Dietary supplementation with a high dose of daidzein enhances the antioxidant capacity in swine muscle but experts pro-oxidant function in liver and fat tissues

Background： Although isoflavones are natural dietary antioxidants, they may have toxicological effects. This study aimed to evaluate the redox system in tissues of finishing pigs by supplementation with high dose of daidzein（640 mg/kg）.Results： The supplementation of high dose of daidzein for 64 d increased the activity of superoxide dismutase and total antioxidant capacity in longissimus muscle but down-regulated the expression of reactive oxygen species（ROS）-producing enzyme NADPH oxidase-2 and cyclooxygenase-2. In contrast, high-level supplementation with daidzein exerted pro-oxidant changes in back fat, abdominal fat, liver, and plasma, as reflected by increased contents of malondialdehyde, a lipid peroxidation product, in these tissues. Furthermore, daidzein supplementation resulted in higher expression of ROS-producing enzymes, including NADPH oxidase-1 and cyclooxygenase-1in liver, 5-lipoxygenase（5-LOX） in backfat and NADPH oxidase-2 both in abdominal fat and backfat. The supplementation of daidzein did not affect meat quality parameters in longissimus muscle, including marbling score,eye muscle areas, intramuscular fat, shear force, drip loss, p H and meat color.Conclusions： This experiment suggests that dietary supplementation of finishing pigs with daidzein at a high dose level improves redox status in muscle but exerts pro-oxidant effect in liver and fat tissues.

Helicobacter pylori infection is not associated with nonalcoholic fatty liver disease

AIM: To determine whether Helicobacter pylori (H. pylori) infection confers a higher risk of Nonalcoholic fatty liver disease (NAFLD).METHODS: Healthy people who underwent health screening were analyzed retrospectively. Inclusion criteria were age ≥ 20 years, history of H. pylori infection, and recorded insulin level. Participants were classified as H. pylori positive or negative according to 13C urea breath tests. NAFLD was defined using the hepatic steatosis index (HSI) and NAFLD liver fat score (NAFLD-LFS). Those with an HSI > 36 or NAFLD-LFS > -0.640 were considered to have NAFLD. Multivariable logistic regression was performed to identify risk factors for NAFLD.RESULTS: Three thousand six hundred and sixty-three people were analyzed and 1636 (44.7%) were H. pylori positive. H. pylori infection was associated with older age, male gender, hypertension, higher body mass index, and a dyslipidemic profile. HSI differed significantly between H. pylori positive and negative subjects (median 33.2, interquartile range (IQR) 30.0-36.2 for H. pylori-positive vs median 32.6, IQR 29.8-36.0 for negative participants, P = 0.005), but NAFLD-LSF did not [median -1.7, IQR -2.4 - -0.7 vs median -1.8, IQR -2.4-(-0.7), respectively, P = 0.122]. The percentage of people with NAFLD did not differ between infected and uninfected groups: HIS, 26.9% vs 27.1%, P = 0.173; NAFLD-LFS, 23.5% vs 23.1%, P = 0.778. H. pylori infection was not a risk factor, but C-reactive protein concentration and smoking were significant risk factors for NAFLD.CONCLUSION: H. pylori infection is not a risk factor for NAFLD as indicated by HSI or NAFLD-LFS. Prospective, large-scale studies involving liver biopsies should be considered.

Physical activity support or weight loss counseling for nonalcoholic fatty liver disease?

AIM: To determine the clinical effectiveness of intense psychological support to physical activity (PA) in nonalcoholic fatty liver disease (NAFLD), compared with cognitive-behavioral treatment (CBT).

Role of autophagy in the pathophysiology of nonalcoholic fatty liver disease:A controversial issue

Autophagy is a mechanism involved in cellular homeostasis under basal and stressed conditions delivering cytoplasmic content to the lysosomes for degradation to macronutrients.The potential role of autophagy in disease is increasingly recognised and investigated in the last decade.Nowadays it is commonly accepted that autophagy plays a role in the hepatic lipid metabolism.Hence,dysfunction of autophagy may be an underlying cause of non-alcoholic fatty liver disease.However,controversy of the exact role of autophagy in the lipid metabolism exists:some publications report a lipolytic function of autophagy,whereas others claim a lipogenic function.This review aims to give an update of the present knowledge on autophagy in the hepatic lipid metabolism,hepatic insulin resistance,steatohepatitis and hepatic fibrogenesis.

Skeletal muscle loss is associated with diabetes in middle-aged and older Chinese men without non-alcoholic fatty liver disease

BACKGROUND Skeletal muscle,a key insulin target organ,has been reported to be associated with diabetes mellitus(DM).Compared to non-diabetic patients,diabetic patients have decreased muscle mass and a higher prevalence of sarcopenia,and patients with sarcopenia may be at increased risk of developing diabetes.In individuals with nonalcoholic fatty liver disease(NAFLD),sarcopenia is associated with the severity of fibrosis and steatosis.Previous studies have demonstrated that NAFLD is strongly associated with DM and sarcopenia.AIM To determine the relationship between skeletal muscle mass and DM in Chinese middle-aged and elderly men,and whether the association is affected by NAFLD.METHODS Skeletal muscle mass was calculated as appendicular skeletal muscle mass(ASM)in kg/body weight×100%.Liver fat content(LFC)was measured using a quantitative ultrasound method.RESULTS As the ASM decreased,fasting blood glucose(FBG),2-h postprandial blood glucose(2hBG),and LFC increased in both genders,as did the prevalence of DM and NAFLD.Spearman analysis showed that the ASM was negatively correlated with the FBG,2hBG,and LFC.Stepwise logistic regression analysis showed that after adjustments,the ASM quartile was negatively associated with the presence of DM in males,but not in females.Subgroup analysis showed that the ASM quartiles remained negatively correlated with the presence of DM in the non-NAFLD population(including males and females),but no correlation was found between ASM quartiles and the presence of DM in the NAFLD population.When stratified by LFC quartiles,ASM was negatively correlated with the presence of DM in the first and second LFC quartiles in males.CONCLUSION Skeletal muscle mass loss was shown to be associated with the presence of DM in males,but not in females;NAFLD weakens this association.The results suggested that the stratified management of diabetes mellitus should be considered according to skeletal muscle mass and NAFLD.

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.

Hypolipidemic Activity of Olive Oil (Olea europaea) against High Fat Diet-Induced Nonalcoholic Fatty Liver Disease (NAFLD) in Mice

Aim: The aim of the present study is to access the effect of olive oil supplementation against high fat diet induced fatty liver disease in mice. Methods: Mice were divided into five groups: Group I (normal diet), Group II (high fat diet), Group III (olive oil), Group IV and V (High Fat Diet along with olive oil). All mice were fed for 16 weeks with weight measurements every 2 weeks and then sacrificed. Biochemical analysis of blood samples was done and mice livers were histologically examined. Results: Group II mice showed significant increase in body weight as compared with Group I (p < 0.05). Group IV and V mice were significantly (p < 0.05) reduced in body weight as compared with Group II. Olive oil groups had significantly decreased triglyceride and low density lipoprotein levels as compared with Group II whereas high density lipoprotein levels were significantly increased (p < 0.05). The liver enzymes were significantly increased in Group II as compared with other groups (p < 0.05). Liver histopathology revealed drastically increased lipid droplets in Group II mice as compared with Group IV & V. Conclusion: Olive oil causes weight reduction, decreases the serum triglycerides, normalizes the liver enzymes and significantly reduces the accumulation of fat in liver. Therefore, olive oil may represent a potential therapeutic alternative for NAFLD and other fatty diseases.

Effectiveness of exercise in hepatic fat mobilization in nonalcoholic fatty liver disease: Systematic review

AIM: To investigate the efficacy of exercise interventions on hepatic fat mobilization in non-alcoholic fatty liver disease(NAFLD) patients.METHODS: Ovid-Medline, Pub Med, EMBASE and Cochrane database were searched for randomized trials and prospective cohort studies in adults aged ≥ 18 which investigated the effects of at least 8 wk of exercise only or combination with diet on NAFLD from 2010 to 2016. The search terms used to identify articles, in which exercise was clearly described by type, duration, intensity and frequency were: "NASH", "NAFLD", "nonalcoholic steatohepatitis", "non-alcoholic fatty liver disease", "fat", "steatosis", "diet", "exercise", "MR spectroscopy" and "liver biopsy". NAFLD diagnosis, as well as the outcome measures, was confirmed by either hydrogen-magnetic resonance spectroscopy(H-MRS) or biopsy. Trials that included dietary interventions along with exercise were accepted if they met all criteria. RESULTS: Eight studies met selection criteria(6 with exercise only, 2 with diet and exercise with a total of 433 adult participants). Training interventions ranged between 8 and 48 wk in duration with a prescribed exercise frequency of 3 to 7 d per week, at intensities between 45% and 75% of VO2 peak. The most commonly used imaging modality was H-MRS and one study utilized biopsy. The effect of intervention on fat mobilization was 30.2% in the exercise only group and 49.8% in diet and exercise group. There was no difference between aerobic and resistance exercise intervention, although only one study compared thetwo interventions. The beneficial effects of exercise on intrahepatic triglyceride(IHTG) were seen even in the absence of significant weight loss. Although combining an exercise program with dietary interventions augmented the reduction in IHTG, as well as improved measures of glucose control and/or insulin sensitivity, exercise only significantly decreased hepatic lipid contents.CONCLUSION: Prescribed exercise in subjects with NAFLD reduces IHTG independent of dietary intervention. Diet and exercise was more effective than exercise alone in reducing IHTG.

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.

Pancreatic fat and β-cell function in overweight/obese children with nonalcoholic fatty liver disease

AIM: To analyze the associations of pancreatic fat with other fat depots and β-cell function in pediatric nonalcoholic fatty liver disease(NAFLD).METHODS: We examined 158 overweight/obese children and adolescents, 80 with NAFLD [hepatic fat fraction(HFF) ≥ 5%] and 78 without fatty liver. Visceral adipose tissue(VAT), pancreatic fat fraction(PFF) and HFF were determined by magnetic resonance imaging. Estimates of insulin sensitivity were calculated using the homeostasis model assessment of insulin resistance(HOMA-IR), defined by fasting insulin and fasting glucose and whole-body insulin sensitivity index(WBISI), based on mean values of insulin and glucose obtained from oral glucose tolerance test and the corresponding fasting values. Patients were considered to have prediabetes if they had either:(1) impaired fasting glucose, defined as a fasting glucose level ≥ 100 mg/d L to < 126 mg/d L;(2) impaired glucose tolerance, defined as a 2 h glucose concentration between ≥ 140 mg/d L and < 200 mg/d L; or(3) hemoglobin A1 c value of ≥ 5.7% to < 6.5%.RESULTS: PFF was significantly higher in NAFLD patients compared with subjects without liver involvement. PFF was significantly associated with HFF and VAT, as well as fasting insulin, C peptide, HOMA-IR, and WBISI. The association between PFF and HFF was no longer significant after adjusting for age, gender, Tanner stage, body mass index(BMI)-SD score, and VAT. In multiple regression analysis withWBISI or HOMA-IR as the dependent variables, against the covariates age, gender, Tanner stage, BMI-SD score, VAT, PFF, and HFF, the only variable significantly associated with WBISI(standardized coefficient B,-0.398; P = 0.001) as well as HOMA-IR(0.353; P = 0.003) was HFF. Children with prediabetes had higher PFF and HFF than those without. PFF and HFF were significantly associated with prediabetes after adjustment for clinical variables. When all fat depots where included in the same model, only HFF remained significantly associated with prediabetes(OR = 3.38; 95%CI: 1.10-10.4; P = 0.034).CONCLUSION: In overweight/obese children with NAFLD, pancreatic fat is increased compared with those without liver involvement. However, only liver fat is independently related to prediabetes.

Anthropometric indicators of visceral adiposity as predictors of non-alcoholic fatty liver disease: A review

The objective was to critically analyze studies that evaluated the predictive capacity of indicators of visceral adiposity in non-alcoholic fatty liver disease(NAFLD). The bibliographic research was carried out using the electronic database PubMed, LILACS and SciELO, references of selected articles. Although we found few studies, they have already used several indicators of visceral adiposity as waist circumference, waist-to-hip ratio, waist-to-height ratio, Lipid accumulation product, Body Shape Index, Body Roundness Index and most them were good predictors of NAFLD. Thus, the anthropometric indicators may contribute for the diagnosis of NAFLD in a simple, low-cost and noninvasive way, allowing early therapeutic measures to prevent the evolution to non-alcoholic steatohepatitis.

What is the role of adiponectin in obesity related non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries.Insulin resistance is a key factor in the pathogenesis of NAFLD,the latter being considered as the hepatic component of insulin resistance or obesity.Adiponectin is the most abundant adipose-specific adipokine.There is evidence that adiponectin decreases hepatic and systematic insulin resistance,and attenuates liver inflammation and fibrosis.Adiponectin generally predicts steatosis grade and the severity of NAFLD;however,to what extent this is a direct effect or related to the presence of more severe insulin resistance or obesity remains to be addressed.Although there is no proven pharmacotherapy for the treatment of NAFLD,recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications.In this adiponectin-focused review,the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are analyzed systematically.

Liver fat accumulation measured by high-speed T2-corrected multiecho magnetic resonance spectroscopy can predict risk of cholelithiasis

BACKGROUND Liver fat accumulation is associated with increased cholesterol synthesis and hypersecretion of biliary cholesterol,which may be related to the development of cholelithiasis.AIM To investigate whether liver fat accumulation measured by high-speed T2-corrected multi-echo magnetic resonance spectroscopy(MRS)is a risk factor for cholelithiasis.METHODS Forty patients with cholelithiasis and thirty-one healthy controls were retrospectively enrolled.The participants underwent high-speed T2-corrected multi-echo single-voxel MRS of the liver at a 3T MR scanner.The proton density fat fraction(PDFF)and R2 value were calculated.Serum parameters and waist circumference(WC)were recorded.Spearman’s correlation analysis was used to analyze the relationship between PDFF,R2,and WC values.Multivariate logistic regression analysis was carried out to determine the significant predictors of the risk of cholelithiasis.Receiver operating characteristic curve(ROC)analysis was used to evaluate the discriminative performance of significant predictors.RESULTS Patients with cholelithiasis had higher PDFF,R2,and WC values compared with healthy controls(5.8%±4.2%vs 3.3%±2.4%,P=0.001;50.4±24.8/s vs 38.3±8.8/s,P=0.034;85.3±9.0 cm vs 81.0±6.9 cm,P=0.030;respectively).Liver iron concentration extrapolated from R2 values was significantly higher in the cholelithiasis group(2.21±2.17 mg/g dry tissue vs 1.22±0.49 mg/g dry tissue,P=0.034)than in the healthy group.PDFF was positively correlated with WC(r=0.502,P<0.001)and R2(r=0.425,P<0.001).Multivariate logistic regression analysis showed that only PDFF was an independent risk factor for cholelithiasis(odds ratio=1.79,95%CI:1.22-2.62,P=0.003).ROC analysis showed that the area under the curve of PDFF was 0.723 for discriminating cholelithiasis from healthy controls,with a sensitivity of 55.0%and specificity of 83.9%when the cut-off value of PDFF was 4.4%.CONCLUSION PDFF derived from high speed T2-corrected multi-echo MRS can predict the risk of cholelithiasis.

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

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 increased abundance of Firmicutes and decreased abundance of Parabacteroides bacteria(P < 0.05). The RSUG group showed an increased abundance of Bacteroidetes and Sutterella bacteria, higher ratio of Bacteroidetes to Firmicutes, and a decreased abundance of Firmicutes(P < 0.05). The PRO group showed an increased abundance of Bacteroidetes, Prevotella, Oscillospira and Sutterella bacteria, and a decreased abundance of Firmicutes(P < 0.05). Compared with the FFAT group, the RFAT group had an increased abundance of Bacteroidetes, higher ratio of Bacteroidetes to Firmicutes, and decreased abundance of Firmicutes and Oscillospira bacteria(P < 0.05).CONCLUSION Compared with the high-protein diet, the NAFLDinducing effects of high-fat and high-sugar diets are independent from calories, and may be associated with changed intestinal microbiota.

Prolonged high-fat-diet feeding promotes non-alcoholic fatty liver disease and alters gut microbiota in mice

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has become an epidemic largely due to the worldwide increase in obesity. While lifestyle modifications and pharmacotherapies have been used to alleviate NAFLD, successful treatment options are limited. One of the main barriers to finding safe and effective drugs for long-term use in NAFLD is the fast initiation and progression of disease in the available preclinical models. Therefore, we are in need of preclinical models that (1) mimic the human manifestation of NAFLD and (2) have a longer progression time to allow for the design of superior treatments. AIM To characterize a model of prolonged high-fat diet (HFD) feeding for investigation of the long-term progression of NAFLD. METHODS In this study, we utilized prolonged HFD feeding to examine NAFLD features in C57BL/6 male mice. We fed mice with a HFD (60% fat, 20% protein, and 20% carbohydrate) for 80 wk to promote obesity (Old-HFD group, n = 18). A low-fat diet (LFD)(14% fat, 32% protein, and 54% carbohydrate) was administered for the same duration to age-matched mice (Old-LFD group, n = 15). An additional group of mice was maintained on the LFD (Young-LFD, n = 20) for a shorter duration (6 wk) to distinguish between age-dependent and age-independent effects. Liver, colon, adipose tissue, and feces were collected for histological and molecular assessments.RESULTS Prolonged HFD feeding led to obesity and insulin resistance. Histological analysis in the liver of HFD mice demonstrated steatosis, cell injury, portal and lobular inflammation and fibrosis. In addition, molecular analysis for markers of endoplasmic reticulum stress established that the liver tissue of HFD mice have increased phosphorylated Jnk and CHOP. Lastly, we evaluated the gut microbial composition of Old-LFD and Old-HFD. We observed that prolonged HFD feeding in mice increased the relative abundance of the Firmicutes phylum. At the genus level, we observed a significant increase in the abundance of Adercreutzia, Coprococcus, Dorea, and Ruminococcus and decreased relative abundance of Turicibacter and Anaeroplasma in HFD mice. CONCLUSION Overall, these data suggest that chronic HFD consumption in mice can mimic pathophysiological and some microbial events observed in NAFLD patients.

Freeze-dried Si-Ni-San powder can ameliorate high fat diet-induced non-alcoholic fatty liver disease

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a common chronic liver disease worldwide.However,to date,there is no ideal therapy for this disease.AIM To study the effects of Si-Ni-San freeze-dried powder on high fat diet-induced NAFLD in mice.METHODS Twenty-four male C57BL/6 mice were randomized into three groups of eight.The control group(CON)was allowed ad libitum access to a normal chow diet.The high fat diet group(FAT)and Si-Ni-San group(SNS)were allowed ad libitum access to a high fat diet.The SNS group was intragastrically administered Si-Ni-San freeze-dried powder(5.0 g/kg)once daily,and the CON and FAT groups were intragastrically administered distilled water.After 12 wk,body weight,liver index,visceral fat index,serum alanine aminotransferase(ALT),portal lipopoly-saccharide(LPS),liver tumor necrosis factor(TNF)-αand liver triglycerides were measured.Intestinal microbiota were analyzed using a 16S r DNA sequencing technique.RESULTS Compared with the FAT group,the SNS group exhibited decreased body weight,liver index,visceral fat index,serum ALT,portal LPS,liver TNF-αand liver triglycerides(P<0.05).Intestinal microbiota analysis showed that the SNS group had different bacterial composition and function compared with the FAT group.In particular,Oscillospira genus was a bacterial biomarker of SNS group samples.CONCLUSION The beneficial effects of Si-Ni-San freeze-dried powder on high fat diet-induced NAFLD in mice may be associated with its anti-inflammatory and changing intestinal microbiota effects.

mi R-192-5p regulates lipid synthesis in non-alcoholic fatty liver disease through SCD-1

AIM To evaluate the levels of mi R-192-5 p in non-alcoholic fatty liver disease(NAFLD) models and demonstrate the role of mi R-192-5 p in lipid accumulation. METHODS Thirty Sprague Dawley rats were randomly divided into three groups, which were given a standard diet, a high-fat diet(HFD), and an HFD with injection of liraglutide. At the end of 16 weeks, hepatic mi R-192-5 p and stearoyl-Co A desaturase 1(SCD-1) levels were measured. Mi R-192-5 p mimic and inhibitor and SCD-1 si RNA were transfected into Huh7 cells exposed to palmitic acid(PA). Lipid accumulation was evaluated by oil red O staining and triglyceride assays. Direct interaction was validated by dual-luciferase reporter gene assays.RESULTS The HFD rats showed a 0.46-fold decrease and a 3.5-fold increase in hepatic mi R-192-5 p and SCD-1 protein levels compared with controls, respectively, which could be reversed after disease remission by liraglutide injection(P < 0.01). The Huh7 cells exposed to PA also showed down-regulation and up-regulation of mi R-192-5 p and SCD-1 protein levels, respectively(P < 0.01). Transfection with mi R-192-5 p mimic and inhibitor in Huh7 cells induced dramatic repression and promotion of SCD-1 protein levels, respectively(P < 0.01). Luciferase activity was suppressed and enhanced by mi R-192-5 p mimic and inhibitor, respectively, in wild-type SCD-1(P < 0.01) but not in mutant SCD-1. Mi R-192-5 p overexpression reduced lipid accumulation significantly in PA-treated Huh7 cells, and SCD-1 si RNA transfection abrogated the lipid deposition aggravated by mi R-192-5 p inhibitor(P < 0.01).CONCLUSION This study demonstrates that mi R-192-5 p has a negative regulatory role in lipid synthesis, which is mediated through its direct regulation of SCD-1.

SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: A systematic review

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a common comorbidity with type 2 diabetes.The existing therapeutic options for NAFLD are not adequate.Hypocaloric diet and exercise is the cornerstone of therapy in NAFLD.Pioglitazone is the only drug recommended in diabetes patients with biopsy proven non-alcoholic steatohepatitis.The frequent coexistence of NAFLD and type 2 diabetes with their combined adverse health consequences and inadequate therapeutic options makes it necessary to search for newer alternatives.AIM To assess the effect of sodium glucose cotransporter-2(SGLT-2)inhibitors on liver enzymes in type 2 diabetes patients with NAFLD.METHODS We searched PubMed/MEDLINE,Cochrane library,Google scholar,and Clinicaltrials.gov for the relevant articles to be included in this systematic review.Human studies done in type 2 diabetes patients with NAFLD treated with SGLT-2 inhibitors for at least 12 wk were included.Data from eight studies(four randomised controlled trials and four observational studies)were extracted and a narrative synthesis was done.A total of 214 patients were treated with SGLT-2 inhibitors in these studies(94 in randomised controlled trials and 120 in observational studies).RESULTS The primary outcome measure was change in serum alanine aminotransferase level.Out of eight studies,seven studies showed a significant decrease in serum alanine aminotransferase level.Most of the studies revealed reduction in serum level of other liver enzymes like aspartate aminotransferase and gamma glutamyl transferase.Five studies that reported a change in hepatic fat exhibited a significant reduction in hepatic fat content in those treated with SGLT-2 inhibitors.Likewise,among the three studies that evaluated a change in indices of hepatic fibrosis,two studies revealed a significant improvement in liver fibrosis.Moreover,there was an improvement in obesity,insulin resistance,glycaemia,and lipid parameters in those subjects taking SGLT-2 inhibitors.The studies disclosed that about 17%(30/176)of the subjects taking SGLT-2 inhibitors developed adverse events and more than 40%(10/23)of them had genitourinary tract infections.CONCLUSION Based on low to moderate quality of evidence,SGLT-2 inhibitors improve the serum level of liver enzymes,decrease liver fat,and fibrosis with additional beneficial effects on various metabolic parameters in type 2 diabetes patients with NAFLD.

Effects of alkaline-electrolyzed and hydrogen-rich water,in a high-fat-diet nonalcoholic fatty liver disease mouse model

AIM To identify the effect of hydrogen-rich water(HRW) and electrolyzed-alkaline water(EAW) on high-fat-induced non-alcoholic fatty acid disease in mice.METHODS Mice were divided into four groups:(1) Regular diet(RD)/regular water(RW);(2) high-fat diet(HFD)/RW;(3) RD/EAW; and(4) HFD/EAW. Weight and body composition were measured. After twelve weeks, animals were sacrificed, and livers were processed for histology and reverse-transcriptase polymerase chain reaction. A similar experiment was performed using HRW to determine the influence and importance of molecular hydrogen(H2) in EAW. Finally, we compared the response of hepatocytes isolated from mice drinking HRW or RW to palmitate overload.RESULTS EAW had several properties important to the study:(1) pH = 11;(2) oxidation-reduction potential of-495 mV; and(3) H2 = 0.2 mg/L. However, in contrast to other studies, there were no differences between the groups drinking EAW or RW in either the RD or HFD groups. We hypothesized that the null result was due to low H2 concentrations. Therefore, we evaluated the effects of RW and low and high HRW concentrations(L-HRW = 0.3 mg H2/L and H-HRW = 0.8 mg H2/L, respectively) in mice fed an HFD. Compared to RW and L-HRW, H-HRW resulted in a lower increase in fat mass(46% vs 61%), an increase in lean body mass(42% vs 28%), and a decrease in hepatic lipid accumulation(P < 0.01). Lastly, exposure of hepatocytes isolated from mice drinking H-HRW to palmitate overload demonstrated a protective effect from H2 by reducing hepatocyte lipid accumulation in comparison to mice drinking regular water.CONCLUSION H2 is the therapeutic agent in electrolyzed-alkaline water and attenuates HFD-induced nonalcoholic fatty liver disease in mice.

达格列净对2型糖尿病病人肝脏脂肪含量及胱抑素C的影响

目的:比较使用达格列净+二甲双胍联合用药与单纯使用二甲双胍治疗对2型糖尿病病人肝脏脂肪含量(LFC)和胱抑素C(Cys C)水平的影响。方法:选取住院病人121例,按照治疗方案不同分为二甲双胍治疗组(甲组,n=51)和二甲双胍联合达格列净治疗组(乙组,n=70),所有病人均连续稳定使用上述治疗方案达半年以上,利用氢质子磁共振波谱法检测LFC,血清Cys C水平使用免疫比浊法进行检测,收集病人的一般人口学资料及实验室检测指标数据。分析不同实验室指标与LFC的关联,探讨不同治疗方式及其他实验指标对LFC和Cys C的影响。结果:2组病人的年龄、性别构成比、患病时长和体质量指数(BMI)的差异均无统计学意义(P>0.05);与甲组相比,乙组病人的LFC、血清Cys C水平、总胆固醇(TC)均明显降低(P<0.05~P<0.01),但三酰甘油(TG)和极低密度脂蛋白(VLDL)均升高(P<0.05);甲组的非酒精性脂肪肝(90.2%)比例高于乙组(30.0%)(P<0.01);相关分析结果发现,BMI、空腹血糖(FBG)和Cys C均与LFC存在关联(P<0.05~P<0.01)。以LFC为因变量,BMI、FBG、Cys C、病程、TC、TG和药物治疗作为自变量进行多元线性回归分析,发现与甲组相比,乙组可降低0.440个单位的LFC(P<0.01);同时以Cys C为因变量,BMI、FBG、LFC、病程、TC、TG和药物治疗作为自变量进行多元线性回归分析,与甲组相比,乙组联合用药能够降低0.689个单位的血清Cys C(P<0.01)。结论:二甲双胍联合达格列净能有效降低2型糖尿病病人LFC、血清Cys C水平,是LFC、血清Cys C的重要影响因素。