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Noura S Abul-Husn, Xiping Cheng, Alexander H Li, Yurong Xin, Claudia Schurmann, Panayiotis Stevis, Yashu Liu, Julia Kozlitina, Stefan Stender, G Craig Wood, Ann N Stepanchick, Matthew D Still, Shane McCarthy, Colm O'Dushlaine, Jonathan S Packer, Suganthi Balasubramanian, Nehal Gosalia, David Esopi, Sun Y Kim, Semanti Mukherjee, Alexander E Lopez, Erin D Fuller, John Penn, Xin Chu, Jonathan Z Luo, Uyenlinh L Mirshahi, David J Carey, Christopher D Still, Michael D Feldman, Aeron Small, Scott M Damrauer, Daniel J Rader, Brian Zambrowicz, William Olson, Andrew J Murphy, Ingrid B Borecki, Alan R Shuldiner, Jeffrey G Reid, John D Overton, George D Yancopoulos, Helen H Hobbs, Jonathan C Cohen, Omri Gottesman, Tanya M Teslovich, Aris Baras, Tooraj Mirshahi, Jesper Gromada, Frederick E Dewey
BACKGROUND: Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS: We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples...
March 22, 2018: New England Journal of Medicine
Jayanta Paul, Raj Vigna Venugopal, Lorance Peter, Kula Naresh Kumar Shetty, Mohit P Shetti
BACKGROUND: Liver biopsy is a gold standard method for hepatic steatosis assessment. However, liver biopsy is an invasive and painful procedure and can cause severe complications therefore it cannot be frequently used in case of follow-up of patients. Non-invasive assessment of steatosis and fibrosis is of growing relevance in non-alcoholic fatty liver disease (NAFLD). To evaluate hepatic steatosis, transient elastography with controlled attenuation parameter (CAP) measurement is an option now days...
January 2018: Arquivos de Gastroenterologia
Shuying He, Weihong Guo, Feihong Deng, Kequan Chen, Yonghong Jiang, Minyu Dong, Liang Peng, Xueqing Chen
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and precision therapeutic will be a benefit for the NAFLD regression. In this study, we observed low microRNA 146 b (miR-146 b) expression in NAFLD mice model induced by methionine-choline-deficient diet (MCD) compared with control group. Furthermore, miR-146b-/- mice induced MCD exhibited severe liver steatosis and hepatitis. A bio-distribution study showed that novel Lactosylated PDMAEMA nanoparticles effectively targeted hepatocytes Lac-PDMAEMA...
March 21, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Kazushige Nirei, Tatsuo Kanda, Hitomi Nakamura, Shunichi Matsuoka, Tadatoshi Takayama, Masahiko Sugitani, Mitsuhiko Moriyama
Objective: Hepatitis C virus (HCV) infection has long been treated with interferon therapy (IFN). Currently, more than 90% of IFN-treated patients show a sustained virological response (SVR) when also treated with ribavirin and/or a protease inhibitor. Histological inflammation and fibrosis improve in IFN-treated patients, which indicates HCV clearance. IFN also reduces the incidence of hepatocellular carcinoma (HCC). However, a small proportion of patients with SVR develop HCC. To investigate the causes of hepatic carcinogenesis after SVR, we compared the liver histological findings before IFN to those after the development of HCC...
2018: International Journal of Medical Sciences
Dina A Schneider, Soo-Ho Choi, Colin Agatisa-Boyle, Laurence Zhu, Jungsu Kim, Jennifer Pattison, Dorothy D Sears, Philip L S M Gordts, Longhou Fang, Yury I Miller
Apolipoprotein A-I Binding Protein (AIBP) has been shown to augment cholesterol efflux from endothelial cells and macrophages. In zebrafish and mice, AIBP-mediated regulation of cholesterol levels in the plasma membrane of endothelial cells controls angiogenesis. The goal of this work was to evaluate metabolic changes and atherosclerosis in AIBP loss-of-function and gain-of-function animal studies. Here we show that Apoa1bp-/-Ldlr-/- mice fed a high-cholesterol, high-fat diet had exacerbated weight gain, liver steatosis, glucose intolerance, hypercholesterolemia and hypertriglyceridemia, and larger atherosclerotic lesions compared to Ldlr-/- mice...
March 20, 2018: Journal of Lipid Research
Jelena Krstic, Markus Galhuber, Tim J Schulz, Michael Schupp, Andreas Prokesch
Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the prevalence of liver pathologies is steadily increasing in modern societies, there are currently no approved drugs other than chemotherapeutic intervention in late stage HCC. Hence, there is a pressing need to identify and investigate causative molecular pathways that can yield new therapeutic avenues...
March 20, 2018: International Journal of Molecular Sciences
Mariana Verdelho Machado, Anna Mae Diehl
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer...
March 20, 2018: Critical Reviews in Biochemistry and Molecular Biology
Hui Cao, Senlin Li, Rui Xie, Na Xu, Ying Qian, Hongdan Chen, Qinyu Hu, Yihong Quan, Zhihong Yu, Junjun Liu, Ming Xiang
Dangguiliuhuang decoction (DGLHD) has been demonstrated to be effective in treating inflammatory, hepatic steatosis, and insulin resistance. In the study, we tried to elucidate the pharmacological efficacy and mechanism of DGLHD against liver fibrosis and predicate potential active ingredients and targets via network analysis and experimental validation. In the formula, we totally discovered 76 potential active ingredients like baicalein, berberine, and wogonin, and 286 corresponding targets including PTGS (prostaglandin-endoperoxide synthase) 2, PPAR (peroxisome proliferator-activated receptors) -γ, and NF-κB (nuclear factor-κB)...
2018: Frontiers in Pharmacology
Naiqian Zhao, Xiaoyan Li, Ying Feng, Jinxiang Han, Ziling Feng, Xifeng Li, Yanfang Wen
Excessive triglyceride accumulation in hepatocytes is the hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). Elevated levels of the saturated free fatty acid palmitate in obesity are a major contributor to excessive hepatic lipid accumulation. The nuclear orphan receptor Nur77 is a transcriptional regulator and a lipotoxicity sensor. Using human HepG2 hepatoma cells, this study aimed to investigate the functional role of Nur77 in palmitate-induced hepatic steatosis. The results revealed that palmitate significantly induced lipid accumulation and suppressed lipolysis in hepatocytes...
March 19, 2018: Scientific Reports
Liping Luo, Wanxiang Jiang, Hui Liu, Jicheng Bu, Ping Tang, Chongyangzi Du, Zhipeng Xu, Hairong Luo, Bilian Liu, Bo Xiao, Zhiguang Zhou, Feng Liu
The growth receptor binding protein Grb10 is an imprinted gene product and a key negative regulator of the insulin, IGF1 and mTORC1 signaling pathways. Grb10 is highly expressed in mouse fetal liver but almost completely silenced in adult mice, suggesting a potential detrimental role of this protein in adult liver function. Here we show that the grb10 gene could be reactivated in adult mouse liver by acute endoplasmic reticulum stress (ER stress) such as tunicamycin or a short-term high fat diet (HFD) challenge, concurrently with increased unfolded protein response (UPR) and hepatosteatosis...
March 19, 2018: Journal of Molecular Endocrinology
Ming Zhang, Xiaoming Chi, Na Qu, CongYing Wang
Non-alcoholic fatty liver disease and steatohepatitis (NAFLD and NASH) account for the majority of liver disease in industrialized countries. However, the pathogenesis still unclear. Long non-coding RNAs (lncRNAs) has been reported to be involved in various pathophysiological processes. Here, we reported a novel role of lncARSR in hepatic lipogenesis in NAFLD. The expression of lncARSR was induced both in NAFLD patients and mouse model, as well as in hepatocytes treated with fatty acid. Moreover, overexpression of lncARSR enhanced while knockdown of lncARSR ameliorated hepatic lipid accumulation in vivo and in vitro...
March 16, 2018: Biochemical and Biophysical Research Communications
Ritu S Sharma, David J Harrison, Dorothy Kisielewski, Diane M Cassidy, Alison D McNeilly, Jennifer R Gallagher, Shaun V Walsh, Tadashi Honda, Rory J McCrimmon, Albena T Dinkova-Kostova, Michael L J Ashford, John F Dillon, John D Hayes
Background & Aims: Nonalcoholic steatohepatitis (NASH) is associated with oxidative stress. We surmised that pharmacologic activation of NF-E2 p45-related factor 2 (Nrf2) using the acetylenic tricyclic bis(cyano enone) TBE-31 would suppress NASH because Nrf2 is a transcriptional master regulator of intracellular redox homeostasis. Methods: Nrf2 +/+ and Nrf2 -/- C57BL/6 mice were fed a high-fat plus fructose (HFFr) or regular chow diet for 16 weeks or 30 weeks, and then treated for the final 6 weeks, while still being fed the same HFFr or regular chow diets, with either TBE-31 or dimethyl sulfoxide vehicle control...
March 2018: Cellular and Molecular Gastroenterology and Hepatology
Hyo Young Lee, Dae Won Jun, Hyun Jung Kim, Hyunwoo Oh, Waqar Khalid Saeed, Hyeongsik Ahn, Ramsey C Cheung, Mindie H Nguyen
Background/Aims: A number of clinical trials reported varying effects of cholesterol lowering agents in nonalcoholic fatty liver disease (NAFLD) patients. We, therefore, assessed the changes in hepatic steatosis and NAFLD activity score (NAS) after treatment with cholesterol lowering agents in NAFLD patients by metaanalysis. Methods: The Cochrane Library, the MEDLINE, and the Embase databases were searched until May 2015, without any language restrictions, for randomized controlled trials (RCTs) and nonrandomized studies (NRSs)...
March 20, 2018: Korean Journal of Internal Medicine
Jian Bi, Kang Sun, Hao Wu, Xiuli Chen, Haiying Tang, Jingwei Mao
Peroxisome proliferator-activated receptor gamma (PPARγ) participates in the process of insulin resistance (IR), a crucial pathophysiology in non-alcoholic fatty liver disease (NAFLD). Meanwhile, suppressor of cytokine signaling3 (SOCS3) also regulates IR in NAFLD. Both PPARγ and SOCS3 play a role in NAFLD through regulating IR, while it is unclear whether these two proteins interact to regulate hepatic steatosis. PPARγ, SOCS3 and its associated JAK2/STAT3 pathway were analyzed using Kuppfer cells (KCs) treatment with LPS and BRL-3A cells treatment with palmitic acid, KC-conditioned medium (KCCM), PPARγ agonist rosiglitazone (ROZ) or JAK2 inhibitor AG490 to demonstrate the role of PPARγ and SOCS3 in hepatocytes steatosis...
March 14, 2018: Biochemical and Biophysical Research Communications
Audrey M Neyrinck, Sophie Hiel, Caroline Bouzin, Vicenta Garcia Campayo, Patrice D Cani, Laure B Bindels, Nathalie M Delzenne
BACKGROUND: Non-digestible carbohydrates present in cereals such as fructans and arabinoxylans represent promising prebiotic nutrients to prevent the development of obesity and related metabolic disorders. OBJECTIVE AND DESIGN:  The aim of this study was to determine the corrective effects of wheat bran-derived arabinoxylan oligosaccharides in obese mice fed a western diet (WD). WD was given for 4 weeks before wheat bran extract (WBE) supplementation (5%) for an additional 4 weeks, whereas a control group received the standard diet...
March 7, 2018: Nutrition & Diabetes
Ayesha Fawad, Andreas Bergmann, Joachim Struck, Peter M Nilsson, Marju Orho-Melander, Olle Melander
Context: The gut hormone neurotensin promotes fat absorption, diet-induced weight gain and liver steatosis. Its stable precursor-hormone fragment "proneurotensin" predicts cardiometabolic disease in middle-aged populations, especially in women. Objective: To test if proneurotensin predicts cardiovascular disease (CVD) and diabetes development in an elderly population and whether there are gender differences in this respect. Design, Setting and Participants: Fasting proneurotensin was measured in plasma from 4804 participants (mean age 69±6 years) of the Malmö Preventive Project (MPP) and subjects were followed up for development of CVD and diabetes during 5...
March 13, 2018: Journal of Clinical Endocrinology and Metabolism
Shi Cheng, Yan Yang, Yong Zhou, Wei Xiang, Hua Yao, Ling Ma
The development of nonalcoholic fatty liver disease (NAFLD) is caused by the steatosis of hepatocytes, which induces oxidative stress (OS). Thus, OS has an important role in the development of NAFLD. In the present study, the L-02 hepatocyte cell line was used to develop a steatosis cell model. The best model was determined using an MTT assay and the triglyceride levels. Model cells were treated with high concentrations of uric acid (UA; 0, 5, 10, 20 and 30 mg/dl) for 24, 48, 72 and 96 h. Indicators of oxidation were then measured, which included total superoxide dismutase (SOD), malonaldehyde (MDA) and reduced glutathione (GSH), and the transcriptional and translational levels of SOD1 and γ-glutamate-cysteine ligase (γ-GCLC) were also determined...
April 2018: Experimental and Therapeutic Medicine
Jun-Ho Cho, Goo-Young Kim, Brian C Mansfield, Janice Y Chou
Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), a key enzyme in endogenous glucose production. This autosomal recessive disorder is characterized by impaired glucose homeostasis and long-term complications of hepatocellular adenoma/carcinoma (HCA/HCC). We have shown that hepatic G6Pase-α deficiency-mediated steatosis leads to defective autophagy that is frequently associated with carcinogenesis. We now show that hepatic G6Pase-α deficiency also leads to enhancement of hepatic glycolysis and hexose monophosphate shunt (HMS) that can contribute to hepatocarcinogenesis...
March 12, 2018: Biochemical and Biophysical Research Communications
Charles Cai, Taimur Ahmad, Gloria B Valencia, Jacob V Aranda, Jiliu Xu, Kay D Beharry
OBJECTIVES: Extremely low gestational age neonates with chronic lung disease requiring oxygen therapy frequently experience fluctuations in arterial oxygen saturation or intermittent hypoxia (IH). These infants are at risk for multi-organ developmental delay, reduced growth, and short stature. The growth hormone (GH)/insulin-like growth factor-I (IGF-1) system, an important hormonal regulator of lipid and carbohydrate metabolism, promotes neonatal growth and development. We tested the hypothesis that increasing episodes of IH delay neonatal growth by influencing the GH/IGF-I axis...
March 8, 2018: Growth Hormone & IGF Research
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
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