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steatohepatitis

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https://www.readbyqxmd.com/read/29457838/bax-inhibitor-1-protects-from-non-alcoholic-steatohepatitis-by-limiting-ire1%C3%AE-signaling
#1
Cynthia Lebeaupin, Déborah Vallée, Déborah Rousseau, Stéphanie Patouraux, Stéphanie Bonnafous, Gilbert Adam, Frederic Luciano, Carmelo Luci, Rodolphe Anty, Antonio Iannelli, Sandrine Marchetti, Guido Kroemer, Sandra Lacas-Gervais, Albert Tran, Philippe Gual, Béatrice Bailly-Maitre
Endoplasmic reticulum (ER) stress is activated in non-alcoholic fatty liver disease (NAFLD), raising the possibility that ER stress-dependent metabolic dysfunction, inflammation and cell death underlie the transition from steatosis to steatohepatitis (NASH). Bax inhibitor-1 (BI-1), a negative regulator of the ER stress sensor IRE1α, has yet to be explored in NAFLD as a hepatoprotective agent. We hypothesized that the genetic ablation of BI-1 would render the liver vulnerable to NASH due to unrestrained IRE1α signaling...
February 19, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29454967/sarm1-deletion-restrains-nafld-induced-by-high-fat-diet-hfd-through-reducing-inflammation-oxidative-stress-and-lipid-accumulation
#2
Zhen-Guo Pan, Xu-Sheng An
SARM1 (Sterile alpha and armadillo motif-containing protein 1) is the recently identified TIR domain-containing cytosolic protein, which is involved in toll-like receptors (TLRs) signaling transduction. In the present study, the role of SARM1 in high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) progression was explored. We found that SARM1 was expressed highly in fatty liver. And SARM1-knockout (KO) reduced steatohepatitis and metabolic disorders induced by HFD. SARM1-deletion decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in HFD-fed mice...
February 15, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29454647/dynamic-plasticity-of-macrophage-functions-in-diseased-liver
#3
Thomas Ritz, Oliver Krenkel, Frank Tacke
Liver macrophages attract increasing interest due to their crucial roles in homeostasis and hepatic diseases. Recent findings in mice and man suggest a remarkable phenotypic and functional diversity of liver macrophages. Kupffer cells, the subset of tissue resident macrophages with sentinel functions in liver, mainly arise from embryogenic precursors, whereas in injury, liver tissue is engrafted by monocyte-derived macrophages. Both principal macrophage populations respond to local or systemic signals and have substantial effects on reduction as well as aggravation of hepatic diseases...
December 20, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/29452601/reactive-hyperemia-index-rhi-and-cognitive-performance-indexes-are-associated-with-histologic-markers-of-liver-disease-in-subjects-with-non-alcoholic-fatty-liver-disease-nafld-a-case-control-study
#4
Antonino Tuttolomondo, Salvatore Petta, Alessandra Casuccio, Carlo Maida, Vittoriano Della Corte, Mario Daidone, Domenico Di Raimondo, Rosaria Pecoraro, Roberto Fonte, Anna Cirrincione, Rita Zafonte, Daniela Cabibi, Calogero Cammà, Vito Di Marco, Anna Licata, Franco Magliozzo, Giulio Marchesini, Giovanni Merlino, Antonio Craxì, Antonio Pinto
BACKGROUND: No study evaluated vascular health markers in subjects with non-alcoholic fatty liver disease (NAFLD) through a combined analysis of reactive hyperemia peripheral arterial tonometry (RH-PAT) and arterial stiffness indexes. AIM OF THE STUDY: We aimed to assess whether NAFLD and its histological severity are associated with impairment of arterial stiffness and RH-PAT indexes in a mixed cohort of patients with biopsy-proven NAFLD. MATERIALS AND METHODS: The Kleiner classification was used to grade NAFLD grade...
February 16, 2018: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/29452403/mechanisms-controlling-nucleic-acid-sensing-toll-like-receptors
#5
Kensuke Miyake, Takuma Shibata, Umeharu Ohto, Toshiyuki Shimizu, Shin-Ichiroh Saitoh, Ryutaro Fukui, Yusuke Murakami
Nucleic acid (NA)-sensing Toll-like receptors (TLRs) respond to DNA/RNA derived from pathogens and dead cells. Structural studies have revealed a variety of molecular mechanisms by which TLRs sense NAs. Double-stranded RNA and single-stranded DNA directly bind to TLR3 and TLR9, respectively, whereas TLR7 and 8 bind to nucleosides and oligoribonucleotides derived from RNAs. Activation of ligand-bound TLRs is influenced by the functional status of TLRs. Proteolytic cleavage of NA-sensing TLRs enables ligand-dependent TLR dimerization...
February 14, 2018: International Immunology
https://www.readbyqxmd.com/read/29450137/liver-and-metformin-lessons-of-a-fructose-diet-in-mice
#6
Iara Karise, Fernanda Ornellas, Sandra Barbosa-da-Silva, Cristiane Matsuura, Mariano Del Sol, Marcia Barbosa Aguila, Carlos A Mandarim-de-Lacerda
Studies show that the continuous consumption of fructose can lead to nonalcoholic fatty liver disease (NAFLD) and steatohepatitis. We aimed to investigate the role of Metformin in an animal model of liver injury caused by fructose intake, focusing on the molecular markers of lipogenesis, beta-oxidation, and antioxidant defenses. Male three months old C57BL/6 mice were divided into control group (C) and fructose group (F, 47% fructose), maintained for ten weeks. After, the groups received Metformin or vehicle for a further eight weeks: control (C), control + Metformin (CM), fructose (F), and fructose + Metformin (FM)...
June 2017: Biochimie open
https://www.readbyqxmd.com/read/29448843/cenicriviroc-for-the-treatment-of-non-alcoholic-steatohepatitis-and-liver-fibrosis
#7
Frank Tacke
Nonalcoholic fatty liver disease (NAFLD) has an increasing prevalence worldwide. At present, no specific pharmacotherapy is approved for NAFLD. Simple steatosis and nonalcoholic steatohepatitis (NASH) can progress to liver fibrosis that is associated with mortality in NAFLD. The recruitment of inflammatory monocytes and macrophages via chemokine receptor CCR2 as well as of lymphocytes and hepatic stellate cells via CCR5 promote the progression of NASH to fibrosis. Areas covered: I summarize preclinical and clinical data on the efficacy and safety of the dual CCR2/CCR5 inhibitor cenicriviroc (CVC, also TBR-652 or TAK-652) for the treatment of NASH and fibrosis...
February 16, 2018: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29446942/design-synthesis-and-evaluation-of-a-novel-series-of-indole-sulfonamide-peroxisome-proliferator-activated-receptors-ppar-%C3%AE-%C3%AE-%C3%AE-triple-activators-discovery-of-lanifibranor-a-new-anti-fibrotic-clinical-candidate
#8
Benaissa Boubia, Olivia Poupardin, Martine Barth, Jean Binet, Philippe Peralba, Laurent Mounier, Elise Jacquier, Emilie Gauthier, Valerie Lepais, Maryline Chatar, Stephanie Ferry, Anne Thourigny, Fabrice Guillier, Jonathan Llacer, Jerome Amaudrut, Pierre Dodey, Olivier Lacombe, Philippe Masson, Christian Montalbetti, Guillaume Wettstein, Jean Michel Luccarini, Christiane Legendre, Jean Louis Junien, Pierre Broqua
Here we describe the identification and synthesis of novel indole sulfonamide derivatives that activate the three peroxisome proliferator activated receptor (PPAR) isoforms. Starting with a PPARα activator, compound 4, identified during a high throughput screening (HTS) of our proprietary screening library, a systematic optimization led to the discovery of lanifibranor (IVA337) 5, a moderately potent and well balanced pan PPAR agonist with an excellent safety profile. In vitro and in vivo, compound 5 demonstrated strong activity in models that are relevant to NonAlcoholic SteatoHepatitis (NASH) pathophysiology suggesting therapeutical potential for NASH patients...
February 15, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29445232/the-cerebellum-of-patients-with-steatohepatitis-shows-lymphocyte-infiltration-microglial-activation-and-loss-of-purkinje-and-granular-neurons
#9
Tiziano Balzano, Jerónimo Forteza, Pilar Molina, Juan Giner, Ana Monzó, Jennifer Sancho-Jiménez, Amparo Urios, Carmina Montoliu, Vicente Felipo
Peripheral inflammation contributes to minimal hepatic encephalopathy in chronic liver diseases, which could be mediated by neuroinflammation. Neuroinflammation in cerebellum of patients with chronic liver diseases has not been studied in detail. Our aim was to analyze in cerebellum of patients with different grades of liver disease, from mild steatohepatitis to cirrhosis and hepatic encephalopathy: (a) neuronal density in Purkinje and granular layers; (b) microglial activation; (c) astrocyte activation; (d) peripheral lymphocytes infiltration; (e) subtypes of lymphocytes infiltrated...
February 14, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29444136/ly2405319-an-analog-of-fibroblast-growth-factor-21-ameliorates-%C3%AE-smooth-muscle-actin-production-through-inhibition-of-the-succinate-g-protein-couple-receptor-91-gpr91-pathway-in-mice
#10
Cong Thuc Le, Giang Nguyen, So Young Park, Dae Hee Choi, Eun-Hee Cho
Fibroblast growth factor 21 (FGF21) is an important metabolic regulator expressed predominantly in the liver. In this study, we evaluated the role of LY2405319, an analogue of FGF21, in hepatic stellate cell (HSC) activation and in a methionine and choline-deficient (MCD)-diet induced mouse model of liver fibrosis. During liver injury, HSCs trans-differentiate into activated myofibroblasts which produce alpha-smooth muscle actin (α-SMA) and become a major cell type in hepatic fibrogenesis. Succinate and succinate receptor (GPR91) signaling has emerged as a regulator to promote α-SMA production in MCD diet- induced mice...
2018: PloS One
https://www.readbyqxmd.com/read/29438418/bile-acid-detoxifying-enzymes-limit-susceptibility-to-liver-fibrosis-in-female-shrsp5-dmcr-rats-fed-with-a-high-fat-cholesterol-diet
#11
Husna Yetti, Hisao Naito, Yuan Yuan, Xiaofang Jia, Yumi Hayashi, Hazuki Tamada, Kazuya Kitamori, Katsumi Ikeda, Yukio Yamori, Tamie Nakajima
During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics...
2018: PloS One
https://www.readbyqxmd.com/read/29437870/cpt2-downregulation-adapts-hcc-to-lipid-rich-environment-and-promotes-carcinogenesis-via-acylcarnitine-accumulation-in-obesity
#12
Naoto Fujiwara, Hayato Nakagawa, Kenichiro Enooku, Yotaro Kudo, Yuki Hayata, Takuma Nakatsuka, Yasuo Tanaka, Ryosuke Tateishi, Yohko Hikiba, Kento Misumi, Mariko Tanaka, Akimasa Hayashi, Junji Shibahara, Masashi Fukayama, Junichi Arita, Kiyoshi Hasegawa, Hadassa Hirschfield, Yujin Hoshida, Yoshihiro Hirata, Motoyuki Otsuka, Keisuke Tateishi, Kazuhiko Koike
OBJECTIVE: Metabolic reprogramming of tumour cells that allows for adaptation to their local environment is a hallmark of cancer. Interestingly, obesity-driven and non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) mouse models commonly exhibit strong steatosis in tumour cells as seen in human steatohepatitic HCC (SH-HCC), which may reflect a characteristic metabolic alteration. DESIGN: Non-tumour and HCC tissues obtained from diethylnitrosamine-injected mice fed either a normal or a high-fat diet (HFD) were subjected to comprehensive metabolome analysis, and the significance of obesity-mediated metabolic alteration in hepatocarcinogenesis was evaluated...
February 6, 2018: Gut
https://www.readbyqxmd.com/read/29435319/serum-magnesium-concentration-is-independently-associated-with-non-alcoholic-fatty-liver-and-non-alcoholic-steatohepatitis
#13
Ahad Eshraghian, Saman Nikeghbalian, Bita Geramizadeh, Seyed Ali Malek-Hosseini
Background: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) has not been well recognized yet. Objective: This study aimed to investigate the association between serum magnesium concentration and NAFLD. Methods: Study participants were healthy individuals who had undergone liver biopsies between January 2012 and August 2015 as a routine pre-transplant check-up before living donor liver transplantation. Liver biopsy specimens were evaluated by an expert pathologist regarding presence of hepatic steatosis and steatohepatitis...
February 2018: United European Gastroenterology Journal
https://www.readbyqxmd.com/read/29431526/the-potential-role-of-statins-in-treating-liver-disease
#14
Konstantinos P Imprialos, Konstantinos Stavropoulos, Michael Doumas, Anastasia Skalkou, Ioanna Zografou, Vasilios G Athyros
Statins are commonly use for the management of dyslipidemia, worldwide. Various studies have demonstrated that statins offer significant reduction in the risk of cardiovascular morbidity and mortality. However, this class of drugs has been implicated in potential liver toxicity, thus has been considered as a "forbidden-drug" in patients with increased liver enzymes. Areas covered: Studies have shown that statins might offer clinical benefits in the setting of viral hepatitis, progression of cirrhosis, and hepatocellular carcinoma...
February 12, 2018: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/29428719/combination-effects-of-alogliptin-and-pioglitazone-on-steatosis-and-hepatic-fibrosis-formation-in-a-mouse-model-of-non-alcoholic-steatohepatitis
#15
Yuichiro Amano, Shuntarou Tsuchiya, Mayumi Imai, Kimio Tohyama, Jun Matsukawa, Osamu Isono, Hironobu Yasuno, Kazuaki Enya, Emiko Koumura, Hiroshi Nagabukuro
This study aimed to evaluate the effects of combination therapy with a dipeptidyl peptidase-4 inhibitor, alogliptin, and a peroxisome proliferator-activated receptor-γ agonist, pioglitazone, in a preclinical model of nonalcoholic steatohepatitis using low-density lipoprotein receptor-knockout mice fed a modified choline-deficient l-amino acid-defined diet. Monotherapy with either alogliptin (10-200 mg/kg) or pioglitazone (6-20 mg/kg) significantly decreased hepatic triglyceride content and fibrosis. The concomitant treatment of alogliptin (30 mg/kg), pioglitazone (20 mg/kg) also decreased hepatic triglyceride and hepatic collagen-I mRNA at greater extent compared to monotherapy...
February 8, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29428127/dyslipidemia-steatohepatitis-and-atherogenesis-in-lipodystrophic-apoe-deficient-mice-with-seipin-deletion
#16
Jiawei Liao, Xuejing Liu, Mingming Gao, Mengyu Wang, Yuhui Wang, Feng Wang, Wei Huang, George Liu
SEIPIN is an integral membrane protein located in the endoplasmic reticulum, regulating adipocytes differentiation and lipolysis. Deficiency of Seipin in mice causes severe general lipodystrophy, accompanied by insulin resistance, postprandial hypertriglyceridemia and steatohepatitis. In atherosclerosis-prone Ldlr null (Ldlr -/- ) mice, lipodystrophy caused by Seipin deletion even led to severe hypercholesteremia and accelerated atherogenesis, when challenged with an atherogenic diet. However, whether the phenotypes observed in Seipin -/- Ldlr -/- mice were a common consequence due to lipodystrophy, rather than genetic background restricted or diet dependent, was unknown...
March 30, 2018: Gene
https://www.readbyqxmd.com/read/29427621/brg1-promotes-liver-fibrosis-via-activation-of-hepatic-stellate-cells
#17
Haijie Li, Jingqin Lan, Caishun Han, Kaixuan Guo, Guihua Wang, Junbo Hu, Jianping Gong, Xuelai Luo, Zhixin Cao
Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by the persistent deposition of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Brg1, the core subunit of the SWI/SNF chromatin remodeling complex, has been proved to associated with nonalcoholic steatohepatitis which may progress to cirrhosis. Herein, we determined whether Brg1 regulates liver fibrosis and examined its mechanism by focusing on HSCs activation...
February 7, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29427497/diagnosis-of-non-alcoholic-fatty-liver-disease-non-alcoholic-steatohepatitis-why-liver-biopsy-is-essential
#18
REVIEW
Pierre Bedossa
The pattern of non-alcoholic fatty liver disease is complex with an association of several lesions, each of them related to different pathophysiological mechanisms. Despite the progress in non-invasive tools, liver biopsy remains the only diagnostic procedure that can reliably assess these various patterns, their related severity and associations. The most important difficulties of liver biopsy can be avoided if this procedure is performed by an experienced hepatologist and read by a liver pathologist. However, for obvious reasons, biopsy should be restricted to selected patients, especially in the context of clinical trials...
February 2018: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/29427494/diagnosis-of-non-alcoholic-fatty-liver-disease-non-alcoholic-steatohepatitis-non-invasive-tests-are-enough
#19
REVIEW
Laurent Castera
Non-alcoholic fatty liver disease is a major cause of liver disease worldwide and the most common liver disorder in Western countries, affecting around 25% of the general population. Fibrosis is the major long-term histological prognostic criteria of this disease. Liver biopsy cannot be realistically performed in such a huge population and, moreover, has well-known limitations (invasiveness, rare but potentially life-threatening complications and sampling variability). Over the past decade, there has been a growing interest in alternative novel strategies for the non-invasive evaluation of fibrosis...
February 2018: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/29427492/future-therapy-for-non-alcoholic-fatty-liver-disease
#20
REVIEW
Danny Issa, Vaishali Patel, Arun J Sanyal
Non-alcoholic fatty liver disease is a leading cause of chronic liver disease and can lead to cirrhosis, hepatocellular cancer and end stage liver disease. It is also associated with increased cardiovascular and cancer related morbidity and mortality. The pathogenesis of non-alcoholic fatty liver disease includes metabolic stress to the liver associated with insulin resistance with downstream cell stress from reactive oxygen species and unfolded protein response with activation of inflammatory and fibrotic pathways...
February 2018: Liver International: Official Journal of the International Association for the Study of the Liver
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