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Effects of different diets on intestinal microbiota and nonalcoholic fatty liver disease development

World Journal of Gastroenterology 2016年第32期22卷 7353-7364页

作者： Jian-Ping Liu Wen-Li Zou Shui-Jiao Chen Hong-Yun Wei Ya-Ni Yin Yi-You Zou Fang-Gen Lu Department of Gastroenterology Second Xiangya Hospital of Central South University Department of Nephrology Zhejiang Provincial People’s Hospital Department of Gastroenterology Xiangya Hospital of Central South University

AIM To study the effects of different diets on intestinal microbiota and nonalcoholic fatty liver disease(NAFLD) development at the same caloric intake.METHODS Thirty male Sprague-Dawley rats were randomized into five groups(six rats each). The control diet(CON) group and free high-fat diet(FFAT) group were allowed ad libitum access to a normal chow diet and a highfat diet, respectively. The restrictive high-fat diet(RFAT) group, restrictive high-sugar diet(RSUG) group, and high-protein diet(PRO) group were fed a highfat diet, a high-sugar diet, and a high-protein diet, respectively, in an isocaloric way. All rats were killed at 12 wk. Body weight, visceral fat index(visceral fat/body weight), liver index(liver/body weight), insulin resistance, portal lipopolysaccharide(LPS), serum alanine aminotransferase(ALT), serum aspartate aminotransferase(AST), and liver triglycerides were measured. The intestinal microbiota in the different groups of rats was sequenced using high-throughput sequencing technology.RESULTS The FFAT group had higher body weight, visceral fat index, liver index, peripheral insulin resistance, portal LPS, serum ALT, serum AST, and liver triglycerides compared with all other groups(P < 0.05). Taking the same calories, the RFAT and RSUG groups demonstrated increased body weight, visceral fat index, peripheral insulin resistance and liver triglycerides compared with the PRO group(P < 0.05). The RFAT group also showed increased portal LPS compared with the PRO group(P < 0.05). Unweighted Uni Frac principal coordinates analysis of the sequencing data revealed that the intestinal microbiota structures of the CON, FFAT, RSUG and PRO groups were roughly separated away from each other. Taxon-based analysis showed that, compared with the CON group, the FFAT group had an increased abundance of Firmicutes, Roseburia and Oscillospira bacteria, a higher ratio of Firmicutes to Bacteroidetes, and a decreased abundance of Bacteroidetes, Bacteroides and Parabacteroides bacteria(P < 0.05). The RFAT group showed an

关键词： nonalcoholic fatty liver disease High-fat diet Restrictive high-fat diet Restrictive high-sugar diet High-protein diet Intestinal microbiota

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Liver transplantation for nonalcoholic fatty liver disease:New challenges and new opportunities

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World Journal of Gastroenterology 2014年第18期20卷 5320-5330页

作者： Mina Shaker Adam Tabbaa Mazen Albeldawi Naim Alkhouri Department of Gastroenterology and Hepatology Digestive Disease InstituteCleveland ClinicOH 44195United States

nonalcoholic fatty liver disease(NAFLD)is becoming rapidly one of the most common indications for orthotopic liver transplantation in the world.Development of graft steatosis is a significant problem during the posttransplant course,which may happen as a recurrence of pre-existing disease or de novo NAFLD.There are different risk factors that might play a role in development of graft steatosis including post-transplant metabolic syndrome,immune-suppressive medications,genetics and others.There are few studies that assessed the effects of NAFLD on graft and patient survival;most of them were limited by the duration of follow up or by the number of patients.With this review article we will try to shed light on post-liver transplantation NAFLD,significance of the disease,how it develops,risk factors,clinical course and treatment options.

关键词： nonalcoholic fatty liver disease nonalcoholic stea

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Cross-talk between the thyroid and liver:A new target for nonalcoholic fatty liver disease treatment

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World Journal of Gastroenterology 2013年第45期19卷 8238-8246页

作者： Yue-Ye Huang Aaron M Gusdon Shen Qu Department of Endocrinology and Metabolism Shanghai 10th People’s Hospital School of Medicine Tongji University Department of Neurology and Neuroscience Weill Cornell Medical College New York NY 10065 United States Department of Endocrinology and Metabolism Nanjing Medical University

nonalcoholic fatty liver disease(NAFLD)has been recognized as the most common liver metabolic disease,and it is also a burgeoning health problem that affects one-third of adults and is associated with obesity and insulin resistance now.Thyroid hormone(TH)and its receptors play a fundamental role in lipid metabolism and lipid accumulation in the liver.It is found that thyroid receptor and its isoforms exhibit tissue-specific expression with a variety of functions.TRβ1 is predominantly expressed in the brain and adipose tissue and TRβ2 is the major isoform in the liver,kidney and fat.They have different functions and play important roles in lipid metabolism.Recently,there are many studies on the treatment of NAFLD with TH and its analogues.We review here that thyroid hormone and TR are a potential target for pharmacologic treatments.Lipid metabolism and lipid accumulation can be regulated and reversed by TH and its analogues.

关键词： Thyroid hormone Thyroid hormone receptor nonalcoholic fatty liver disease Obesity

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A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia

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World Journal of Gastroenterology 2014年第11期20卷 3002-3010页

作者： Luca Valenti Anna Ludovica Fracanzani Paola Dongiovanni Serena Rovida Raffaela Rametta Erika Fatta Edoardo Alessandro Pulixi Marco Maggioni Silvia Fargion Department of Pathophysiology and Transplantation Metabolic Liver Diseases Research CenterUniversità degli Studi di MilanoFondazione IRCCS Ca' Granda Ospedale Policlinicovia F Sforza 3520122MilanoItaly

AIM:To compare iron depletion to lifestyle changes alone in patients with severe nonalcoholic fatty liver disease(NAFLD)and hyperferritinemia,a frequent feature associated with more severe liver damage,despite at least 6 mo of lifestyle changes.METHODS:Eligible subjects had to be 18-75 years old who underwent liver biopsy for ultrasonographically detected liver steatosis and hyperferritinemia,ferritin levels≥250 ng/mL,and NAFLD activity score>1.Iron depletion had to be achieved by removing 350 cc of blood every 10-15 d according to baseline hemoglobin values and venesection tolerance,until ferritin<30 ng/mL and/or transferrin saturation(TS)<25%.Thirty-eight patients were randomized 1:1 to phlebotomy(n=21)or lifestyle changes alone(n=17).The main outcome of the study was improvement in liver damage according to the NAFLD activity score at 2 years,secondary outcomes were improvements in liver enzymes[alanine aminotransferases(ALT),aspartate aminotransferase(AST),and gamma-glutamyl-transferases(GGT)].RESULTS:Phlebotomy was associated with normalization of iron parameters without adverse events.In the21 patients compliant to the study protocol,the rate of histological improvement was higher in iron depleted vs control subjects(8/12,67%vs 2/9,22%,P=0.039).There was a better improvement in steatosis grade in iron depleted vs control patients(P=0.02).In patients followed-up at two years(n=35),ALT,AST,and GGT levels were lower in iron-depleted than in control patients(P<0.05).The prevalence of subjects with improvement in histological damage or,in the absence of liver biopsy,ALT decrease≥20%(associated with histological improvement in biopsied patients)was higher in the phlebotomy than in the control arm(P=0.022).The effect of iron depletion on liver damage improvement as assessed by histology or ALT decrease≥20%was independent of baseline AST/ALT ratio and insulin resistance(P=0.0001).CONCLUSION:Iron depletion by phlebotomy is likely associated with a higher rate of improvement of histological liver damage than lifestyl

关键词： nonalcoholic fatty liver disease Iron depletion Ra

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Female spontaneously diabetic Torii fatty rats develop nonalcoholic steatohepatitis-like hepatic lesions

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World Journal of Gastroenterology 2015年第30期21卷 9067-9078页

作者： Yukihito Ishii Yu Motohashi Makoto Muramatsu Yoshiaki Katsuda Katsuhiro Miyajima Tomohiko Sasase Takahisa Yamada Tohru Matsui Shinichi Kume Takeshi Ohta Japan Tobacco Inc. Central Pharmaceutical Research Institute Japan Tobacco Inc. Central Pharmaceutical Research InstituteToxicology Research Laboratories Niigata University Graduate School of Science and Technology Kyoto University Graduate School of Agriculture

AIM:To investigate the histological features of the liver in spontaneously diabetic Torii(SDT) fatty rats compared with age-matched Sprague-Dawley(SD) rats.METHODS:Female SDT Leprfa(SDT fatty) rats and age-matched SD rats were fed ad libitum. Body weight and biochemical parameters,such as serum glucose,triglyceride(TG),total cholesterol(TC),alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels as well as fatty acid and TG accumulation in the liver were evaluated at 8 wk of age in the nonfasting state and at 8-wk intervals from 8 to 40 wk of age. Histopathological examinations of the liver were performed using hematoxylin and eosin and Sirius Red staining as well as double staining for ED-1 and toluidine blue. The expression of genes involved in TG synthesis,inflammation,and fibrosis was examined in the liver.RESULTS:SDT fatty rats showed significantly increased body weight compared with SD rats. Serum glucose,TG,and TC levels were significantly higher in SDT fatty rats compared with SD rats. The serum AST and ALT levels in SDT fatty rats were significantly elevated at 8 wk of age compared with the levels in SD rats. Hepatic TG content was marked in SDT fatty rats from 8 to 32 wk of age. Histopathologically,severe hepatosteatosis accompanied by inflammation was observed at 8 wk of age,and fibrosis started to occur at 32 wk of age. Furthermore,Sirius Red and ED-1 staining were increased in the liver at 32 wk of age. Hepatic gene expression related to TG synthesis,inflammation and fibrosis tended to increase in SDT fatty rats compared with SD rats,and the gene expression related to TG secretion was decreased in SDT fatty rats compared with SD rats. CONCLUSION:Female SDT fatty rats have the potential to become an important animal model of nonalcoholic steatohepatitis with type 2 diabetes and obesity.

关键词： nonalcoholic steatohepatitis Spontaneouslydiabetic Torii fatty rat Fibrosis Fatty liver Metabolicsyndrome

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Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2014年第23期20卷 7381-7391页

作者： Kouichi Miura Hirohide Ohnishi Department of Gastroenterology Akita University Graduate School of MedicineAkita 010-8543Japan

Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease(NAFLD).The change in gut microbiota may alter nutritional absorption and storage.In addition,gut microbiota are a source of Toll-like receptor(TLR)ligands,and their compositional change can also increase the amount of TLR ligands delivered to the liver.TLR ligands can stimulate liver cells to produce proinflammatory cytokines.Therefore,the gut-liver axis has attracted much interest,particularly regarding the pathogenesis of NAFLD.The abundance of the major gut microbiota,including Firmicutes and Bacteroidetes,has been considered a potential underlying mechanism of obesity and NAFLD,but the role of these microbiota in NAFLD remains unknown.Several reports have demonstrated that certain gut microbiota are associated with the development of obesity and NAFLD.For instance,a decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut permeability,which allows the leakage of bacterial components.Interventions to increase Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD.In children,the levels of Escherichia were significantly increased in nonalcoholic steatohepatitis(NASH)compared with those in obese control.Escherichia can produce ethanol,which promotes gut permeability.Thus,normalization of gut microbiota using probiotics or prebiotics is a promising treatment option for NAFLD.In addition,TLR signaling in the liver is activated,and its downstream molecules,such as proinflammatory cytokines,are increased in NAFLD.To data,TLR2,TLR4,TLR5,and TLR9 have been shown to be associated with the pathogenesis of NAFLD.Therefore,gut microbiota and TLRs are targets for NAFLD treatment.

关键词： nonalcoholic fatty liver disease nonalcoholic stea

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Inhibition of apoptosis in the management of nonalcoholic fatty liver disease

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World Journal of Gastrointestinal Pharmacology and Therapeutics 2013年第1期4卷 4-8页

作者： Stella D Bouziana Konstantinos Tziomalos First Propaedeutic Department of Internal Medicine Medical School Aristotle University of Thessaloniki AHEPA Hospital 54636 Thessaloniki Greece

nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the developed world. The pathogenesis of NAFLD is multifactorial, involving obesity, insulin resistance, inflammation and oxidative stress. Accordingly, several treatments targeting these pathways have been evaluated in patients with NAFLD but have either shown limited efficacy or an unfavorable safety profile. On the other hand, increased hepatocyte apoptosis also appears to be implicated in the development and progression of NAFLD and recent pilot studies suggest that inhibition of apoptosis might represent a useful approach in this disease. However, several issues pertaining both to the efficacy and safety of this new class of agents remain unresolved and larger studies are required to clarify the role of this therapeutic modality in the management of NAFLD.

关键词： Apoptosis nonalcoholic fatty liver disease nonalcoholic steatohepatitis Fatty liver Carcinogenesis Cirrhosis Caspase

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Fatty acid changes help to better understand regression of nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2015年第1期21卷 301-310页

作者： Dominika Maciejewska Arleta Drozd Piotr Ossowski Karina Ryterska Dominika Jamio-Milc Marcin Banaszczak Joanna Raszeja-Wyszomirska Magorzata Kaczorowska Anna Sabinicz Ewa Stachowska Department of Biochemistry and Human Nutrition Pomeranian Medical University70-204 SzczecinPoland Department of General Transplant and Liver SurgeryMedical University of Warsaw02-672 WarsawPoland

AIM: To investigate whether liver steatosis reduction due to a six-month dietary intervention results in significant changes in the concentrations of fatty acids.METHODS: A group of 35 Caucasian individuals diagnosed with different levels of steatosis were prospectively enrolled in the present study.Analysis of the fatty acid profiles was performed according to changes in liver steatosis(liver steatosis reduction by one or two degrees) after a six-month dietary intervention.The diet helped reduce body mass in obese and overweight patients,and stabilize both glycemia and dyslipidemia.Fatty acids were extracted according to the Folch method and analyzed by gas chromatography.RESULTS: This study showed significant changes in fatty acid profiles in patients who had reduced liver steatosis by one as well as two degrees.A reduction in liver steatosis by one degree caused a significant increase in the level of the n-3 family: eicosapentaenoic acid(P nonalcoholic fatty liver disease.

关键词： nonalcoholic fatty liver disease Fatty acids Bioch

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Effects of salvianolic acid B on liver mitochondria of rats with nonalcoholic steatohepatitis

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World Journal of Gastroenterology 2015年第35期21卷 10104-10112页

作者： Ying-Chun Wang Wei-Zong Kong Qing-Mei Jin Juan Chen Lei Dong Department of Gastroenterology the Second Affiliated HospitalXi’an Jiaotong University Department of Gastroenterology Affiliated Zhongshan Hospital of Dalian University

AIM: To investigate the effects of salvianolic acid B(Sal B) on the morphological characteristics and functions of liver mitochondria of rats with nonalcoholic steatohepatitis(NASH).METHODS: A total of 60 male Sprague-Dawley rats were randomly divided into three groups:(1) a normal group fed a normal diet;(2) an NASH model group; and(3) a Sal B-treated group fed a high-fat diet. Two rats from each group were executed at the end of the 12 th week to detect pathological changes. The rats in the Sal B-treated group were gavaged with 20 m L/kg Sal B(1 mg/m L) daily. The model group received an equal volume of distilled water as a control. At the end of the 24 th weekend, the remaining rats were executed. Serum biochemical parameters and liver histological characteristics were observed. Malondialdehyde(MDA) and superoxide dismutase(SOD) in the liver were determined. Protein expression of Cyt C and caspase-3 was determined by immunohistochemistry. The m RNA transcripts of mitofusin-2(Mfn2) and NF-κB in the liver tissue were detected by real-time PCR. Mitochondrial membrane potential was detected using a fluorescence spectrophotometer. Mitochondrial respiratory function was detected using a Clark oxygen electrode.RESULTS: The model group showed significantly higher ALT, AST, TG, TC and MDA but significantly lower SOD than the normal group. In the model group,the histological characteristics of inflammation and steatosis were also evident; mitochondrial swelling and crest were shortened or even disappeared. Cyt C(18.46 ± 1.21 vs 60.01 ± 3.43, P < 0.01) and caspase-3 protein expression(30.26 ± 2.56 vs 83.31 ± 5.12, P < 0.01) increased significantly. The m RNA expression of NF-κB increased(0.81 ± 0.02 vs 0.91 ± 0.03, P < 0.05), whereas the m RNA expression of Mfn2 decreased(1.65 ± 0.31 vs 0.83 ± 0.16, P < 0.05). Mitochondrial membrane potential also decreased and breathing of rats was weakened. Steatosis and inflammation degrees in the treatment group were significantly alleviated compared with those of the model group. In

关键词： nonalcoholic steatohepatitis Salvianolic acid B Ap

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Increased serum soluble lectin-like oxidized low-density lipoprotein receptor-1 levels in patients with biopsy-proven nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2015年第26期21卷 8096-8102页

作者： Oguzhan Ozturk Yasar Colak Ebubekir Senates Yusuf Yilmaz Celal Ulasoglu Levent Doganay Seyma Ozkanli Yasemin Musteri Oltulu Ender Coskunpinar Ilyas Tuncer Department of Gastroenterology Goztepe Teaching and Research HospitalIstanbul Medeniyet University Department of Gastroenterology Marmara University School of MedicineIstanbulTurkey Institute of Gastroenterology Marmara University Department of Pathology Goztepe Teaching and Research HospitalIstanbul Medeniyet University Department of Molecular Medicine Institute of Experimental Medicine ResearchIstanbul University

AIM: To analyze the relationship between the serum lectin-like oxidized low-density lipoprotein receptor-1(LOX-1) levels and clinical and histopathological features of biopsy-confirmed nonalcoholic fatty liver disease(NAFLD) patients.METHODS: Fifty-three consecutive,biopsy-proven NAFLD patients(31 males and 22 females,mean age 42.5 ± 9.6 years) and 26 age- and gender-matched,healthy controls(14 males and 12 females,mean age 39 ± 10.7 years) were included.The patientswith NAFLD were consecutive patients who had been admitted to the hepatology outpatient clinic within the last year and had been diagnosed with NAFLD as the result of liver biopsy.The healthy controls were individuals who attended the outpatient clinic for routine health control and had no known chronic illnesses.The histological evaluation was conducted according t o t he N AF LD ac t ivi ty scoring syst em recommended by The National Institute of Diabetes and Digestive and Kidney Diseases nonalcoholic Steatohepatitis Clinical Research Network.The serum LOX-1 levels were measured using an ELISA kit(Life Science Inc.USCN.Wuhan,Catalog No.E1859Hu) in both patients and healthy controls.A receiver operating characteristic(ROC) curve analysis was used to identify the optimal cutoff value of LOX-1 and thereby distinguish between patients with nonalcoholic steatohepatitis(NASH) and healthy controls.A P-value < 0.05 was considered statistically significant.RESULTS: NAFLD and healthy control groups were similar in terms of age and sex.NAFLD patients consisted of 8 patients with simple steatosis(15%),27 with borderline NASH(51%) and 18 with definitive NASH(34%).Metabolic syndrome was found in 62.2% of the patients with NAFLD.The mean serum LOX-1 level in biopsy-proven NAFLD patients was 8.49 ± 6.43 ng/m L compared to 4.08 ± 4.32 ng/m L in healthy controls(P = 0.001).The LOX-1 levels were significantly different between controls,simple steatosis and NASH(borderline+definite) cases(4.08 ± 4.32 ng/m L,6.1 ± 6.16 ng/m L,8.92 ± 6.45 ng/m L,respectively,P = 0.004).W

关键词： Insulin resistance Liver fibrosis Metabolicsyndrome nonalcoholic fatty liver disease Steatohepatitis

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