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LB100 ameliorates Nonalcoholic fatty liver disease via the AMPK/Sirt1 pathway

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World Journal of Gastroenterology 2019年第45期25卷 6607-6618页

作者： Xue-Yang Chen Chang-Zhou Cai Meng-Li Yu Ze-Min Feng Yu-Wei Zhang Pei-Hao Liu Hang Zeng Chao-Hui Yu Department of Gastroenterology The First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310003Zhejiang ProvinceChina Clinical Research Center for Hepatobiliary and Pancreatic Diseases of Zhejiang Province Hangzhou 310003Zhejiang ProvinceChina

BACKGROUND It is well known that Nonalcoholic fatty liver disease(NAFLD)is associated with insulin resistance(IR).LB100,a serine/threonine protein phosphatase 2A(PP2A)inhibitor,is closely related to IR.However,there is little data regarding its direct influence on NAFLD.AIM To elucidate the effect and underlying mechanism of LB100 in NAFLD.METHODS After 10 wk of high fat diet(HFD)feeding,male C57BL/6 mice were injected intraperitoneally with vehicle or LB100 for an additional 6 wk(three times a week).The L02 cell line was treated with LB100 and free fatty acids(FFAs)for 24 h.Hematoxylin and eosin and oil red O staining were performed for histological examination.Western blot analysis was used to detect the protein expression of Sirtuin 1(Sirt1),total and phosphorylated AMP-activated protein kinaseα(AMPKα),and the proteins involved in lipogenesis and fatty acid oxidation.The mRNA levels were determined by qPCR.Pharmacological inhibition of AMPK was performed to further examine the exact mechanism of LB100 in NAFLD.RESULTS LB100 significantly ameliorated HFD-induced obesity,hepatic lipid accumulation and hepatic injury in mice.In addition,LB100 significantly downregulated the protein levels of acetyl-CoA carboxylase,sterol regulatory element-binding protein 1 and its lipogenesis target genes,including stearoyl-CoA desaturase-1 and fatty acid synthase,and upregulated the levels of proteins involved in fatty acidβ-oxidation,such as peroxisome proliferator-activated receptorα(PPARα),peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α),carnitine palmitoyltransferase 1α,acyl-CoA oxidase 1 and uncoupling protein 2,as well as the upstream mediators Sirt1 and AMPKαin the livers of HFD-fed mice.In vitro,LB100 alleviated FFA-induced lipid accumulation in L02 cells through the AMPK/Sirt1 signaling pathway.Further studies showed that the curative effect of LB100 on lipid accumulation was abolished by inhibiting AMPKαin L02 cells.CONCLUSION PP2A inhibition by LB100 significantly ameliorates hepatic steatosis

关键词： LB100 Nonalcoholic fatty liver disease Serine/threonine-protein phosphatase 2A Lipid metabolism AMP-activated protein kinaseα Sirtuin 1

Role of sodium-glucose co-transporter-2 inhibitors in the management of Nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2019年第28期25卷 3664-3668页

作者： Anastasia Kontana Konstantinos Tziomalos First Propedeutic Department of Internal Medicine Medical School Aristotle University of Thessaloniki AHEPA Hospital

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. NAFLD is considerably more frequent in patients with type 2 diabetes mellitus (T2DM) than in the general population and is also more severe histologically in this group. Sodium-glucose co-transporter-2 (SGLT2) inhibitors, the newest class of antidiabetic agents, appear to represent a promising option for the management of NAFLD in patients with T2DM. In a number of studies, treatment with SGLT2 inhibitors resulted in a reduction in hepatic steatosis and in transaminase levels. However, existing studies are small, their follow-up period was short and none evaluated the effects of SGLT2 inhibitors on liver histology. Accordingly, larger studies are needed to verify these preliminary results and define the role of SGLT2 inhibitors in the treatment of NAFLD in patients with T2DM.

关键词： Nonalcoholic fatty liver disease Type 2 diabetes mellitus Sodium-glucose co-transporter-2 inhibitors Steatosis Fibrosis Transaminases

Mediterranean diet and Nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2018年第19期24卷 2083-2094页

作者： Caterina Anania Francesco Massimo Perla Francesca Olivero Lucia Pacifico Claudio Chiesa Policlinico Umberto I Hospital Sapienza University of Rome Institute of Translational Pharmacology National Research Council

Nonalcoholic fatty liver disease(NAFLD) is emerging as the most common chronic liver disease, and is characterized by a wide spectrum of fat-liver disorders that can result in severe liver disease and cirrhosis. Inflammation and oxidative stress are the major risk factors involved in the pathogenesis of NAFLD. Currently, there is no consensus concerning the pharmacological treatment of NAFLD. However, lifestyle interventions based on exercise and a balanced diet for quality and quantity, are considered the cornerstone of NAFLD management. Mediterranean diet(MD), rich in polyunsaturated fats, polyphenols, vitamins and carotenoids, with their anti-inflammatory and antioxidant effects, has been suggested to be effective in preventing cardiovascular risk factors. In adults, MD has also been demonstrated to be efficacious in reducing the risk of metabolic syndrome. However, few studies are available on the effects of the MD in both adult and pediatric subjects with NAFLD. Thus, the aims of the present narrative review are to analyze the current clinical evidence on the impact of MD in patients with NAFLD, and to summarize the main mechanisms of action of MD components on this condition.

关键词： Mediterranean diet children Nonalcoholic fatty liver disease adults

Nonalcoholic fatty liver disease and liver transplantation-Where do we stand?

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World Journal of Gastroenterology 2018年第14期24卷 1491-1506页

作者： Ivana Mikolasevic Tajana Filipec-Kanizaj Maja Mijic Ivan Jakopcic Sandra Milic Irena Hrstic Nikola Sobocan Davor Stimac Patrizia Burra Department of Gastroenterology UHC Rijeka School of Medicine University of Rijeka Department of Gastroenterology University Hospital MerkurSchool of Medicine University of Zagreb Department of Internal medicine General Hospital Pula Pula School of Medicine University of Rijeka and Zagreb Multivisceral Transplant Unit Department of Surgery Oncology and Gastroenterology Padua University Hospital

Nonalcoholic fatty liver disease/Nonalcoholic steatohepatitis(NAFLD/NASH) is a challenging and multisystem disease that has a high socioeconomic impact. NAFLD/NASH is a main cause of macrovesicular steatosis and has multiple impacts on liver transplantation(LT), on patients on the waiting list for transplant, on posttransplant setting as well as on organ donors. Current data indicate new trends in the area of chronic liver disease. Due to the increased incidence of metabolic syndrome(Met S) and its components, NASH cirrhosis and hepatocellular carcinoma caused by NASH will soon become a major indication for LT. Furthermore, due to an increasing incidence of Met S and, consequently, NAFLD, there will be more steatotic donor livers and less high quality organs available for LT, in addition to a lack of available liver allografts. Patients who have NASH and are candidates for LT have multiple comorbidities and are unique LT candidates. Finally, we discuss long-term grafts and patient survival after LT, the recurrence of NASH and NASH appearing de novo after transplantation. In addition, we suggest topics and areas that require more research for improving the health care of this increasing patient population.

关键词： Nonalcoholic steatohepatitis chronic liver disease liver transplantation Nonalcoholic fatty liver disease outcome

Evaluation of safety for hepatectomy in a novel mouse model with Nonalcoholic-steatohepatitis

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World Journal of Gastroenterology 2018年第15期24卷 1622-1631页

作者： Yusuke Ozawa Takafumi Tamura Yohei Owada Yoshio Shimizu Akira Kemmochi Katsuji Hisakura Takashi Matsuzaka Hitoshi Shimano Hiroko Isoda Nobuhiro Ohkohchi Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery Faculty of Medicine University of Tsukuba Department of Endocrinology and Metabolism Faculty of Medicine University of Tsukuba Faculty of Life and Environmental Sciences University of Tsukuba

AIM To investigate whether the liver resection volume in a newly developed Nonalcoholic steatohepatitis(NASH) model influences surgical outcome.METHODS For establishment of a NASH model, mice were fed a high-fat diet for 4 wk, administered CCl_4 for the last 2 wk, and administered T0901317 for the last 5 d. We divided these mice into two groups: A 30% partial hepatectomy(PH) of NASH liver group and a 70% PH of NASH liver group. In addition, a 70% PH of normal liver group served as the control. Each group was evaluated for survival rate, regeneration, apoptosis, necrosis and DNA expression after PH.RESULTS In the 70% PH of NASH group, the survival rate was significantly decreased compared with that in the control and 30% PH of NASH groups(P < 0.01). 10 of 32 mice in the NASH 70% PH group died within 48 h after PH. Serum aspartate aminotransferase(AST) levels and total bilirubin(T-Bil) in the NASH 70% PH group were significantly higher than the levels in the other two groups(AST: P < 0.05, T-Bil: P < 0.01). In both PH of NASH groups, signaling proteins involved in regeneration were expressed at lower levels than those in the control group(P < 0.01). The 70% PH of NASH group also exhibited a lower number of Ki-67-positive cells and higher rates of apoptosis and necrosis than the NASH 30% PH group(P < 0.01). In addition, DNA microarray assays showed differences in gene expression associated with cell cycle arrest and apoptosis.CONCLUSION The function of the residual liver is impaired in fatty liver compared to normal liver. A larger residual volume is required to maintain liver functions in mice with NASH.

关键词： Hepatectomy Liver regeneration Residual liver Liver proliferation Nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction

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World Journal of Gastroenterology 2018年第16期24卷 1748-1765页

作者： Michelle L Boland Stephanie Oldham Brandon B Boland Sarah Will Jean-Martin Lapointe Silvia Guionaud Christopher J Rhodes James L Trevaskis Cardiovascular and Metabolic Diseases MedImmune LLC Pathology MedImmune Ltd. Pathology Drug Safety and MetabolismIMED Biotech UnitAstraZeneca

AIM To comprehensively evaluate mitochondrial(dys) function in preclinical models of Nonalcoholic steatohepatitis(NASH).METHODS We utilized two readily available mouse models of Nonalcoholic fatty liver disease(NAFLD) with or without progressive fibrosis: Lep^(ob)/Lep^(ob)(ob/ob) and FATZO mice on high trans-fat, high fructose and high cholesterol(AMLN) diet. Presence of NASH was assessed using immunohistochemical and pathological techniques, and gene expression profiling. Morphological features of mitochondria were assessed via transmission electron microscopy and immunofluorescence, and function was assessed by measuring oxidative capacity in primary hepatocytes, and respiratory control and proton leak in isolated mitochondria. Oxidative stress was measured by assessing activity and/or expression levels of Nrf1, Sod1, Sod2, catalase and 8-OHdG. RESULTS When challenged with AMLN diet for 12 wk, ob/ob and FATZO mice developed steatohepatitis in the presence of obesity and hyperinsulinemia. NASH development was associated with hepatic mitochondrial abnormalities, similar to those previously observed in humans, including mitochondrial accumulation and increased proton leak. AMLN diet also resulted in increased numbers of fragmented mitochondria in both strains of mice. Despite similar mitochondrial phenotypes, we found that ob/ob mice developed more advanced hepatic fibrosis. Activity of superoxide dismutase(SOD) was increased in ob/ob AMLN mice, whereas FATZO mice displayed increased catalase activity, irrespective of diet. Furthermore, 8-OHd G, a marker of oxidative DNA damage, was significantly increased in ob/ob AMLN mice compared to FATZO AMLN mice. Therefore, antioxidant capacity reflected as the ratio of catalase:SOD activity was similar between FATZO and C57 BL6 J control mice, but significantly perturbed in ob/ob mice. CONCLUSION Oxidative stress, and/or the capacity to compensate for increased oxidative stress, in the setting of mitochondrial dysfunction, is a key factor for development of hepatic injury

关键词： Nonalcoholic steatohepatitis Steatosis Fibrosis Mitochondrial function Oxidative stress

Biomarkers and subtypes of deranged lipid metabolism in Nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2019年第24期25卷 3009-3020页

作者： José M Mato Cristina Alonso Mazen Noureddin Shelly C Lu CIC bioGUNE Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd)Technology Park of BizkaiaDerio 48160BizkaiaSpain OWL Metabolomics Technology Park of BizkaiaDerio 48160BizkaiaSpain Division of Digestive and Liver Diseases Comprehensive Transplant CenterCedars-Sinai Medical CenterLos AngelesCA 90048United States

Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,Nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.

关键词： S-adenosylmethionine Methionine adenosyltransferase Lipid metabolism Multiomics Lipidomics Nonalcoholic steatohepatitis One-carbon metabolism Very low-density lipoproteins Steatosis Precision medicine

Nonalcoholic fatty liver disease in patients with inflammatory bowel disease: Beyond the natural history

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World Journal of Gastroenterology 2019年第37期25卷 5676-5686页

作者： Salvatore Magrì Danilo Paduano Fabio Chicco Arianna Cingolani Cristiana Farris Giovanna Delogu Francesca Tumbarello Mariantonia Lai Alessandro Melis Laura Casula Massimo C Fantini Paolo Usai Department of Medical Sciences and Public Health University of CagliariMonserrato 09042Italy Department of Systems Medicine University of Rome"Tor Vergata"Rome 00133Italy

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is a frequently reported condition in patients with inflammatory bowel disease(IBD).Both intestinal inflammation and metabolic factors are believed to contribute to the pathogenesis of IBDassociated NAFLD.AIM To evaluate the prevalence of steatosis and liver fibrosis(LF)in a cohort of IBD patients and the identification of metabolic-and IBD-related risk factors for NAFLD and LF.METHODS IBD patients were consecutively enrolled from December 2016 to January 2018.Demographic,anthropometric and biochemical data were collected so as eating habits.Abdominal ultrasound and transient elastography were performed to evaluate the presence of NAFLD and LF respectively.RESULTS A total of 178 consecutive patients were enrolled and included in the analysis(95 Ulcerative colitis,83 Crohn’s disease).NAFLD was detected by imaging in 72(40.4%)patients.Comparison between patients with and without NAFLD showed no significant differences in terms of IBD severity,disease duration,location/extension,use of IBD-related medications(i.e.,steroids,anti-TNFs,and immunomodulators)and surgery.NAFLD was significantly associated with the presence of metabolic syndrome[MetS;odds ratio(OR):4.13,P=0.001]and obesity defined by body mass index(OR:9.21,P=0.0002).IBD patients with NAFLD showed higher caloric intake and lipid consumption than those without NAFLD,regardless disease activity.At the multivariate analysis,male sex,advanced age and high lipid consumption were independent risk factors for the development of NAFLD.An increased liver stiffness was detected in 21 patients(16%)and the presence of MetS was the only relevant factor associated to LF(OR:3.40,P=0.01).CONCLUSION In this study,we demonstrate that risk factors for NAFLD and LF in the IBD population do not differ from those in the general population.

关键词： Nonalcoholic fatty liver disease Liver fibrosis Inflammatory bowel disease Risk factors Dietary habits

Role of cenicriviroc in the management of Nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2018年第48期24卷 5415-5417页

作者： Georgios Neokosmidis Konstantinos Tziomalos First Propedeutic Department of Internal Medicine Medical SchoolAristotle University of ThessalonikiAHEPA Hospital

Nonalcoholic fatty liver disease(NAFLD) is the commonest chronic liver disease in high-income countries and is associated with increased morbidity and mortality. Macrophages appear to play an important role in the development and progression of hepatic fibrosis in patients with NAFLD. Accordingly, modulation of macrophage trafficking might represent an attractive therapeutic strategy in this population. Cenicriviroc is an oral inhibitor of the chemokine ligand 2/C-C chemokine receptor 2 pathway, which plays an important role in the hepatic recruitment of the macrophages. Preclinical studies and a phase 2b study in humans suggest that this agent might hold promise in the management of NAFLD.

关键词： Cenicriviroc Macrophages Nonalcoholic fatty liver disease Fibrosis Nonalcoholic steatohepatitis