Effects of Omethoate on Liver Insulin Signaling in Mice

According to the report of the International Diabetes Federation, there were 382 million people affected with diabetes in 2013 and it is expected that this number will increase to 592 million by the year 2035;. Diabetes is caused due to the interaction between environmental and genetic factors;.

Insulin resistance in development and progression of nonalcoholic fatty liver disease

Although insulin resistance(IR)is strongly associated with nonalcoholic fatty liver disease(NAFLD),the association of IR and NAFLD is not universal and correlation between IR and severity of NAFLD is still controversial.In this review,we summarize recent evidence that partially dissociates insulin resistance from NAFLD.It has also been reported that single-nucleotide polymorphisms in the diacylglycerol acyltransferase gene,rather than IR,account for the variability in liver fat content.Polymorphisms of the patatin-like phospholipase 3 gene have also been reported to be associated with NAFLD without metabolic syndrome,which suggests that genetic conditions that promote the development of fatty changes in the liver may occur independently of IR.Moreover,environmental factors such as nutrition and physical activity as well as small intestinal bacterial overgrowth have been linked to the pathogenesis of NAFLD,although some of the data are conflicting.Therefore,findings from both genetically engineered animal models and humans with genetic conditions,as well as recent studies that have explored the role of environmental factors,have confirmed the view that NAFLD is a polygenic disease process caused by both genetic and environmental factors.Therefore,IR is not the sole predictor of the pathogenesis of NAFLD.

Mitofusin-2 ameliorates high-fat diet-induced insulin resistance in liver of rats

AIM:To investigate the effects of mitofusin-2(MFN2) on insulin sensitivity and its potential targets in the liver of rats fed with a high-fat diet(HFD).METHODS:Rats were fed with a control or HFD for 4 or 8 wk,and were then infected with a control or an MFN2 expressing adenovirus once a week for 3wk starting from the 9th wk.Blood glucose(BG),plasma insulin and insulin sensitivity of rats were determined at end of the 4th and 8th wk,and after treatment with different amounts of MFN2 expressing adenovirus(108,109 or 1010 vp/kg body weight).BG levels were measured by Accu-chek Active Meter.Plasma insulin levels were analyzed by using a Rat insulin enzymelinked immunosorbent assay kit.Insulin resistance was evaluated by measuring the glucose infusion rate(GIR) using a hyperinsulinemic euglycemic clamp technique.The expression or phosphorylation levels of MFN2 and essential molecules in the insulin signaling pathway,such as insulin receptor(INSR),insulin receptor substrate 2(IRS2),phosphoinositide-3-kinase(PI3K),protein kinase beta(AKT2) and glucose transporter type 2(GLUT2) was assayed by quantitative real-time polymerase chain reaction and Western-blotting.RESULTS:After the end of 8wk,the body weight of rats receiving the normal control diet(ND) and the HFD was not significantly different(P>0.05).Compared with the ND group,GIR in the HFD group was significantly decreased(P<0.01),while the levels of BG,triglycerides(TG),total cholesterol(TC) and insulin in the HFD group were significantly higher than those in the ND group(P<0.05).Expression of MFN2 mRNA and protein in liver of rats was significantly downregulated in the HFD group(P<0.01) after 8 wk of HFD feeding.The expression of INSR,IRS2 and GLUT2 were down-regulated markedly(P<0.01).Although there were no changes in PI3K-P85 and AKT2 expression,their phosphorylation levels were decreased significantly(P<0.01).After intervention with MFN2 expressing adenovirus for 3wk,the expression of MFN2 mRNA and protein levels were up-regulated(P<0.01).There was no difference in body weight of rats between the groups.The levels of BG,TG,TC and insulin in rats were lower than those in the Ad group(P<0.05),but GIR in rats infected with Ad-MFN2 was significantly increased(P<0.01),compared with the Ad group.The expression of INSR,IRS2 and GLUT2 was increased,while phosphorylation levels of PI3K-P85 and AKT2 were increased(P<0.01),compared with the Ad group.CONCLUSION:HFDs induce insulin resistance,and this can be reversed by MFN2 over-expression targeting the insulin signaling pathway.

Elevated alanine aminotransferase activity is not associated with dyslipidemias,but related to insulin resistance and higher disease grades in non-diabetic non-alcoholic fatty liver disease

Objective:To explore demographic and metabolic factors associated with increased alanine aminotransferase(ALT)activity in non-diabetic non-alcoholic fatty liver disease(NAFLD)patients.Methods:Overall 372 patients who consecutively attended to Gastroenterology Clinic of Baqiyatallah University of Medical Sciences,Tehran,Iran awere diagnosed as NAFLD entered into analysis.Exclusion criteria were having diabetes mellitus and fasting blood glucose over126 mg/dL,active hepatitis B virus infection,having hepatitis C virus positive serology,and to be under corticosteroid therapy.ALT levels were considered pathologically high when it was over30 IU/L for men and over 19 IU/L for women.Results:Bivariate analyses using t test and chisquare test showed that patients with pathologically augmented ALT levels had significantly higher NAFLD grades in their ultrasonographic evaluations(P=0.003).Moreover,these patients represented significantly higher homeostatic model assessment levels(P=0.003),levels of serum insulin(P=0.002),fasting blood glucose(P<0.001),and uric acid(P=0.02).The prevalence of insulin resistance was also higher in patients with increased serum ALT concentrations.Multifactorial logistic regression models showed that ultrasonographic grading of NAFLD(P=0.027)and insulin resistance(P=0.013)were the only variables significantly associated with abnormal ALT levels.Conclusions:This study shows that the associations of increased ALT serum levels in NAFLD patients are different from what are supposed before.By excluding diabetic patients from our population,we find that increased ALT levels are not associated with dyslipidemias but are independently associated with insulin resistance and NAFLD grading on ultrasonographic evaluations.Further studies are needed to confirm our results.

Effects of Insulin Treatment on Intracellular Lipid Metabolism in Liver of Diabetic Rats

The effects and the mechanism of insulin treatment on intracellular lipid metabolism in liver of diabetic rats were evaluated. Type 2 diabetic rats were induced by injecting the streptozotocin （25 mg/kg） and fat rich food. According to the results of oral glucose tolerance test （OGTT） and glucose-induced insulin secretion test （IRT）, the rats were divided into two groups： untreated group （UT） and insulin-treated group （IT）. Normal rats （NC） served as controls. The treatment with either Humulin N （4-6 U/kg every day）, or saline lasted for 4 weeks. Body weight, OGTT, IRT, blood lipids, intracellular lipids in liver, hepatic fatty acid oxidation and the activity of fatty acid synthase （FAS） were detected. The change of liver histology was observed. The insulin sensitivity index （ISI） was applied to assess the status of insulin resistance. The results showed that as compared with NC group, the plasma and hepatic intracellular Triglyceride （TG）, total cholesterol （TC） and free fatty acids （FFAs） were increased significantly in UT group （P〈0.05）, and lipid droplets could be seen dispersedly in the liver specimens, the hepatic fatty acid oxidation was increased markedly （P〈0.05）, while the fatty acid synthase activity decreased （P〈0.05）. Insulin treatment resulted in a further accumulation of lipids in liver by 55.7 %, 19.87 % and 22.2 % increase in TG, TC, FFAs respectively. The size of hepatocytes was enlarged and the cells were filled with fat drops. Plasma lipids showed little decrease and still significantly higher than those in NC group after the insulin treatment. Meanwhile, insulin treatment was companied by 20 % decrease in the rate of fatty acid oxidation and 31 % increase in hepatic FAS activity compared to, UT group. It was concluded that treatment with insulin on type 2 diabetic rat increases hepatic intracellular lipid accumulation by inhibiting hepatic fatty acid oxidation and activating FAS.

Insulin resistance and liver steatosis in chronic hepatitis C infection genotype 3

Hepatitis C virus(HCV) infection is a common chronic liver disease worldwide.Non-alcoholic fatty liver disease and insulin resistance(IR) are the major determinants of fibrosis progression and response to antiviral therapy.The pathogenetic link between IR and chronic HCV infection is complex,and is associated with HCV genotype.Liver steatosis is the most common in the patients infected with genotype 3 virus,possibly due to direct effects of genotype 3 viral proteins.To the contrary,hepatic steatosis in the patients infected with other genotypes is thought to be mostly due to the changes in host metabolism,involving IR.In HCV genotype 3,liver steatosis correlates with viral load,reverts after reaching the sustained virologic response and reoccurs in the relapsers.A therapeutic strategy to improve IR and liver steatosis and subsequently the response to antiviral treatment in these patients is warranted.

The State of Insulin Resistance in Patients with Nonalcoholic Fatty Liver and the Intervention with Gankangyin(肝康饮)

Objective: To explore the correlation of nonalcoholic fatty liver (NAFL) with insulin resistance and the intervention of it by Gankangyin(肝康饮, GKY).Methods: Ninety-six patients with NAFL were randomly assigned into the treated group and the control group. They were treated with GKY and Silymarin for 3 months respectively. Oral glucose tolerance test (OGTT) and insulin release test (IRT) were conducted and insulin sensitivity indexes were determined before and after treatment. And 32 healthy nonalcoholic persons were enrolled and used as the healthy control group. Results: Before treatment, the levels of blood glucose and insulin at different time points in OGTT test, and the insulin resistance index (IRI) were significantly higher (P<0.05 or P<0.01) while insulin sensitivity index (ISI) and insulin active index (IAI) were lower (P<0.05 or P<0.01) in the NAFL patients than those in the healthy persons. After treatment, the above-mentioned raised criteria were significantly lowered (P<0.05,P<0.01) and the lowered criteria were significantly increased (P<0.01) in the treated group, while in the control group all the criteria were insignificantly changed (P>0.05).Conclusion: Evident insulin resistance exists in NAFL patients. GKY could increase the insulin sensitivity, thus improving the state of insulin resistance in NAFL patients.

Life style modification improves insulin resistance and liver histology in patients with non-alcoholic fatty liver disease

AIM: To study the effect of regular aerobic exercise on insulin resistance, serum aminotransferase and liver histology in nonalcoholic fatty liver disease (NAFLD) patients. METHODS: Sixty (mean age 40.0 ± 8.5 years, 75% male) NAFLD patients were included in the study. After baseline anthropometric measurement i.e., body mass index (BMI), waist circumference (WC); all patients were advised regular aerobic exercise for 30 min/d, for at least 5 d/wk and trained to achieve around 70% of his maximal heart rate. In addition, moderately energy restricted diet was advised to patients with high BMI (> 25 kg/m 2 ). Monthly follow up was done by measuring BMI, WC, aspartate aminotransferase, and alanine aminotransferase (ALT). Insulin resistance was calculated using homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) model, at baseline and after 6mo. Insulin resistance was arbitrarily considered altered when it was ≥ 2. Liver biopsy was done in a section of patients at baseline and after 6 mo. RESULTS: Seventy percent (42/60) patients were overweight or obese; 95% (57/60) had central obesity (WC > 90 cm in men, > 80 cm in women). In the 45 exercise compliant patients insulin resistance decreased from 6.4 ± 6.1 to 1.3 ± 1.0, BMI from 26.7 ± 3.3 kg/m 2 to 25.0 ± 3.3 kg/m 2 , WC from 95.7 ± 8.9 cm to 90.8 ± 7.3 cm and ALT from 84.8 ± 43.5 U/L to 41.3 ± 18.2 U/L (P < 0.01). In 15 exercise noncompliant patient's insulin resistance, BMI, WC and ALT did not show significant change at 6 mo follow up. Six of 8 patients in compliant group on repeat liver biopsy showed significant change in steatosis and necroinflammation. Nonalcoholic steatohepatitis scores improved form 5.3 ± 1.5 to 3.35 ± 1.5. The decline in insulin resistance correlated with decline in ALT (P = 0.01, r s = 0.90) and liver histology (P = 0.03, r s = 0.73). CONCLUSION: Life style modification improves insulin resistance resulting in improvement in ALT and liver histology in NAFLD patients.

EXPRESSION OF INSULIN-LIKE GROWTH FACTOR Ⅱ(IGF-Ⅱ)IN HUMAN HEPATOCELLULAR CARCINOMA AND LIVER CIRRHOSIS:ITS RELATIONSHIP WITH HEPATITIS B VIRUS X PROTEIN EXPRESSION

Sixty cases of hepatocellular carcinoma (HCC) and 47 cases of liver cirrhosis (LC) were examined with immunocytochemistry method using antibodies against IGF-II and HBxAg on formalin-fixed, paraffin-embedded tissue sections. 32 HCC and 37 LC were found to be positive to HBxAg, in which the positive rates of IGF-II were 100% (32/32) and 94.6% (35/37) respectively. 28 HCC and 10 LC were found to be HBxAg negative, IGF-II was positive in 23 HCC (83.1%) and 6 LC (60%). The positive expression rates of IGF-II in HBxAg positive tissues were significantly higher than those in HBxAg negative tissues (P<0.05). There were three types of distribution of IGF-II expression in HCC and LC: (1) perinucleus; (2) diffuse in cytoplasm; (3) inside nucleus. IGF-II was highly expressed in most of hyperplastic and neoplastic nodules hepatocytes and some of regeneration nodules. Small polygonal liver cells (SPLCs) were found in the liver tissues surrounding the tumor and cirrhosis and they were positive to both IGF-II and HBxAg. The positive rates of IGF-II in SPLC were 86.4% (38/44) in the HBxAg-positive tissues and 40.5%, (15/37) in the HBxAg-negative tissues. The above findings suggest that IGF-II plays an important role in abnormal proliferation of HCC and SPLC. The relation between IGF-II andHBxAg and the nature of SPLCs are also discussed.

Insulin sensitizers for the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is the leading cause of liver disease in the Western world and is closely associated with metabolic syndrome,which includes hypertension,central obesity,dyslipidemia and insulin resistance.NAFLD includes a wide spectrum of liver alterations,ranging from simple hepatic steatosis to variable degrees of fibrosis,cirrhosis and even hepatocellular carcinoma.Although the etiology and progression of the disorder remain poorly understood,insulin resistance is considered to play a pivotal role in the pathogenesis.Insulin sensitizers such as biguanides,thiazolidinediones(TZDs),glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have been studied as therapeutic approaches for NAFLD in recent years.Metformin improves insulin sensitivity and serum alanine transaminase and aspartate transaminase(ALT/AST) levels in the majority of subjects; however,it has no significant effect on liver histology.TZDs improve insulin sensitivity,serum ALT/ AST levels and histology in some cases,but there are some concerns about the safety of long-term therapy.Selection of appropriate patients for avoiding side effects and the treatment of underlying disease are themain points.These drugs are the best choice for the treatment of NAFLD in patients with type 2 DM who are also candidates for treatment with an insulin sensitizer.The present review provides an overview of insulin sensitizers in the treatment of NAFLD.

UP780, a Chromone-Enriched <i>Aloe</i>Composition, Enhances Adipose Insulin Receptor Signaling and Decreases Liver Lipid Biosynthesis

Nutrigenomic studies were conducted to uncover the mechanism of action for the hypoglycemic and insulin sensitizing effects of UP780. From high fat diet-induced obesity mouse model for UP780, livers and white adipose tissues (WAT) from groups of lean control, high fat diet (HFD), and HFD treated with UP780 were collected for microarray study. Microarray generated gene expression changes were applied to Ingenuity Pathway Analysis for changes in canonical metabolic and signaling pathways. Microarray was validated by quantitative reverse transcriptase-polymerase chain reaction (QPCR), Western blots, liver triglyceride, liver cholesterol, liver steatosis, and insulin ELISA. UP780 treatment decreased liver gene expressions for multiple enzymes involved in fatty acid biosynthesis and triglyceride production. UP780 treatment increased gene expressions globally for the insulin receptor signaling pathway in WAT. Both liver triglyceride and liver cholesterol levels were significantly reduced by UP780 over HFD. The reduction of liver fat was confirmed by microscopic analysis of liver steatosis. Finally, UP780 significantly decreased fasting plasma insulin level over HFD. The mechanism of action for UP780 indicated a reduction of liver fat accumulation and an enhancement in adipose tissue insulin signaling pathway. This provided mechanistic explanation for the in vivo UP780 effects of enhanced insulin sensitiveity and decreased blood glucose in mouse diabetes and prediabetes models.

Modified upper abdominal cluster transplantation in patients with end-stage liver diseases associated with insulin dependent type 2 diabetes mellitus

Objective Modified upper abdominal cluster transplantation ( MCT) ,which was inspired by classical cluster transplant technique,has been proven more effective and feasible in the treatment of patients with end stage liver diseases associated with insulin - dependent

Non-alcoholic fatty liver disease and obesity: Biochemical, metabolic and clinical presentations

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Presentation of the disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NAFLD is a hepatic manifestation of metabolic syndrome that includes central abdominal obesity along with other components. Up to 80% of patients with NAFLD are obese, defined as a body mass index (BMI) > 30 kg/m2. However, the distribution of fat tissue plays a greater role in insulin resistance than the BMI. The large amount of visceral adipose tissue (VAT) in morbidly obese (BMI > 40 kg/m2) individuals contributes to a high prevalence of NAFLD. Free fatty acids derived from VAT tissue, as well as from dietary sources and de novo lipogenesis, are released to the portal venous system. Excess free fatty acids and chronic low-grade inflammation from VAT are considered to be two of the most important factors contributing to liver injury progression in NAFLD. In addition, secretion of adipokines from VAT as well as lipid accumulation in the liver further promotes inflammation through nuclear factor kappa B signaling pathways, which are also activated by free fatty acids, and contribute to insulin resistance. Most NAFLD patients are asymptomatic on clinical presentation, even though some may present with fatigue, dyspepsia, dull pain in the liver and hepatosplenomegaly. Treatment for NAFLD and NASH involves weight reduction through lifestyle modifications, anti-obesity medication and bariatric surgery. This article reviews the available information on the biochemical and metabolic phenotypes associated with obesity and fatty liver disease. The relative contribution of visceral and liver fat to insulin resistance is discussed, and recommendations for clinical evaluation of affected individuals is provided.

Fructose as a key player in the development of fatty liver disease

We aimed to investigate whether increased consumption of fructose is linked to the increased prevalence of fatty liver.The prevalence of nonalcoholic steatohepatitis(NASH) is 3% and 20% in nonobese and obese subjects,respectively.Obesity is a low-grade chronic inflam-m-atory condition and obesity-related cytokines such as interleukin-6,adiponectin,leptin,and tumor necrosis factor-α may play important roles in the developm-ent of nonalcoholic fatty liver disease(NAFLD).Additionally,the prevalence of NASH associated with both cirrhosis and hepatocellular carcinom-a was reported to be high am-ong patients with type 2 diabetes with or without obesity.Our research group previously showed that consumption of fructose is associated with adverse alterations of plasma lipid profiles and metabolic changes in m-ice,the Am-erican Lifestyle-Induced Obesity Syndrom-e m-odel,which included consum-ption of a high-fructose corn syrup in amounts relevant to that consum-ed by som-e Am-ericans.The observation reinforces the concerns about the role of fructose in the obesity epidem-ic.Increased availability of fructose(e.g.,high-fructose corn syrup) increases not only abnorm-al glucose flux but also fructose m-etabolism-in the hepatocyte.Thus,the anatomic position of the liver places it in a strategic buffering position for absorbed carbohydrates and am-ino acids.Fructose was previously accepted as a beneficial dietary com-ponent because it does not stim-ulate insulin secretion.However,since insulin signaling plays an important role in central m-echanism-s of NAFLD,this property of fructose m-ay be undesirable.Fructose has a selective hepatic m-etabolism,and provokes a hepatic stress response involving activation of c-Jun N-term-inal kinases and subsequent reduced hepatic insulin signaling.As high fat diet alone produces obesity,insulin resistance,and som-e degree of fatty liver with m-inim-al inflam-m-ation and no fibrosis,the fast food diet which includes fructose and fats produces a gene expression signature of increased hepatic fibrosis,inflam-m-ation,endoplasm-ic reticulumstress and lipoapoptosis.Hepatic de novo lipogenesis(fatty acid and triglyceride synthesis) is increased in patients with NAFLD.Stable-isotope studies showed that increased de novo lipogenesis(DNL) in patients with NAFLD contributed to fat accum-ulation in the liver and the developm-ent of NAFLD.Specifically,DNL was responsible for 26% of accum-ulated hepatic triglycerides and 15%-23% of secreted very low-density lipoprotein triglycerides in patients with NAFLD com-pared to an estim-ated less than 5% DNL in healthy subjects and 10% DNL in obese people with hyperinsulinem-ia.In conclusion,understanding the underlying causes of NAFLD form-s the basis for rational preventive and treatm-ent strategies of this m-ajor form-of chronic liver disease.

WJH 6^(th) Anniversary Special Issues(7): Nonalcoholic fatty liver disease Pathogenesis and therapeutic approaches for non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease affects approximately one-third of the population worldwide, and its incidence continues to increase with the increasing prevalence of other metabolic disorders such as type 2 diabetes. As non-alcoholic fatty liver disease can progress to liver cirrhosis, its treatment is attracting greater attention. The pathogenesis of non-alcoholic fatty liver disease is closely associated with insulin resistance and dyslipidemia, especially hypertriglyceridemia. Increased serum levels of free fatty acid and glucose can cause oxidative stress in the liver and peripheral tissue, leading to ectopic fat accumulation, especially in the liver. In this review, we summarize the mechanism underlying the progression of hepatic steatosis to steatohepatitis and cirrhosis. We also discuss established drugs that are already being used to treat non-alcoholic fatty liver disease, in addition to newly discovered agents, with respect to their mechanisms of drug action, focusing mainly on hepatic insulin resistance. As well, we review clinical data that demonstrate the efficacy of these drugs, together with improvements in biochemical or histological parameters.

Incretin based therapies:A novel treatment approach for non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease is considered a hepatic manifestation of metabolic syndrome(MS).The current treatment of non-alcoholic fatty liver disease(NAFLD)principally includes amelioration of MS components by lifestyle modifications but the lack of success in their implementation and sustainment arises the need for effective pharmacological agent in fatty liver treatment.Incretins are gut derived hormones secreted into the circulation in response to nutrient ingestion that enhances glucose-stimulated insulin secretion.Glucagon-like peptide-1(GLP-1)is the most important incretin.Its receptor agonist and inhibitors of dipeptidyl peptidase-4(DPP-4)are used in treatment of type2 diabetes mellitus.DPP-4 serum activity and hepatic expression are shown to be elevated in several hepatic diseases.There are several experimental and clinical trials exploring the efficacy of incretin based therapies in NAFLD treatment.They suggest that GLP-1 analogues might have beneficial effect on hepatic steatosis acting as insulin sensitizers and directly by stimulating GLP-1 receptors expressed on hepatocytes.The use of DPP-4 inhibitors also results in hepatic fat reduction but the mechanism of action remains unclear.There is growing evidence that incretin based therapies have beneficial effects on hepatocytes,however further study analysis are needed to assess the long term effect of incretin based therapies on NAFLD.

Effects of probiotics on nonalcoholic fatty liver disease:A meta-analysis

AIM:To investigate the relationship between the gutliver axis and nonalcoholic fatty liver disease(NAFLD),we performed a meta-analysis to evaluate the effects of probiotic therapy in NAFLD.METHODS:We searched PubMed,Medline,Embase,Web of Science,the Cochrane Library and Chinese Biomedicine Database for all relevant randomized controlled trials on probiotics in patients with NAFLD/nonalcoholic steatohepatitis(NASH).A statistical analysis was performed using RevMan 5.0 software.RESULTS:Four randomized trials involving 134 NAFLD/NASH patients were included.The results showed that probiotic therapy signifcantly decreased alanine aminotransferase(ALT),aspartate transaminase(AST),total-cholesterol(T-chol),high density lipoprotein(HDL),tumor necrosis factor(TNF)-αand homeostasis model assessment of insulin resistance(HOMAIR)[ALT:weighted mean difference(WMD)-23.71,95%CI:-33.46--13.95,P<0.00001;AST:WMD-19.77,95%CI:-32.55--7.00,P=0.002;T-chol:WMD-0.28,95%CI:-0.55--0.01,P=0.04;HDL:WMD-0.09,95%CI:-0.16-0.01,P=0.03;TNF-α:WMD-0.32,95%CI:-0.48--0.17,P<0.0001;HOMA-IR:WMD-0.46,95%CI:-0.73--0.19,P=0.0008].However,the use of probiotics was not associated with changes in body mass index(BMI),glucose(GLU)and low density lipoprotein(LDL)(BMI:WMD 0.05,95%CI:-0.18-0.29,P=0.64;GLU:WMD 0.05,95%CI:-0.25-0.35,P=0.76;LDL:WMD-0.38,95%CI:-0.78-0.02,P=0.06).CONCLUSION:Probiotic therapies can reduce liver aminotransferases,total-cholesterol,TNF-αand improve insulin resistance in NAFLD patients.Modulation of the gut microbiota represents a new treatment for NAFLD.

Potential role of Helicobacter pylori infection in nonalcoholic fatty liver disease

Accumulating evidence has implicated Helicobacter pylori(H.pylori)infection in extragastrointestinal diseases,including obesity,type 2 diabetes mellitus,cardiovascular disease,and liver disease.Recently,there has been a special focus on H.pylori infection as a risk factor for the development of nonalcoholic fatty liver disease(NAFLD).NAFLD is currently considered to be the most common liver disorder in western countries,and is rapidly becoming a serious threat to public health.The mechanisms of pathogenesis underlying NAFLD remain unclear at present and therapeutic options are limited.The growing awareness of the role of H.pylori in NAFLD is thus important to aid the development of novel intervention and prevention strategies,because the eradication of H.pylori is easy and much less expensive than long-term treatment of the other risk factors.H.pylori infection is involved in the pathogenesis of insulin resistance(IR),which is closely linked with NAFLD.It provides a new insight into the pathogenesis of NAFLD.This review probes the possible relationship between H.pylori and NAFLD,from the perspective of the potential mechanism of how H.pylori infection brings about IR and other aspects concerning this correlation.

Iron and non-alcoholic fatty liver disease

The mechanisms that promote liver injury in non-alcoholic fatty liver disease(NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis.

Plasma betatrophin levels in patients with liver cirrhosis

AIM: To investigate the plasma levels of betatrophin in patients with cirrhosis.METHODS: Forty patients diagnosed at the clinic with liver cirrhosis according to biological, ultrasonographic,or histological criteria were included.The severity of cirrhosis was classified according to Pugh's modification of Child's classification and MELD score. Insulin resistance(IR) was assessed by the Homeostasis Model Assessment. A total of 20 patients showed a MELD score higher than 14. The control group consisted in 15 sex-and aged-matched subjects.Fasting blood samples were obtained for subsequent analysis. Serum insulin was determined by Liaison automated immune chemiluminiscence assay(DiaSorin S.p.A.) using a sandwich assay. The sensitivity of the assay was 0.2 μU/mL. The intra and interassay variation coefficients were < 4% and < 10%,respectively. The normal values were between 2 and17 μU/mL. Human active betatrophin was analyzed by specific quantitative sandwich ELISA(Aviscera Bioscience). The sensitivity of the assay was 0.4 ng/mL, and the intra and interassay reproducibility were< 6% and < 10%, respectively.RESULTS: Plasma betatrophin levels were significantly increased in patients with cirrhosis compared with those in healthy subjects(P = 0.0001). Betatrophin levels were also associated with disease severity, being higher in Child-Pugh C patients compared to Child-Pugh B(P< 0.0005) and in patients who displayed a MELD score higher than 14 points compared to patients with lower punctuation(P = 0.01). In addition, we found a positive correlation between plasma betatrophin levels and the severity of cirrhosis according to Child-Pugh classification(r = 0.53; P < 0.01) or MELD score(r = 0.45; P <0.01). In the overall cohort, a moderate correlation between serum betatrophin and plasmatic bilirrubin(r= 0.39; P < 0.01) has been observed, as well as an inverse correlation between betatrophin and albumin(r =-0.41; P < 0.01) or prothrombin time(r =-0.44;P <0.01). Moreover, insulin resistance was observed in82.5% of the cirrhotic patients. In this group of patients,betatrophin levels were significantly higher than those in the group of patients without IR(P < 0.05).CONCLUSION: Plasma betatrophin is increased in patients with cirrhosis. This increase is related to the severity of cirrhosis, as well as with the emergence of insulin resistance.