicology
Eleonora Scorletti, Christopher D Byrne
For many years it has been known that high doses of long chain omega-3 fatty acids are beneficial in the treatment of hypertriglyceridaemia. Over the last three decades, there has also been a wealth of in vitro and in vivo data that has accumulated to suggest that long chain omega-3 fatty acid treatment might be beneficial to decrease liver triacylglycerol. Several biological mechanisms have been identified that support this hypothesis; notably, it has been shown that long chain omega-3 fatty acids have a beneficial effect: a) on bioactive metabolites involved in inflammatory pathways, and b) on alteration of nuclear transcription factor activities such as peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP), involved in inflammatory pathways and liver lipid metabolism...
March 12, 2018: Molecular Aspects of Medicine
Milla-Maria Tauriainen, Ville Männistö, Dorota Kaminska, Maija Vaittinen, Vesa Kärjä, Pirjo Käkelä, Sari Venesmaa, Helena Gylling, Jussi Pihlajamäki
Background & aims : Non-alcoholic fatty liver disease (NAFLD) associates with low levels of serum plant sterols in cross-sectional studies. However, parenterally given plant sterols may lead to liver injury. In addition, it has been suggested that the hepatic sterol transport mechanisms are altered in NAFLD. Therefore, we investigated the association between serum, liver and bile plant sterols and sitostanol with NAFLD. Methods : Out of the 138 individuals (age: 46.3±8.9, BMI: 43.3±6.9 kg/m², 28% men and 72% women), 44 could be histologically categorized to have normal liver, and 94 to have NAFLD...
March 14, 2018: Bioscience Reports
Chen Qu, Dandan Zheng, Sai Li, Yingjun Liu, Anna Lidofsky, Jacinta A Holmes, Jianning Chen, Lu He, Lan Wei, Yadi Liao, Hui Yuan, Qimeng Jin, Zelong Lin, Qiaoting Hu, Yuchuan Jiang, Mengxian Tu, Xijun Chen, Weiming Li, Wenyu Lin, Bryan C Fuchs, Raymond T Chung, Jian Hong
Spleen tyrosine kinase (SYK) plays a critical role in immune cell signaling pathways and has been reported as a novel biomarker for human hepatocellular carcinoma (HCC). We sought to investigate the mechanism by which SYK promotes liver fibrosis and to evaluate SYK as a therapeutic target for liver fibrosis. We evaluated the cellular localization of SYK and the association between SYK expression and liver fibrogenesis in normal, HBV-infected, HCV-infected and non-alcoholic steatohepatitis (NASH) liver tissue (n=36, 127, 22 and 30, respectively)...
March 14, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Prahlad K Rao, Kate Merath, Eugene Drigalenko, Avinash Y L Jadhav, Richard A Komorowski, Matthew I Goldblatt, Anand Rohatgi, Mark A Sarzynski, Samer Gawrieh, Michael Olivier
Background: Metabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function. Recent studies suggested that patients with non-alcoholic fatty liver disease (NAFLD), including individuals with non-alcoholic steatohepatitis (NASH), have smaller HDL particles when compared to individuals without liver pathologies. However, no studies have investigated potential changes in HDL particle protein composition in patients with NAFLD, in addition to changes related to obesity, to explore putative functional changes of HDL which may increase the risk of cardiovascular complications...
2018: Clinical Proteomics
Karen Louise Thomsen, Francesco De Chiara, Krista Rombouts, Hendrik Vilstrup, Fausto Andreola, Rajeshwar P Mookerjee, Rajiv Jalan
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases ranging from steatosis, through non-alcoholic steatohepatitis (NASH) to cirrhosis. The development of fibrosis is the most important factor contributing to NASH-associated morbidity and mortality. Hepatic stellate cells (HSCs) are responsible for extracellular matrix deposition in conditions of frank hepatocellular injury and are key cells involved in the development of fibrosis. In experimental models and patients with NASH, urea cycle enzyme gene and protein expression is reduced resulting in functional reduction in the in vivo capacity for ureagenesis and subsequent hyperammonemia at a pre-cirrhotic stage...
April 2018: Medical Hypotheses
Claus Uhrenholt Christensen, Emilie Glavind, Karen Louise Thomsen, Yong Ook Kim, Sara Heebøll, Detlef Schuppan, Stephen Hamilton-Dutoit, Christian Würtz Heegaard, Henning Grønbæk
BACKGROUND AND AIMS: Hepatic cholesterol deposition drives inflammation and fibrosis in non-alcoholic steatohepatitis (NASH). The Niemann-Pick type C2 (NPC2) protein plays an important role in regulating intracellular cholesterol trafficking and homeostasis. We hypothesized that intravenous NPC2 supplementation reduces cholesterol accumulation, hepatic inflammation and fibrogenesis in a nutritional NASH rat model. METHODS: Rats were fed a high-fat, high-cholesterol (HFHC) diet for four weeks resulting in moderately severe NASH...
2018: PloS One
Stephen A Harrison, Mary E Rinella, Manal F Abdelmalek, James F Trotter, Angelo H Paredes, Hays L Arnold, Marcelo Kugelmas, Mustafa R Bashir, Mark J Jaros, Lei Ling, Stephen J Rossi, Alex M DePaoli, Rohit Loomba
BACKGROUND: Non-alcoholic steatohepatitis is a chronic liver disease characterised by the presence of hepatic steatosis, inflammation, and hepatocellular injury, for which no Food and Drug Administration (FDA)-approved treatment exists. FGF19 is a hormone that regulates bile acid synthesis and glucose homoeostasis. We aimed to assess the safety and efficacy of NGM282, an engineered FGF19 analogue, for the treatment of non-alcoholic steatohepatitis. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 study, we recruited patients aged 18-75 years with biopsy-confirmed non-alcoholic steatohepatitis as defined by the non-alcoholic steatohepatitis clinical research network histological scoring system, from hospitals and gastroenterology and liver clinics in Australia and the USA...
March 5, 2018: Lancet
Myong-Min Lee, Hyeong-Geug Kim, Sung-Bae Lee, Jin-Seok Lee, Won-Yong Kim, Seung-Hoon Choi, Sam-Keun Lee, Chang-Kyu Byun, Pung-Mi Hyun, Chang-Gue Son
BACKGROUND: The prevalence of Non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH) has increased by 15-39% worldwide, but no pharmaceutical therapeutics exists. HYPOTHESIS/PURPOSE: This study investigated anti-hepatosteatotic effect of CGplus (a standardized herbal composition of Artemisia iwayomogi, Amomum xanthioides, and Salvia miltiorrhiza) and its underlying mechanisms in a tunicamycin-induced NASH model. METHODS: C57/BL6J male mice were orally administrated CGplus (50, 100, or 200 mg/kg), dimethyl dimethoxy biphenyl dicarboxylate (DDB, 50 mg/kg) or distilled water daily for 5 days...
March 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
J W M Greve, N D Bouvy
The EndoBarrier (duodenal-jejunal bypass liner) became available in 2009 as an endoscopic treatment method for obesity and type 2 diabetes mellitus (T2D). The treatment results in significant weight loss and improvement of the obesity-related morbidities such as T2D, non-alcoholic steatohepatitis, hypertension and other cardiovascular diseases. However, unexpected complications such as liver abscesses can occur, in addition to expected adverse events such as bleeding, obstruction, and migration. The incidence of these complications is low however, and to date no treatment-related mortality has occurred with the use of EndoBarrier...
2018: Nederlands Tijdschrift Voor Geneeskunde
Shoji Yamada, Yoko Takashina, Mitsuhiro Watanabe, Ryogo Nagamine, Yoshimasa Saito, Nobuhiko Kamada, Hidetsugu Saito
Gut microbiota plays a significant role in the development of hepatocellular carcinoma (HCC) in non-alcoholic steatohepatitis (NASH). However, understanding of the precise mechanism of this process remains incomplete. A new class steatohepatitis-inducing high-fat diet (HFD), namely STHD-01, can promote the development of HCC without the administration of chemical carcinogens. Using this diet, we comprehensively analyzed changes in the gut microbiota and its metabolic functions during the development of HCC in NASH...
February 9, 2018: Oncotarget
Shinji Takai, Denan Jin
Non-alcoholic steatohepatitis (NASH) is characterized by inflammation and fibrosis, in addition to steatosis, of the liver, but no therapeutic agents have yet been established. The mast cell protease chymase can generate angiotensin II, matrix metalloproteinase-9 and transforming growth factor-β, all of which are associated with liver inflammation or fibrosis. In animal models of NASH, augmented chymase has been observed in the liver. In histological analysis, chymase inhibitor prevented hepatic steatosis, inflammation, and fibrosis...
2018: Frontiers in Pharmacology
Kyosuke Yamanishi, Keiichiro Mukai, Takuya Hashimoto, Kaoru Ikubo, Keiji Nakasho, Yosif El-Darawish, Wen Li, Daisuke Okuzaki, Yuko Watanabe, Tetsu Hayakawa, Hiroshi Nojima, Hiromichi Yamanishi, Haruki Okamura, Hisato Matsunaga
BACKGROUND: The cytokine interleukin-18 was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence to suggest that it has non-immunological effects on physiological functions. We previously investigated the potential pathophysiological relationship between interleukin-18 and dyslipidemia, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis, and suggested interleukin-18 as a possible novel treatment for not only these diseases but also for cancer immunotherapy...
March 7, 2018: Journal of Translational Medicine
Jonathan G Stine, Blake A Niccum, Alex N Zimmet, Nicolas Intagliata, Stephen H Caldwell, Curtis K Argo, Patrick G Northup
OBJECTIVE: Patients with cirrhosis are at increased risk for venous thromboembolism (VTE) and portal vein thrombosis (PVT). Cirrhosis due to non-alcoholic steatohepatitis (NASH) appears to be particularly prothrombotic. We investigated hospitalized patients with NASH cirrhosis to determine if they are at increased risk for VTE. METHODS: Data on adult hospitalized patients with cirrhosis and VTE (deep vein thrombosis and/or pulmonary embolism) between November 1, 2010 and December 31, 2015 were obtained...
March 6, 2018: Clinical and Translational Gastroenterology
Hui Liang, Yutong Wang
Abnormal lipid metabolism may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). The ATP-binding cassette transporter A1 (ABCA1) protein mediates the transport of cholesterol and phospholipids from cells to apolipoprotein A-I (apoA-I) to generate nascent HDL particles. Previous studies revealed that the overexpression of ABCA1 alleviated hepatic lipid levels by modifying lipid transport. Here, we examined the effect of berberine (BBR) on ABCA1 in QSG-7701 hepatocytes and in mice. BBR decreased hepatic cholesterol and triglyceride levels...
March 2, 2018: Biochemical and Biophysical Research Communications
Shuhei Naka, Kaoruko Wato, Rina Hatakeyama, Rena Okawa, Ryota Nomura, Kazuhiko Nakano
Background : We previously reported that intravenous administration of Streptococcus mutans strain TW871 caused typical non-alcoholic steatohepatitis (NASH)-like findings in a high-fat diet (HFD) mouse model at 16 weeks after initiating the experiment. Objective : The purpose of the present study was to analyse mice administered S. mutans TW871 fed a HFD for various periods of time. Methods : First, 6-week-old C57BL/6J mice were fed an HFD for 4 weeks, then TW871 (1 × 107 CFU) or phosphate-buffered saline (PBS) were intravenously administered...
2018: Journal of Oral Microbiology
Sarah Faasse, Hayley Braun, Miriam Vos
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world, yet the complex pathogenesis remains to be fully elucidated. The prevalence of NAFLD has risen precipitously in recent years and is now a leading indication for liver transplantation. New waitlist registrants with non-alcoholic steatohepatitis-induced cirrhosis increased by 170% from 2004 to 2013. In addition, patients with NAFLD are at increased risk of both cardiovascular disease and type II diabetes...
2018: F1000Research
Jane I Grove, Prarthana Thiagarajan, Stuart Astbury, Rebecca Harris, Toby Delahooke, I Neil Guha, Guruprasad P Aithal
BACKGROUND & AIMS: Chronic liver disease presents a major global public health challenge. Stratification of asymptomatic, at-risk patients in primary care using non-invasive methods has the potential to address this by identifying those likely to progress. We therefore evaluated variant alleles at loci associated with non-alcoholic fatty liver disease (NAFLD) as genetic determinants of substantial liver injury in patients with disease risk factors. METHODS: Levels of serum procollagen III (PIIINP), an established fibrosis and steatohepatitis marker, were determined in 467 people who had type 2 diabetes and/or BMI>27...
March 1, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
Momoko Akashi, Kazuto Tajiri, Akinori Wada, Koichi Tsuneyama, Kengo Kawai, Satoshi Yasumura, Masami Minemura, Terumi Takahara, Toshiro Sugiyama
A 68-year-old woman with liver dysfunction was diagnosed with nonalcoholic steatohepatitis (NASH) stage 1. Three years later, she showed massive ascites and jaundice. A trans-jugular liver biopsy confirmed advanced cirrhosis, suggesting that her liver fibrosis had progressed rapidly. At the same time, she was diagnosed with multiple myeloma (MM). In this case, the plasma levels of osteopontin (OPN), a proinflammatory cytokine that promotes liver fibrosis progression through the hedgehog pathway and is increased in patients with MM, were increased...
February 28, 2018: Internal Medicine
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