Influence of Gut Microbiota and its Metabolites on Progression of Metabolic Associated Fatty Liver Disease

Metabolic associated fatty liver disease(MAFLD)has become a prevalent chronic liver disease worldwide because of lifestyle and dietary changes.Gut microbiota and its metabolites have been shown to play a critical role in the pathogenesis of MAFLD.Understanding of the function of gut microbiota and its metabolites in MAFLD may help to elucidate pathological mechanisms,identify diagnostic markers,and develop drugs or probiotics for the treatment of MAFLD.Here we review the pathogenesis of MAFLD by gut microbiota and its metabolites and discuss the feasibility of treating MAFLD from the perspective of gut microbes.

Construction and validation of a severity prediction model for metabolic associated fatty liver disease

Objective:To analyze the independent risk factors for the occurrence of moderate-to-severe metabolic-associated fatty liver disease(MAFLD),to construct a prediction model for moderate-to-severe MAFLD,and to verify the validity of the model.Methods:In the first part,278 medical examiners who were diagnosed with MAFLD in Medical Examination Center at the Second Affiliated Hospital of Hainan University from January to May 2022 were taken as the study subjects(training set),and they were divided into mild MAFLD group(200)and moderate-severe MAFLD group(78)based on ultrasound results.Demographic data and laboratory indexes were collected,and risk factors were screened by univariate and multifactor analysis.In the second part,a dichotomous logistic regression equation was used to construct a prediction model for moderate-to-severe MAFLD,and the model was visualized in a line graph.In the third part,the MAFLD population(200 people in the external validation set)from our physical examination center from November to December 2022 was collected as the moderate-to-severe MAFLD prediction model,and the risk factors in both groups were compared.The receiver operating characteristic(ROC)curves,calibration curves,and clinical applicability of the model were plotted to represent model discrimination for internal and external validation.Results:The risk factors of moderate-to-severe MAFLD were fasting glucose(FPG),blood uric acid(UA),triglycerides(TG),triglyceride glucose index(TyG),total cholesterol(CHOL),and high-density lipoprotein(HDL-C).UA[OR=1.021,95%CI(1.015,1.027),P<0.001]and FPG[OR=1.575,95%CI(1.158,2.143),P=0.004]were independent risk factors for people with moderate to severe MAFLD.The visualized line graph model showed that UA was the factor contributing more to the risk of moderate to severe MAFLD in this model.The ROC curves showed AUC values of 0.8701,0.8686 and 0.7991 for the training set,internal validation set and external validation set,respectively.The curves almost coincided with the reference line after calibration of the model calibration degree with P>0.05 in Hosmer-Lemeshow test.The decision curve analysis(DCA)plotted by the clinical applicability of the model was higher than the two extreme curves,predicting that patients with moderate to severe MAFLD would benefit from the prediction model.Conclusion:The prediction model constructed by combining FPG with UA has higher accuracy and better clinical applicability,and can be used for clinical diagnosis.

Clinic-pathological features of metabolic associated fatty liver disease with hepatitis B virus infection

BACKGROUND Metabolic associated fatty liver disease(MAFLD)is a novel concept proposed in 2020.AIM To compare the characteristics of MAFLD and MAFLD with hepatitis B virus(HBV)infection.METHODS Patients with histopathologically proven MAFLD from a single medical center were included.Patients were divided into MAFLD group(without HBV infection)and HBV-MAFLD group(with HBV infection).Propensity score matching was utilized to balance the baseline characteristics between two groups.RESULTS A total of 417 cases with MAFLD were included,359(86.1%)of whom were infected with HBV.There were significantly more males in the HBV-MAFLD group than in the MAFLD group(P<0.05).After propensity score matching,58 pairs were successfully matched with no significant differences found in gender,age,body mass index,lipid levels,liver enzymes,and the other metabolic associated comorbidities between the two groups(P>0.05).The rank sum test results showed that the degree of liver steatosis in the MAFLD group was more severe than that in the HBV-MAFLD group,while the degree of inflammation and fibrosis in the liver was less severe(P<0.05).In multivariate analysis,HBV infection was associated with significantly lower grade of hepatic steatosis[odds ratio(OR)=0.088,95%confidence interval(CI):0.027-0.291]but higher inflammation level(OR=4.059,95%CI:1.403-11.742)and fibrosis level(OR=3.016,95%CI:1.087-8.370)after adjusting for age,gender,and other metabolic parameters.CONCLUSION HBV infection is associated with similar metabolic risks,lower steatosis grade,higher inflammation,and fibrosis grade in MAFLD patients.

Validation of conventional non-invasive fibrosis scoring systems in patients with metabolic associated fatty liver disease

BACKGROUND Non-invasive fibrosis scores are not yet validated in the newly defined metabolic associated fatty liver disease(MAFLD).AIM To evaluate the diagnostic performance of four non-invasive scores including aspartate aminotransferase to platelet ratio index(APRI),fibrosis-4 index(FIB-4),body mass index,aspartate aminotransferase/alanine aminotransferase ratio,diabetes score(BARD),and nonalcoholic fatty liver disease fibrosis score(NFS)in patients with MAFLD.METHODS Consecutive patients with histologically confirmed MAFLD were included.The discrimination ability of different non-invasive scores was compared.RESULTS A total of 417 patients were included;156(37.4%)of them had advanced fibrosis(Metavir≥F3).The area under receiver operating characteristic curve of FIB-4,NFS,APRI,and BARD for predicting advanced fibrosis was 0.736,0.724,0.671,and 0.609,respectively.The area under receiver operating characteristic curve of FIB-4 and NFS was similar(P=0.523),while the difference between FIB-4 and APRI(P=0.001)and FIB-4 and BARD(P<0.001)was statistically significant.The best thresholds of FIB-4,NFS,APRI,and BARD for diagnosis of advanced fibrosis in MAFLD were 1.05,-2.1,0.42,and 2.A subgroup analysis showed that FIB-4,APRI,and NFS performed worse in the pure MAFLD group than in the hepatitis B virus-MAFLD group.CONCLUSION APRI and BARD scores do not perform well in MAFLD.The FIB-4 and NFS could be more useful,but a new threshold is needed.Novel non-invasive scoring systems for fibrosis are required for MAFLD.

Metabolic associated fatty liver disease:Addressing a new era in liver transplantation

Metabolic associated fatty liver disease(MAFLD),previously termed nonalcoholic fatty liver disease,is the leading global cause of liver disease and is fast becoming the most common indication for liver transplantation.The recent change in nomenclature to MAFLD refocuses the conceptualisation of this disease entity to its metabolic underpinnings and may help to spur a paradigm shift in the approach to its management,including in the setting of liver transplantation.Patients with MAFLD present significant challenges in the pre-,peri-and posttransplant settings,largely due to the presence of medical comorbidities that include obesity,metabolic syndrome and cardiovascular risk factors.As the community prevalence of MAFLD increases concurrently with the obesity epidemic,donor liver steatosis is also a current and future concern.This review outlines current epidemiology,nomenclature,management issues and outcomes of liver transplantation in patients with MAFLD.

Redefining non-alcoholic fatty liver disease to metabolic associated fatty liver disease: Is this plausible?

Recently,a single letter change has taken the world by storm.A group of experts have developed a consensus to upgrade the term non-alcoholic fatty liver disease(NAFLD)to metabolic associated fatty liver disease(MAFLD),suggesting that MAFLD would more accurately reflect not only the disease pathogenesis but would also help in patient stratification for management with NAFLD.However,the difference of opinion exists,which has made the NAFLD vs MAFLD debate the current talk of the town.This review will focus on the plausibility and implications of redefining NAFLD as MAFLD.

Comments on validation of conventional non-invasive fibrosis scoring systems in patients with metabolic associated fatty liver disease

To evaluate and predict liver fibrosis in patients with nonalcoholic fatty liver disease(NAFLD),several non-invasive scoring systems were built and widely used in the progress of diagnosis and treatment,which showed great diagnostic efficiency,such as aspartate aminotransferase to platelet ratio index,fibrosis-4 index,body mass index,aspartate aminotransferase to alanine aminotransferase ratio,diabetes score and NAFLD fibrosis score.Since the new concept of metabolic associated fatty liver disease(MAFLD)was proposed,the clinical application value of the non-invasive scoring systems mentioned above has not been assessed in MAFLD.The evaluation of the diagnostic performance of these non-invasive scoring systems will provide references for clinicians in the diagnosis of MAFLD.

Metabolic dysfunction-associated fatty liver disease and low muscle strength: A comment

The diagnosis of non-alcoholic fatty liver disease(NAFLD)and metabolic dysfunction-associated fatty liver disease only on the basis of laboratory parameter score such as Hepatic Steatosis Index which includes liver enzymes,gender,basal metabolic index,and presence of diabetic mellitus is not sufficient to exclude other causes of deranged liver enzymes especially medications and autoimmune related liver diseases.As the guideline suggests ultrasound is the preferred first-line diagnostic procedure for imaging of NAFLD,as it provides additional diagnostic information and the combination of biomarkers/scores and transient elastography might confer additional diagnostic accuracy and evident from previous similar studies too.

Interplay between metabolic dysfunction-associated fatty liver disease and renal function: An intriguing pediatric perspective

Over recent years,the nomenclature of non-alcoholic fatty liver disease has undergone significant changes.Indeed,in 2020,an expert consensus panel proposed the term“Metabolic(dysfunction)associated fatty liver disease”(MAFLD)to underscore the close association of fatty liver with metabolic abnormalities,thereby highlighting the cardiometabolic risks(such as metabolic syndrome,type 2 diabetes,insulin resistance,and cardiovascular disease)faced by these patients since childhood.More recently,this term has been further replaced with metabolic associated steatotic liver disease.It is worth noting that emerging evidence not only supports a close and independent association of MAFLD with chronic kidney disease in adults but also indicates its interplay with metabolic impairments.However,comparable pediatric data remain limited.Given the progressive and chronic nature of both diseases and their prognostic cardiometabolic implications,this editorial aims to provide a pediatric perspective on the intriguing relationship between MAFLD and renal function in childhood.

Comparison between metabolic-associated fatty liver disease and nonalcoholic fatty liver disease:From nomenclature to clinical outcomes

As a result of the obesity epidemic,Nonalcoholic fatty liver disease(NAFLD)and its complications have increased among millions of people.Consequently,a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis;metabolic-associated fatty liver disease(MAFLD).This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD.This article discusses the rationale behind the nomenclature change,the main differences,and its clinical implications.

Implications of metabolic dysfunction associated fatty liver disease in COVID-19

Metabolic associated fatty liver disorder(MAFLD)characterizes the contributing etiologies(i.e.,type 2 diabetes mellitus,metabolic syndrome,overweight)of individuals with fatty liver disease that affects 1/3rd of the world population.In 2020,the coronavirus disease 2019(COVID-19)crisis was unprecedented,and people with different comorbidities became more susceptible to the infection caused by severe acute respiratory syndrome coronavirus 2.MAFLD patients are frequently obese with added metabolic menace like diabetes,hypertension,and dyslipidemia leading to greater jeopardy of COVID-19.MAFLD patients are 4 to 6-fold more prone towards infections.COVID-19 induces liver injury with elevated levels of aspartate aminotransferase and alanine aminotransferase and insignificantly elevated bilirubin.Hence,MAFLD in COVID-19 patients worsens the condition significantly.The evidence highlighting the interaction between MAFLD and altered liver functioning in COVID-19 suggested that COVID-19 patients with pre-existing MAFLD are at greater risk of morbidity or intensive care unit admission.Direct hepatic injury,enhanced levels of inflammatory cytokines,declined hepatic mitochondrial activity,and compromised immunity are considered as some underlying mechanisms.The main focus of this review is to discuss the implications of metabolic dysfunction associated with fatty liver disease in COVID-19 patients.The review systematically analyzes the effect of striking two worldwide pandemics(MAFLD and COVID-19)together in the present era.

Quantitative assessment of self-management in patients with nonalcoholic fatty liver disease: An unmet clinical need

In this editorial we comment on the article titled“Establishment and validation of an adherence prediction system for lifestyle interventions in non-alcoholic fatty liver disease”by Zeng et al published in a recent issue of the World Journal of Gastroenterology.Non-alcoholic fatty liver disease(NAFLD)represents one of the current challenges in hepatology and public health,due to its continuous growing prevalence and the rising incidence of NAFLD-related fibrosis,non-alcoholic steatohepatitis and cirrhosis.The only effective therapeutic strategy for this dis-ease is represented by encouraging patients to improve their lifestyle through the modification of dietary intake and increased physical exercise,but the effective application of such modifications is often limited by various factors such as lack of information,psychological barriers or poor social support.While poor adherence to a healthy lifestyle can be decisive in determining the clinical outcome,in daily practice there is a lack of quantitative instruments aimed at identifying patients with the lowest adherence to lifestyle changes and higher risk of disease progre-ssion in the course of follow-up.In this article,Zeng et al propose a quantitative scale to assess the grade of adherence of patients with NAFLD to hea-lthy lifestyle intervention,called the Exercise and Diet Adherence Scale(EDAS).This scale,consisting of 33 items divided into 6 dimensions which relates to six subjective aspects in the self-management of NAFLD,has shown a good correlation with the identification of the sub-cohort of patients with the highest reduction in caloric intake,increase in physical exercise,probability of a reduction in liver stiffness measurement and alanine aminotransferase levels.The cor-relation among clinical outcomes and specific dimensions of this scale also highlights the pivotal role of a good and confidential doctor-patient relationship and of an effective communication.There is an urgent need for practical and effective instruments to assess the grade of self-management of NAFLD patients,together with the development of multidisciplinary teams with the aim of applying structured behavioral interventions.

Cardiovascular and renal burdens of metabolic associated fatty liver disease from serial US national surveys, 1999–2016

Background:Non-communicable chronic diseases have become the leading causes of disease burden worldwide.The trends and burden of“metabolic associated fatty liver disease”(MAFLD)are unknown.We aimed to investigate the cardiovascular and renal burdens in adults with MAFLD and non-alcoholic fatty liver disease(NAFLD).Methods:Nationally representative data were analyzed including data from 19,617 non-pregnant adults aged≥20years from the cross-sectional US National Health and Nutrition Examination Survey periods,1999 to 2002,2003 to 2006,2007 to 2010,and 2011 to 2016.MAFLD was defined by the presence of hepatic steatosis plus general overweight/obesity,type 2 diabetes mellitus,or evidence of metabolic dysregulation.Results:The prevalence of MAFLD increased from 28.4%(95% confidence interval 26.3–30.6)in 1999 to 2002 to 35.8%(33.8–37.9)in 2011 to 2016.In 2011 to 2016,among adults with MAFLD,49.0%(45.8–52.2)had hypertension,57.8%(55.2–60.4)had dyslipidemia,26.4%(23.9–28.9)had diabetes mellitus,88.7%(87.0–80.1)had central obesity,and 18.5%(16.3–20.8)were current smokers.The 10-year cardiovascular risk ranged from 10.5%to 13.1%;19.7%(17.6–21.9)had chronic kidney diseases(CKDs).Throughthe fourperiods,adults withMAFLD showedanincrease in obesity;increase intreatment to lower bloodpressure(BP),lipids,and hemoglobin A1c;and increase in goal achievements for BP and lipids but not in goal achievement for glycemic control in diabetes mellitus.Patients showed a decreasing 10-year cardiovascular risk over time but no change in the prevalence of CKDs,myocardial infarction,or stroke.Generally,although participants with NAFLD and those with MAFLD had a comparable prevalence of cardiovascular disease and CKD,the prevalence of MAFLD was significantly higher than that of NAFLD.Conclusions:From 1999 to 2016,cardiovascular and renal risks and diseases have become highly prevalent in adults with MAFLD.The absolute cardiorenal burden may be greater for MAFLD than for NAFLD.These data call for early identification and risk stratification of MAFLD and close collaboration between endocrinologists and hepatologists.

Network pharmacology and molecular docking study on the effect of Kaempferol in treatment of metabolic associated fatty liver disease

OBJECTIVE: To study therapeutic effect of kaempferol on metabolic associated fatty liver disease(MAFLD) by network pharmacology and molecular docking combined with cell experiments. METHODS: First, use the Swiss Target Prediction database to predict the targets of kaempferol, and collect the targets of MAFLD through the Disgenet database and the Gene Cards database. Then, the common target of kaempferol and MAFLD was enriched and analyzed by the Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes, and the protein-protein interaction(PPI) network was constructed through the string database to obtain the key targets, and carry out molecular docking of key targets with kaempferol;In cell experiment, oleic acid induced steatosis in Hep G2 cells, which was intervened by kaempferol, the level of triglyceride(TG) was detected, the lipid deposition was observed by oil red O staining, and the protein expression was detected by Western blot. RESULTS: The results showed that there are 33 common targets for kaempferol and MAFLD. The biological process of GO is related to the regulation of protein kinase B, cell apoptosis, inflammatory factors, lipoxygenase, etc. Its action pathway is related to the phosphatidylinositol-3-kinase and protein kinase B(PI3K-AKT) signaling pathway, hypoxia-inducible factor 1 signaling pathway, forkhead box protein O signaling pathway, AMP-activated protein kinase signaling pathway, tumor necrosis factor signaling pathway, etc., the key targets are protein kinase B(AKT1), prostaglandin G/H synthase 2, matrix metalloproteinase-9, epidermal growth factor receptor, and the molecular docking of kaempferol with the four key targets shows good binding properties. Cell experiments show that kaempferol can reduce cell TG levels, reduce lipid deposition, increase the expression of PI3K, AKT, and beclin-1, and reduce the expression of caspase-3 and nuclear factor-kappa B. Kaempferol can treat MAFLD by regulating the PI3K-AKT signaling pathway to regulate cell autophagy, apoptosis, and inflammation. CONCLUSIONS: This study shows that kaempferol can regulate lipid metabolism, reduce apoptosis, regulate inflammation and autophagy in the fatty liver cell model. It reveals the therapeutic mechanism of kaempferol on MAFLD and provides a natural product candidate for the treatment of MAFLD.

Metabolic dysfunction is associated with steatosis but no other histologic features in nonalcoholic fatty liver disease

BACKGROUND Recently,nonalcoholic fatty liver disease(NAFLD)has been renamed metabolicassociated fatty liver disease(MAFLD).Based on the definition for MAFLD,a group of non-obese and metabolically healthy individuals with fatty liver are excluded from the newly proposed nomenclature.AIM To analyze the histologic features in the MAFLD and non-MAFLD subgroups of NAFLD.METHODS Eighty-three patients with biopsy-proven NAFLD were separated into MAFLD and non-MAFLD groups.The diagnosis of MAFLD was established as hepatic steatosis along with obesity/diabetes or evidence of metabolic dysfunction.The histologic features were compared according to different metabolic disorders and liver enzyme levels.RESULTS MAFLD individuals had a higher NAFLD activity score(P=0.002)and higher severity of hepatic steatosis(42.6%Grade 1,42.6%Grade 2,and 14.8%Grade 3 in MAFLD;81.8%Grade 1,13.6%Grade 2,and 4.5%Grade 3 in non-MAFLD;P=0.007)than the non-MAFLD group.Lobular and portal inflammation,hepatic ballooning,fibrosis grade,and the presence of nonalcoholic steatohepatitis(NASH)and significant fibrosis were comparable between the two groups.The higher the liver enzyme levels,the more severe the grades of hepatic steatosis(75.0%Grade 1 and 25.0%Grade 2 in normal liver function;56.6%Grade 1,39.6%Grade 2,and 3.8%Grade 3 in increased liver enzyme levels;27.8%Grade 1,27.8%Grade 2,and 44.4%Grade 3 in liver injury;P<0.001).Patients with liver injury(alanine aminotransferase>3×upper limit of normal)presented a higher severity of hepatocellular ballooning(P=0.021).Moreover,the grade of steatosis correlated significantly with hepatocellular ballooning degree(r=0.338,P=0.002)and the presence of NASH(r=0.466,P<0.001).CONCLUSION Metabolic dysfunction is associated with hepatic steatosis but no other histologic features in NAFLD.Further research is needed to assess the dynamic histologic characteristics in NAFLD based on the presence or absence of metabolic disorders.

Comprehensive Understanding of Immune Cells in The Pathogenesis of Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease,defined by several phases,ranging from benign fat accumulation to non-alcoholic steatohepatitis(NASH),which can lead to liver cancer and cirrhosis.Although NAFLD is a disease of disordered metabolism,it also involves several immune cell-mediated inflammatory processes,either promoting and/or suppressing hepatocyte inflammation through the secretion of pro-inflammatory and/or anti-inflammatory factors to influence the NAFLD process.However,the underlying disease mechanism and the role of immune cells in NAFLD are still under investigation,leaving many open-ended questions.In this review,we presented the recent concepts about the interplay of immune cells in the onset and pathogenesis of NAFLD.We also highlighted the specific non-immune cells exhibiting immunological properties of therapeutic significance in NAFLD.We hope that this review will help guide the development of future NAFLD therapeutics.

Metabolic-associated fatty liver disease is associated with low muscle mass and strength in patients with chronic hepatitis B

BACKGROUND Although the prognostic relevance of sarcopenia has been increasingly recognised in the context of liver disease,there is a paucity of data evaluating body composition in patients with chronic hepatitis B(CHB).Beyond virus-related factors,nutritional and metabolic aspects can be associated with skeletal muscle abnormalities in these patients and should not be disregarded.AIM To evaluate the association between components of sarcopenia and demographic,clinical,lifestyle,nutritional,and biochemical variables in CHB patients.METHODS Dual-energy X-ray absorptiometry(DXA)was used to assess muscle mass by quantifying appendicular lean mass(ALM)adjusted for body mass index(ALMBMI).Muscle function was evaluated by hand grip strength(HGS)and the timed up and go test.Metabolic-associated fatty liver disease(MAFLD)was defined according to the criteria proposed by an international expert panel.A body shape index and the International Physical Activity Questionnaire were used to assess central obesity and physical activity level,respectively.RESULTS This cross-sectional study included 105 CHB outpatients followed at the tertiary care ambulatory centre(mean age,48.5±12.0 years;58.1%males;76.2%without cirrhosis;23.8%with compensated cirrhosis).The DXA-derived fat mass percentage was inversely correlated with the ALMBMI(r=-0.87)and HGS(r=-0.63).In the multivariable analysis,MAFLD,sedentarism and central obesity were positively and independently associated with low ALMBMI.MAFLD and central obesity were independently associated with low HGS.CONCLUSION MAFLD and central obesity were associated with low muscle mass and strength in patients with chronic hepatitis B,independent of the liver disease stage.

Intestinal microbiota in the treatment of metabolically associated fatty liver disease

Metabolically associated fatty liver disease (MAFLD) is a common cause ofchronic liver disease, the hepatic manifestation of metabolic syndrome. Despitethe increasing incidence of MAFLD, no effective treatment is available. Recentresearch indicates a link between the intestinal microbiota and liver diseases suchas MAFLD. The composition and characteristics of the intestinal microbiota andtherapeutic perspectives of MAFLD are reviewed in the current study. Animbalance in the intestinal microbiota increases intestinal permeability andexposure of the liver to adipokines. Furthermore, we focused on reviewing thelatest "gut-liver axis" targeted therapy.

Semaglutide might be a key for breaking the vicious cycle of metabolically associated fatty liver disease spectrum?

Metabolically associated fatty liver disease(MAFLD)is a liver manifestation of metabolic syndrome potentially related to unfavorable hepatic and extrahepatic outcomes and progression to cirrhosis.Up to date,there are no approved pharmacotherapies for the treatment of MAFLD,so management focused on lifestyle interventions to encourage weight loss,and treatment of coexisting conditions is the only available option.Unfortunately,the aforementioned is often not potent enough to offer reversal or slow down hepatic inflammation and fibrosis.Glucagon-like peptide-1 receptor agonists have a favorable effect on glycemic management and weight loss of patients with type 2 diabetes mellitus and recently published data suggest their potential in MAFLD treatment.In addition,some of the agents have proven cardiovascular and renal benefits in dedicated cardiovascular outcome trials,making them an interesting therapeutic option.In this opinion review,we discuss the role of semaglutide in MAFLD.

Brain-gut-liver interactions across the spectrum of insulin resistance in metabolic fatty liver disease

Metabolic associated fatty liver disease(MAFLD),formerly named“nonalcoholic fatty liver disease”occurs in about one-third of the general population of developed countries worldwide and behaves as a major morbidity and mortality risk factor for major causes of death,such as cardio-vascular,digestive,metabolic,neoplastic and neuro-degenerative diseases.However,progression of MAFLD and its associated systemic complications occur almost invariably in patients who experience the additional burden of intrahepatic and/or systemic inflammation,which acts as disease accelerator.Our review is focused on the new knowledge about the brain-gut-liver axis in the context of metabolic dysregulations associated with fatty liver,where insulin resistance has been assumed to play an important role.Special emphasis has been given to digital imaging studies and in particular to positron emission tomography,as it represents a unique opportunity for the noninvasive in vivo study of tissue metabolism.An exhaustive revision of targeted animal models is also provided in order to clarify what the available preclinical evidence suggests for the causal interactions between fatty liver,dysregulated endogenous glucose production and insulin resistance.