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Background and Aims: Individuals with steatotic liver disease (SLD) are at high cardiovascular disease (CVD) risk, but approaches to characterise and mitigate this risk are limited. By investigating relations, and shared metabolic pathways, of hepatic steatosis/fibrosis and cardiorespiratory fitness (CRF), we sought to identify new avenues for CVD risk reduction in SLD., Methods: In Framingham Heart Study (FHS) participants (N = 2722, age 54 ± 9 years, 53% women), vibration-controlled transient elastography (VCTE) was performed between 2016-2019 to assess hepatic steatosis (continuous attenuation parameter [CAP]) and fibrosis (liver fibrosis measure [LSM]). Concurrently, participants underwent maximum effort cardiopulmonary exercise testing (CPET), and metabolomic profiling (201 circulating metabolites) was performed in a subsample (N = 1268)., Results: Mean BMI was 28.0 ± 5.3, 27% had hepatic steatosis, 7.6% had fibrosis, and peak oxygen uptake (VO 2 ) was 26.2 ± 6.8 mL/kg/min in men and 20.7 ± 6.0 mL/kg/min in women (95% predicted overall). In linear models adjusted for cardiometabolic risk factors, greater CAP and LSM were associated with lower peak VO 2 (p ≤ 0.002 for all), and the CAP association remained significant after BMI adjustment (p < 0.0001). We observed shared metabolic architecture of CAP, LSM, and peak VO 2 , with metabolites mediating up to 35% (for CAP) and 74% (for LSM) of the association with peak VO 2 . Metabolite mediators included amino acids and derivatives implicated in cardiometabolic risk and both protective and deleterious lipid species., Conclusions: Hepatic steatosis and fibrosis are associated with CRF impairment in the community, and these relations are partly mediated by pathways of altered lipid metabolism and general cardiometabolic risk., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Heart failure with preserved ejection fraction (HFpEF) currently accounts for more than half of patients with HF, with limited approved evidence-based therapies. HFpEF is a complex multifactorial disease associated with hypertension, obesity, diabetes, and renal dysfunction. In addition to our limited understanding of HFpEF pathophysiology, the development of new therapies is partially hindered by the existing translationally relevant preclinical HFpEF models., Methods and Results: Here, we report the development of a novel 2-hit HFpEF male mouse model through adding hypertensive stress from the activation of the renin-angiotensin-aldosterone system with adeno-associated viral-renin (AAV-renin), to the metabolic syndrome nonalcoholic steatohepatitis (MSNASH, formerly FATZO) mouse (MSNASH+AAV-renin). To further demonstrate model translatability, MSNASH+AAV-renin mice were then treated with approved HFpEF therapies sacubitril/valsartan or a combination of sacubitril/valsartan and empagliflozin. We found that the MSNASH+AAV-renin mouse model demonstrates clinically relevant features of human HFpEF, including preserved ejection fraction, cardiac hypertrophy, left atrial enlargement, diastolic dysfunction, elevated natriuretic peptides, inflammation, and low exercise capacity. We also demonstrate that treatment with approved HFpEF therapies sacubitril/valsartan and the combination of sacubitril/valsartan with empagliflozin improves the cardiac phenotypes of HFpEF in this model., Conclusions: The MSNASH+AAV-renin model faithfully represents a severe cardiometabolic HFpEF phenogroup that can be used as a new tool for HFpEF preclinical research and drug discovery.

Background and Aims: Exercise is recommended for the management of metabolic dysfunction-associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training., Methods: We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12-20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI-measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness., Results: Eighty-eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m 2 . Following the intervention, exercise had ~5-fold (OR [95%CI]: 4.86 [1.72, 13.8], p = .002) greater odds of ≥30% relative reduction in MRI-measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (V̇O 2 peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight)., Conclusion: Exercise training led to clinically meaningful improvements in surrogate serum- and imaging-based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight-neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Aim: To analyse the association between serum bile acid (BA) profile and heart failure (HF) with preserved ejection fraction (HFpEF) in patients with metabolic dysfunction-associated fatty liver disease (MAFLD)., Methods: We enrolled 163 individuals with biopsy-proven MAFLD undergoing transthoracic echocardiography for any indication. HFpEF was defined as left ventricular ejection fraction >50% with at least one echocardiographic feature of HF (left ventricular diastolic dysfunction, abnormal left atrial size) and at least one HF sign or symptom. Serum levels of 38 BAs were analysed using ultra-performance liquid chromatography coupled with tandem mass spectrometry., Results: Among the 163 patients enrolled (mean age 47.0 ± 12.8 years, 39.3% female), 52 (31.9%) and 43 (26.4%) met the HFpEF and pre-HFpEF criteria, and 38 serum BAs were detected. Serum ursodeoxycholic acid (UDCA) and hyocholic acid (HCA) species were lower in patients with HFpEF and achieved statistical significance after correction for multiple comparisons. Furthermore, decreases in glycoursodeoxycholic acid and tauroursodeoxycholic acid were associated with HF status., Conclusions: In this exploratory study, specific UDCA and HCA species were associated with HFpEF status in adults with biopsy-confirmed MAFLD., (© 2024 John Wiley & Sons Ltd.)

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD, 2020 diagnostic criteria) and glomerular hyperfiltration share common risk factors, including obesity, insulin resistance, impaired glucose tolerance, diabetes, dyslipidemia, and hypertension., Aims: To assess the prevalence of MAFLD and its association with glomerular hyperfiltration and age-related worsening of kidney function in subjects with normoglycemia, prediabetes and type 2 diabetes mellitus (T2DM)., Methods: We analysed data recorded during occupational health visits of 125,070 Spanish civil servants aged 18-65 years with a de-indexed glomerular filtration rate (GFR) estimated with the chronic-kidney-disease-epidemiological (CKD-EPI) equation (estimated glomerular filtration rate [eGFR]) ≥60 mL/min. Subjects were categorised according to fasting plasma glucose levels <100 mg/dL (normoglycemia), ≥100 and ≤ 125 mg/dL (prediabetes), or ≥126 mg/dL and/or antidiabetic treatment (T2DM). The association between MAFLD and glomerular hyperfiltration, defined as a de-indexed eGFR above the age- and gender-specific 95th percentile, was assessed by multivariable logistic regression., Results: In the whole study group, MAFLD prevalence averaged 19.3%. The prevalence progressively increased from 14.7% to 33.2% and to 48.9% in subjects with normoglycemia, prediabetes and T2DM, respectively (p < 0.001 for trend). Adjusted odds ratio (95% CI) for the association between MAFLD and hyperfiltration was 9.06 (8.53-9.62) in the study group considered as a whole, and 8.60 (8.03-9.21), 9.52 (8.11-11.18) and 8.31 (6.70-10.30) in subjects with normoglycemia, prediabetes and T2DM considered separately. In stratified analyses, MAFLD amplified age-dependent eGFR decline in all groups (p < 0.001)., Conclusions: MAFLD prevalence increases across the glycaemic spectrum. MAFLD is significantly associated with hyperfiltration and amplifies the age-related eGFR decline., (© 2024 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Background The patients with nonalcoholic fatty liver disease demonstrate an increased cardiovascular risk. The adverse influence of liver abnormalities on cardiac function are among many postulated mechanisms behind this association. The aim of the study was to evaluate cardiac morphology and function in patients with morbid obesity referred for bariatric surgery with liver biopsy. Methods and Results We evaluated with echocardiography 171 consecutive patients without known cardiac disease (median age 42 [interquartile range, 37-48] years, median body mass index 43.7 [interquartile range, 41.0-47.5], 67% female patients. Based on the liver biopsy results, there were 44 patients with nonalcoholic steatohepatitis (NASH), 69 patients with isolated steatosis, and 58 patients without steatosis. Patients with NASH demonstrated signs of left ventricular concentric remodeling and hyperdynamic circulation, including indexed left ventricular end-diastolic diameter [cm/m 2 ]: NASH 1.87 [0.22]; isolated steatosis 2.03 [0.33]; without steatosis 2.01 [0.19], P =0.001; relative wall thickness: NASH 0.49±0.05, isolated steatosis 0.47±0.06, without steatosis 0.46±0.06, P =0.011; cardiac index [L/m 2 ]: NASH 3.05±0.54, isolated steatosis 2.80±0.44, without steatosis 2.79±0.50, P =0.013. After adjustment for sex, age, blood pressure, and heart rate, most of the measures of the left ventricular systolic and diastolic function, left atrial size, right ventricular function, and right ventricular size did not differ between groups. Conclusions In a group of patients with extreme obesity, NASH was associated with left ventricular concentric remodeling and hyperdynamic circulation. Increased cardiac output in NASH may represent an additional risk factor for incident cardiovascular events in this population.

Objective: We investigated the protective effects of pyridoxamine against metabolic and microcirculatory complications in nonalcoholic fatty liver disease., Methods: Nonalcoholic fatty liver disease was established by a high-fat diet administration over 28 weeks. Pyridoxamine was administered between weeks 20 and 28. The recruitment of leukocytes and the number of vitamin A-positive hepatic stellate cells were examined by in vivo microscopy. Laser speckle contrast imaging was used to evaluate microcirculatory hepatic perfusion. Thiobarbituric acid reactive substances measurement and RT-PCR were used for oxidative stress and inflammatory parameters. advanced glycation end products were evaluated by fluorescence spectroscopy., Results: The increase in body, liver, and fat weights, together with steatosis and impairment in glucose metabolism observed in the nonalcoholic fatty liver disease group were attenuated by pyridoxamine treatment. Regarding the hepatic microcirculatory parameters, rats with high-fat diet-induced nonalcoholic fatty liver disease showed increased rolling and adhesion of leukocytes, increased hepatic stellate cells activation, and decreased tissue perfusion, which were reverted by pyridoxamine. Pyridoxamine protected against the increased hepatic lipid peroxidation observed in the nonalcoholic fatty liver disease group. Pyridoxamine treatment was associated with increased levels of tumor necrosis factor alpha (TNF-α) mRNA transcripts in the liver., Conclusion: Pyridoxamine modulates oxidative stress, advanced glycation end products, TNF-α transcripts levels, and metabolic disturbances, being a potential treatment for nonalcoholic fatty liver disease-associated microcirculatory and metabolic complications., (© 2019 John Wiley & Sons Ltd.)

Background Non-alcoholic fatty liver disease (NAFLD) is associated with high cardiovascular morbidity/mortality, including heart failure. Abnormalities in left ventricular (LV) structure/function are associated with heart failure risk. Methods and Results Participants from the population-based CARDIA (Coronary Artery Risk Development in Young Adults) study year 25 exam (2010-2011, aged 43-55 years, 61% women, 48% black) with computed tomography measured liver fat and comprehensive echocardiography were included. Echocardiography was repeated at year 30 follow-up (aged 47-62 years, N=1827). NAFLD was defined as liver attenuation ≤40 HU after exclusions. LV geometry was classified into normal and abnormal by integrating relative wall thickness and LV mass index. Diastolic function was defined using Doppler and tissue Doppler imaging. Systolic function was assessed with myocardial strain measured by speckle tracking. NAFLD prevalence was 8.7% (n=159). NAFLD participants had higher LV mass, relative wall thickness, incident LV hypertrophy and abnormal LV geometry versus non-NAFLD ( P <0.02). NAFLD participants had impaired LV relaxation (E/A ratio 1.1 versus 1.2), higher LV filling pressures (E/e' ratio 7.9 versus 7.2), worse longitudinal strain (-13.9% versus -15.3%), and lower LV ejection fraction (58.9% versus 60.2%, P <0.01). In multivariable analyses adjusted for heart failure risk factors, NAFLD was independently associated with incident LV hypertrophy (odds ratio: 1.9, 95% CI: 1.1-3.4), abnormal LV geometry (odds ratio: 1.9, 1.1-3.3) and greater change in strain (odds ratio: 2.2, 1.1-4.7). Adjustment for body mass index attenuated associations to non-significance. Conclusions NAFLD is associated with subclinical changes over time in LV structure/function and obesity explains much of the association. Presence of obesity in mid-life may identify an important at-risk population in whom to focus preventive heart failure strategies.

Background & Aims: Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism is associated with NAFLD severity and the PNPLA3 gene is expressed in the kidneys, but whether PNPLA3 rs738409 polymorphism is also associated with renal tubular injury (RTI) is uncertain. We assessed the effect of PNPLA3 genotypes on biomarkers of RTI and glomerular function in subjects with NAFLD who had either normal (nALT) or abnormal (abnALT) alanine aminotransaminase levels., Methods: Two hundred and seventeen patients with histologically proven NAFLD of which 75 had persistently nALT (below upper limit of normal for 3 months) were included. Multivariable regression analyses were undertaken to test associations between PNPLA3 genotype and biomarkers of kidney dysfunction., Results: The nALT patient group had higher urinary neutrophil gelatinase-associated lipocalin levels (u-NGAL, a biomarker of RTI) (P < .001), higher albuminuria (P = .039) and greater prevalence of chronic kidney disease (CKD; P = .046) than the abnALT group. The association between PNPLA3 GG genotype and risk of CKD and abnormal albuminuria remained significant after adjustment for kidney risk factors and severity of NAFLD histology, mostly in the nALT group. Similarly, PNPLA3 GG genotype was associated with higher u-NGAL levels in the nALT group, even after adjustment for the aforementioned risk factors and glomerular filtration-based markers (β-coefficient: 22.29, 95% CI: 0.99-43.60, P = .041)., Conclusion: Patients with NAFLD and persistently nALT, who carry the PNPLA3 rs738409 G allele, are at higher risk of early glomerular and tubular damage. We suggest PNPLA3 genotyping may help identify patients with NAFLD at higher risk of RTI., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Sarcopenia is reported to be associated with nonalcoholic fatty liver disease (NAFLD). Evaluation of skeletal muscle attenuation and area by computed tomography (CT) may represent a promising approach for evaluation of the risk of NAFLD. We examined the association between skeletal muscle characteristics and NAFLD and investigated the combined effect of these parameters on the prevalence of NAFLD., Methods: In this cross-sectional study, we analysed data from 632 middle-aged Japanese subjects without daily alcohol intake (353 men and 279 women) from a cohort of employees undergoing annual health examinations. The cross-sectional skeletal muscle area was evaluated on the basis of CT data at the level of the third lumbar vertebrae, and the skeletal muscle index (SMI) and density (SMD) were calculated. The subjects were divided into four study groups according to their SMI and SMD relative to median values., Results: One hundred forty men and forty-three women had NAFLD. Total SMI (odds ratio [OR] per 1.0 cm 2 /kg/m 2 increase 0.43, 95% confidence interval [CI] 0.29-0.64 in men and OR 0.21, 95% CI 0.10-0.42 in women) and total SMD (OR, per 1.0 Hounsfield Unit increase 0.88, 95% CI 0.83-0.93 in men and 0.88, 0.82-0.95 in women) were significantly associated with the prevalence of NAFLD after adjusting for covariates. The subgroup with simultaneous presence of low SMI and low SMD was associated with a significantly higher prevalence of NAFLD compared with other groups., Conclusions: Both SMI and SMD are independently associated with the prevalence of NAFLD., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: We recently showed that the functional capacity for ureagenesis is deficient in non-alcoholic fatty liver disease (NAFLD) patients. The aim of this study was to assess expression of urea cycle-related genes to elucidate a possible gene regulatory basis to the functional problem., Methods: Liver mRNA expression analyses within the gene pathway governing hepatic nitrogen conversion were performed in 20 non-diabetic, biopsy-proven NAFLD patients (8 simple steatosis; 12 non-alcoholic steatohepatitis [NASH]) and 12 obese and 14 lean healthy individuals. Sixteen NAFLD patients were included for gene expression validation. Relationship between gene expressions and functional capacity for ureagenesis was described., Results: Gene expression of most urea cycle-related enzymes were downregulated in NAFLD vs both control groups; markedly so for the urea cycle flux-generating carbamoyl phosphate synthetase (CPS1) (~3.5-fold, P < .0001). In NASH, CPS1 downregulation paralleled the deficit in ureagenesis (P = .03). Additionally, expression of several genes involved in amino acid uptake and degradation, and the glucagon receptor gene, were downregulated in NAFLD. Conversely, glutamine synthetase (GS) expression increased >1.5-fold (P ≤ .03), inversely related to CPS1 expression (P = .004)., Conclusions: NAFLD downregulated the expression of urea cycle-related genes. Downregulation of urea cycle flux-generating CPS1 correlated with the loss of functional capacity for ureagenesis in NASH. On gene level, these changes coincided with an increase in the major ammonia scavenging enzyme GS. The effects seemed related to a fatty liver as such rather than NASH or obesity. The findings support gene regulatory mechanisms involved in the deficient ureagenesis of NAFLD, but it remains unexplained how hepatocyte fat accumulation exerts these effects., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To assess left atrial function in type 2 diabetes mellitus (T2DM) patients with nonalcoholic fatty liver disease (NAFLD) by two-dimensional speckle tracking echocardiography (2D-STE)., Methods: We classified 97 patients with T2DM into three groups according to the results of liver ultrasonography: group A (without NAFLD), group B (mild fatty liver), and group C (moderate to severe fatty liver). Conventional echocardiography parameters included left atrial end-systolic diameter (LAD), left ventricular end-systolic and end-diastolic diameter (LVDs, LVDd), end-diastolic thickness of ventricular septumi and LV posterior wall (IVSTd, LVPWTd), peak E and A of mitralis (E, A), septal and lateral early (e') mitral annular diastolic tissue velocities, then calculated E/A and E/mean e'. We measured LV ejection fraction (LVEF) and left atrial (LA) volumes (max, min, and preatrial contraction volume) by Simpson's rule, then calculated LA passive and active ejection fraction (LAPEF, LAAEF), left atrial maximum volume index (LAVImax). The global peak longitudinal systolic strain (LASRs), early diastolic strain (LASRe), and late diastolic strain (LASRa) rates of the LA were obtained by 2D-STE., Results: No differences were found between groups A and B (all P > 0.05). In group C, LAAEF and LASRa were obviously higher, while LAPEF, LASRe, and LASRs were obviously decreased compared with those values in groups A and B (all P < 0.05). The association between the severity of NAFLD and the differences in LA strain values remained significant after adjustment for confounders., Conclusion: Two-dimensional speckle tracking echocardiography can evaluate the left atrial function in T2DM patients with NAFLD., (© 2019 Wiley Periodicals, Inc.)

Objective: To determine whether analysis of microvascular network perfusion using complexity-based methods can discriminate between groups of individuals at an increased risk of developing CVD., Methods: Data were obtained from laser Doppler recordings of skin blood flux at the forearm in 50 participants with non-alcoholic fatty liver disease grouped for absence (n = 28) or presence (n = 14) of type 2 diabetes and use of calcium channel blocker medication (n = 8). Power spectral density was evaluated and Lempel-Ziv complexity determined to quantify signal information content at single and multiple time-scales to account for the different processes modulating network perfusion., Results: Complexity was associated with dilatory capacity and respiration and negatively with baseline blood flux and cardiac band power. The relationship between the modulators of flowmotion and complexity of blood flux is shown to change with time-scale improving discrimination between groups. Multiscale Lempel-Ziv achieved best classification accuracy of 86.1%., Conclusions: Time and frequency domain measures alone are insufficient to discriminate between groups. As cardiovascular disease risk increases, the degree of complexity of the blood flux signal reduces, indicative of a reduced temporal activity and heterogeneous distribution of blood flow within the microvascular network sampled. Complexity-based methods, particularly multiscale variants, are shown to have good discriminatory capabilities., (© 2019 John Wiley & Sons Ltd.)

Background & Aims: The association between nonalcoholic fatty liver disease and lung function has not been fully examined. The aim of this study was to clarify the association between nonalcoholic fatty liver disease and lung function in general population by performing cross-sectional and longitudinal analysis., Methods: Participants without hepatic and respiratory disease who underwent regular health exams including hepatic sonography and spirometry with at least 3 years' follow-up were included. In cross-sectional analysis, the association between nonalcoholic fatty liver disease and lung function at baseline was examined with multiple regression models. The longitudinal analysis was performed by mixed linear regression models with propensity score matching., Results: Of 11 892 eligible participants (mean age, 47.7 years; male, 47.2%), 3815(32.1%) had nonalcoholic fatty liver disease based on sonography. In cross-sectional analysis, the nonalcoholic fatty liver disease group had lower adjusted forced expiratory volume in 1-second (men, 3.52 vs 3.44 L, P < .001; women, 2.62 vs 2.45 L, P < .001) and forced vital capacity (men, 4.33 vs 4.24 L, P < .001; women, 3.11 vs 2.97 L, P < .001) than the control group. In longitudinal analysis, during the mean follow-up period of 6.6 years, there were no significant differences in forced expiratory volume in 1-second or forced vital capacity decline rates between two groups in the propensity score-matched cohorts (n = 4558). However, those with high nonalcoholic fatty liver disease fibrosis score and fibrosis-4 (men, -21.7 vs -27.4 mL/y, P = .001; women, -22.4 vs -27.9 mL/y, P = .016) showed significantly faster decline in forced vital capacity compared to those with low scores., Conclusions: Nonalcoholic fatty liver disease was associated with decreased lung function at baseline but was not associated with accelerated lung function decline in the propensity score-matched cohort. However, hepatic fibrosis was significantly associated with rapid forced vital capacity decline., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Nonalcoholic fatty disease (NAFLD) is the most common liver disease, since it is strongly associated with obesity and metabolic syndrome pandemics. NAFLD may affect drug disposal and has common pathophysiological mechanisms with drug-induced liver injury (DILI); this may predispose to hepatoxicity induced by certain drugs that share these pathophysiological mechanisms. In addition, drugs may trigger fatty liver and inflammation per se by mimicking NAFLD pathophysiological mechanisms., Aims: To provide a comprehensive update on (a) potential mechanisms whereby certain drugs can be more hepatotoxic in NAFLD patients, (b) the steatogenic effects of drugs, and (c) the mechanism involved in drug-induced steatohepatitis (DISH)., Methods: A language- and date-unrestricted Medline literature search was conducted to identify pertinent basic and clinical studies on the topic., Results: Drugs can induce macrovesicular steatosis by mimicking NAFLD pathogenic factors, including insulin resistance and imbalance between fat gain and loss. Other forms of hepatic fat accumulation exist, such as microvesicular steatosis and phospholipidosis, and are mostly associated with acute mitochondrial dysfunction and defective lipophagy, respectively. Drug-induced mitochondrial dysfunction is also commonly involved in DISH. Patients with pre-existing NAFLD may be at higher risk of DILI induced by certain drugs, and polypharmacy in obese individuals to treat their comorbidities may be a contributing factor., Conclusions: The relationship between DILI and NAFLD may be reciprocal: drugs can cause NAFLD by acting as steatogenic factors, and pre-existing NAFLD could be a predisposing condition for certain drugs to cause DILI. Polypharmacy associated with obesity might potentiate the association between this condition and DILI., (© 2018 John Wiley & Sons Ltd.)

Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the USA and many other countries. Although the metabolism and pathogenesis of APAP has been extensively investigated for decades, the mechanisms by which APAP induces liver injury are incompletely known, which hampers the development of effective therapeutic approaches to tackle this important clinical problem. Autophagy is a highly conserved intracellular degradation pathway, which aims at recycling cellular components and damaged organelles in response to adverse environmental conditions and stresses as a survival mechanism. There is accumulating evidence indicating that autophagy is activated in response to APAP overdose in specific liver zone areas, and pharmacological activation of autophagy protects against APAP-induced liver injury. Increasing evidence also suggests that hepatic autophagy is impaired in nonalcoholic fatty livers (NAFLD), and NAFLD patients are more susceptible to APAP-induced liver injury. Here, we summarized the current progress on the role and mechanisms of autophagy in protecting against APAP-induced liver injury., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: The impact of nonalcoholic fatty liver disease (NAFLD) on the natural history of primary biliary cholangitis (PBC) has yet to be described. The aim of this study was to document the activity, severity and progression of PBC in patients with concomitant NAFLD and compare the findings to those with PBC alone., Methods: Disease activity was assessed by serum liver enzyme levels; severity, by Fib-4 scores and percent of patients with APRI >1.5; and progression, by changes in Fib-4 and prevalence of APRI >1.5 during follow-up., Results: The study populations consisted of 168 PBC alone and 68 PBC/NAFLD patients. The mean ages and gender distributions of the two cohorts were similar. At presentation, PBC alone patients had greater disease activity (higher serum ALP and GGT values, P = .003 and 0.01, respectively) and advanced disease (higher Fib-4 (P = .04) scores) than PBC/NAFLD patients. Although the prevalence of APRI >1.5 was also higher in PBC alone (11.1%) vs PBC/NAFLD (4.7%) patients, the difference was not significant (P = .16). During mean follow-up of 6.7 ± 5.5 (PBC alone) and 6.4 ± 4.4 (PBC/NAFLD) years (ranges: 0.5-21 years) annual increases in Fib-4 and prevalence of ≥ APRI 1.5 were greater in PBC alone patients but the differences did not reach statistical significance., Conclusions: The results of this retrospective, single centre study suggest that the activity, severity and progression of PBC are not adversely affected by concomitant NAFLD., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We compared the effects of weight loss induced by the glucagon-like peptide 1-agonist liraglutide with a structured lifestyle intervention in obese adults with non-alcoholic fatty liver disease (NAFLD). Obese (body mass index ≥30 kg/m 2 , mean weight 96.0 ± 16.3 kg) non-diabetic Asian adults, with NAFLD diagnosed by liver fat fraction (LFF) ≥ 5.5% on magnetic resonance imaging without other causes of hepatic steatosis, were randomized to a supervised program of dieting (restriction by 400 kilocalories/d) plus moderate-intensity aerobic exercise (~200 min/wk; DE group, n = 12), or liraglutide at the 3 mg daily dose approved for weight loss (LI group, n = 12), for 26 weeks. Both DE and LI groups had significant (P < .01) and similar reductions in weight (-3.5 ± 3.3 vs -3.5 ± 2.1 kg, respectively, P = .72), LFF (-8.9 ± 13.4 vs -7.2% ± 7.1%, P = .70), serum alanine aminotransferase (-42 ± 46 vs -34 ± 27 U/L, P = .52) and aspartate aminotransferase (-23 ± 24 vs -18 ± 15 U/L, P = .53). In this first randomized study comparing the 2 weight-loss modalities for improving NAFLD, liraglutide was as effective as structured lifestyle modification., (© 2017 John Wiley & Sons Ltd.)

The beneficial effects of mineralocorticoid receptor blockade by spironolactone have been shown in animal models of non-alcoholic fatty liver disease (NAFLD). The aim of the present 52-week randomized controlled trial was to compare the effects of low-dose spironolactone and vitamin E combination with those of vitamin E monotherapy on insulin resistance, non-invasive indices of hepatic steatosis and fibrosis, liver function tests, circulating adipokines and hormones in patients with histologically confirmed NAFLD. Homeostasis model of assessment of insulin resistance (HOMA-IR) and non-invasive indices of steatosis and fibrosis were calculated. Analysis was intention-to-treat. NAFLD liver fat score, an index of steatosis, decreased significantly in the combination treatment group (P = .028), but not in the vitamin E group, and the difference for group*time interaction was significant (P = .047). Alanine aminotransferase-to-platelet ratio index, an index of fibrosis, did not change. Insulin levels and HOMA-IR decreased significantly only within the combination group (P = .011 and P = .011, respectively). In conclusion, the combined low-dose spironolactone plus vitamin E regimen significantly decreased NAFLD liver fat score. Larger-scale trials are needed to clarify the effect of low-dose spironolactone on hepatic histology., (© 2017 John Wiley & Sons Ltd.)

Background: Non-alcoholic fatty liver disease is the fastest growing cause of liver disease in the Western world, yet there is no approved pharmacotherapy. While lifestyle modifications remain the mainstay of treatment, only a proportion of individuals are able to make or sustain them, and so more treatment options are required., Aim: To review the potential benefit of drugs used in clinical practice, those entering phase II trials, and compounds being investigated in pre-clinical studies., Methods: A literature search was performed using PubMed to identify relevant studies; linked references were also reviewed., Results: Vitamin E and pioglitazone have shown efficacy in non-alcoholic steatohepatitis (NASH), but long-term safety concerns, specifically bladder cancer and osteoporosis with pioglitazone, have limited their use. GLP-1 analogues and SGLT-2 inhibitors are currently approved for use in diabetes, have shown early efficacy in NASH and also have beneficial cardiovascular effects. Peroxisome proliferator-activator receptors and FXR agonists have potent effects on lipogenesis, inflammation and fibrosis, respectively, with their efficacy and safety being currently tested in phase 3. As inflammation and apoptosis are key features of NASH agents modulating these pathways are of interest; CCR2/5 antagonists downregulate inflammatory pathways and reduce fibrosis with caspase and apoptosis signal-regulating kinase 1 inhibitors reducing apoptosis and fibrosis., Conclusions: Rising demand and an improved understanding of NASH pathophysiology has led to a surge in development of new therapies. Tailoring pharmacotherapy to the dominant pathogenic pathway in a given patient along with use of combination therapy is likely to represent the future direction in treatment of patients with NASH., (© 2017 John Wiley & Sons Ltd.)

Aims: To assess the prevalence of elevated liver enzymes in adults with type 1 diabetes mellitus (T1DM) in routine clinical care and the association with cardiovascular risk profile in the Diabetes-Prospective-Documentation (DPV) network in Germany and Austria., Subjects and Methods: This cross sectional observational study from the DPV registry includes data from 45 519 adults with T1DM at 478 centres up to September 2016. Liver enzyme measurements were available in 9226 (29%) patients at 270 centres and were analysed for increased alanine aminotransferase (ALT; men >50 U/L, women >35U/L) and/or aspartate aminotransferase (AST; men >50 U/L, women >35U/L) and/or gamma-glutamyltransferase (GGT; men >60U/L, women >40 U/L). A subgroup analysis in patients for whom 2 or more ALT measurements were available (n = 2335, 25%) and whose ALT was increased at least twice (men >30 U/L, women >19U/L) was performed. Associations with glycaemic control, cardiovascular risk factors and late complications were investigated with multiple regression analyses., Results: Twenty percent (19.8%, n = 1824) had increased liver enzyme(s) on one or more occasions. Increased liver enzymes were associated with worse glycaemic control and higher BMI (both P < .0001), dyslipidemia (OR, 1.75; 95% CI, 1.54-2.0), hypertension (OR, 1.48; 95% CI: 1.31-1.68), myocardial infarction (OR, 1.49; 95% CI, 1.17-1.91) and end stage renal disease (OR, 1.59; 95% CI, 1.17-2.17). ALT was increased twice in 29% and was associated with worse glycaemic control (P < .0001), higher BMI (P < .0001), hypertension (OR, 1.58; 95% CI, 1.26-1.97) and dyslipidemia (OR, 1.89; 95% CI, 1.51-2.37)., Conclusions: In this clinical audit in adults with T1DM, elevated liver enzymes on routine assessment were associated with a less favourable cardiovascular risk profile and with poorer glycaemic control., (© 2017 John Wiley & Sons Ltd.)

Background: Several recent studies have shown a strong association between non-alcoholic steatohepatitis (NASH) and chronic kidney disease., Aim: To examine the relationship between changes in liver histology and renal function in patients with NASH., Methods: The present analysis represents a post hoc analysis of a recently published trial that included 261 patients with NASH who were treated with lifestyle modifications during 52 weeks. Kidney function was evaluated through Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rates (eGFR, mL/min/1.73 m 2 ) overtime. We explored correlations between the kidney function and improvement in histological outcomes at 52 weeks., Results: Interestingly, a one-stage reduction in fibrosis (r = 0.20, P < 0.01) and resolution of NASH (r = 0.17, P < 0.01) were significantly correlated with an improvement in the kidney function. The eGFR values significantly increased in patients with fibrosis improvement (+7.6 ± 6.5 mL/min/1.73 m 2 ), compared to those without fibrosis improvement (-1.98 ± 6.4 mL/min/1.73 m 2 ) (P < 0.01) at end of treatment (EOT). Likewise, NASH resolution was associated with an increase in eGFR compared with patients without NASH resolution (2.32 ± 7.8 mL/min/1.73 m 2 vs. -1.04 ± 5.9 mL/min/1.73 m 2 , P = 0.04) at EOT. After controlling for the confounders, the association between fibrosis improvement, NASH resolution and eGFR change remained significant (P < 0.05 for both)., Conclusions: Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in NASH. As new drugs for NASH emerge, studies should address whether improvement in histology in response to pharmacotherapies yield the same improvement in kidney function as weight loss., (© 2016 John Wiley & Sons Ltd.)

Background & Aims: High levels of ferritin in patients with non-alcoholic fatty liver disease (NAFLD) are associated with significant fibrosis and higher NAFLD activity score (NAS). It is unclear if this association has an impact on mortality. We investigated if high levels of ferritin, with or without iron overload, were associated with an increased mortality in NAFLD., Methods: We included 222 patients between 1979 and 2009 with biopsy-proven NAFLD and available serum ferritin concentrations. The cohort was divided into 'high' (n = 89) and 'normal' (n = 133) ferritin values, using a cut-point of 350 μg/L in males, and 150 μg/L in females, and stratified upon iron overload status. Data on mortality were obtained from a national, population-based register. Poisson regression was used to estimate hazard ratios for mortality. The estimates were adjusted for age at biopsy, sex, smoking, BMI, diabetes, hypertension, cardiovascular disease and fibrosis stage at the time of biopsy., Results: The median follow-up time was 15.6 years (range: 0.5-34.2). Patients with high ferritin had more advanced fibrosis and higher NAS than patients with normal ferritin (P < 0.05). Fifteen years after diagnosis, and after adjusting for confounders, the high-ferritin group showed an increasingly higher mortality that was statistically significant (Hazard ratio = 1.10 per year, 95% Confidence interval 1.01-1.21, P < 0.05). There was no difference in mortality between patients with different iron overload patterns., Conclusions: High levels of ferritin are associated with a long-term increased risk of death., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Macrophage activation plays a key pathogenic role in experimental non-alcoholic fatty liver disease (NAFLD) and contributes to the progression of steatohepatitis (NASH) and fibrosis. We studied macrophage activation in human NAFLD by measuring soluble (s)CD163, a specific macrophage activation marker, hypothesizing that sCD163 would be associated with the patients' morphological disease grade. Furthermore, we investigated an association between sCD163 and the apoptosis marker cytokeratin-18 (CK-18) to explore a link between macrophage activation and apoptosis., Methods: sCD163 associations with biochemical and histological measures of NAFLD were investigated in two independent cohorts of 157 Australian and 174 Italian NAFLD patients, with liver biopsies graded for NAFLD severity, steatosis and fibrosis. sCD163 and CK-18 were measured by enzyme-linked immunosorbent assay., Results: In both cohorts sCD163 increased in parallel with the patients' morphological disease grading, being independently associated with the Kleiner fibrosis score (P < 0.001). A high sCD163 predicted advanced fibrosis {F ≥ 3; Australian cohort: area under receiver-operating characteristics curve 0.77 [95% confidence interval (CI): 0.76-0.87], Italian cohort: 0.80 (95% CI: 0.72-0.88)}. In both groups, sCD163 was independently associated with CK-18 (P < 0.001)., Conclusion: Soluble CD163 reflecting macrophage activation is associated with morphological features of NAFLD suggesting their involvement in the pathogenesis of NAFLD, NASH and particularly fibrosis. An independent association between sCD163 and cytokeratin-18 suggests that apoptosis may contribute to macrophage activation in NAFLD/NASH., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: This study aimed to investigate the possible synergistic effects of lipid disorder with renin-angiotensin system (RAS) activation in non-alcoholic fatty liver disease (NAFLD)., Methods: Apolipoprotein E gene-knockout mice, angiotensin II (Ang II) type 1 receptor (AT1) gene-knockout mice and human hepatoblastoma cell line (HepG2) were used for experiments. Lipid accumulation was examined by Filipin staining and intracellular cholesterol quantitative assay. The gene and protein expression of molecules involved in RAS and low-density lipoprotein receptor (LDLr) pathway was examined by real-time PCR, immunofluorescent staining and Western blot., Results: There was significantly increased expression of RAS components and extracellular matrix (ECM) in livers of high-fat-diet-fed apolipoprotein E gene-knockout mice compared with controls. Upregulation of RAS components was positively associated with increased plasma levels of lipid profile. The in vitro study further confirmed that cholesterol loading increased supernatant renin activity and Ang II level of HepG2 cells, accompanied by increased ECM production that was positively associated with increased expression of intracellular RAS components. Interestingly, Ang II treatment increased lipid accumulation in livers of C57BL/6 mice and HepG2 cells. Furthermore, Ang II treatment increased gene and protein expression of sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP), SREBP-2 and LDLr, which were mediated by enhanced SCAP/SREBP-2 complex translocation from endoplasmic reticulum to Golgi. However, LDLr pathway was accordingly downregulated in livers of AT1 gene-knockout C57BL/6 mice or in HepG2 cells treated by telmisartan., Conclusion: These findings demonstrate that lipid disorder and intrahepatic RAS activation synergistically accelerate NAFLD progression., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: High-fat diets are known to contribute to the development of obesity and related co-morbidities including non-alcoholic fatty liver disease (NAFLD). The accumulation of hepatic lipid may increase endoplasmic reticulum (ER) stress and contribute to non-alcoholic steatohepatitis and metabolic disease. We hypothesized that bariatric surgery would counter the effects of a high-fat diet (HFD) on obesity-associated NAFLD., Methods: Sixteen of 24 male Sprague Dawley rats were randomized to Sham (N = 8) or Roux-en-Y gastric bypass (RYGB) surgery (N = 8) and compared to Lean controls (N = 8). Obese rats were maintained on a HFD throughout the study. Insulin resistance (HOMA-IR), and hepatic steatosis, triglyceride accumulation, ER stress and apoptosis were assessed at 90 days post-surgery., Results: Despite eating a HFD for 90 days post-surgery, the RYGB group lost weight (-20.7 ± 6%, P < 0.01) and improved insulin sensitivity (P < 0.05) compared to Sham. These results occurred with no change in food intake between groups. Hepatic steatosis and ER stress, specifically glucose-regulated protein-78 (Grp78, P < 0.001), X-box binding protein-1 (XBP-1) and spliced XBP-1 (P < 0.01), and fibroblast growth factor 21 (FGF21) gene expression, were normalized in the RYGB group compared to both Sham and Lean controls. Significant TUNEL staining in liver sections from the Obese Sham group, indicative of accelerated cell death, was absent in the RYGB and Lean control groups. Additionally, fasting plasma glucagon like peptide-1 was increased in RYGB compared to Sham (P < 0.02)., Conclusion: These data suggest that in obese rats, RYGB surgery protects the liver against HFD-induced fatty liver disease by attenuating ER stress and excess apoptosis., Competing Interests: The authors have no commercial associations that might represent a conflict of interest in relation to this research., (© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background & Aims: This study was designed to determine the effects of the Dietary Approaches to Stop Hypertension (DASH) diet on weight loss and metabolic status in overweight patients with non-alcoholic fatty liver disease (NAFLD)., Methods: This randomized controlled clinical trial was done among 60 overweight and obese patients with NAFLD. Patients were randomly allocated to consume either the control (n = 30) or the DASH eating pattern (n = 30) for 8 weeks. Both diets were designed to be calorie-restricted. Both diets were consisted of 52-55% carbohydrates, 16-18% proteins and 30% total fats; however, the DASH diet was designed to be rich in fruits, vegetables, whole grains, and low-fat dairy products and low in saturated fats, cholesterol and refined grains., Results: Adherence to the DASH eating pattern, compared to the control diet, weight (P = 0.006), BMI (P = 0.01), alanine aminotransferase (ALT) (P = 0.02), alkalin phosphatase (ALP) (P = 0.001), insulin levels (P = 0.01), homoeostasis model of assessment-estimated insulin resistance (HOMA-IR) (P = 0.01) significantly decreased and quantitative insulin sensitivity check index (QUICKI) (P = 0.004) significantly increased. Compared with the control diet, the DASH diet has resulted in significant reductions in serum triglycerides (P = 0.04) and total-/HDL-cholesterol ratio (P = 0.01). Finally, decreased concentrations of serum high-sensitivity C-reactive protein (hs-CRP) (P = 0.03), malondialdehyde (MDA) (P = 0.04), increased levels of nitric oxide (NO) (P = 0.01) and glutathione (GSH) (P = 0.009) were found in the DASH group compared with the control group., Conclusions: Consumption of DASH diet for 8 weeks among patients with NAFLD had beneficial effects on weight, BMI, ALT, ALP, triglycerides, markers of insulin metabolism, inflammatory markers, GSH and MDA., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Recent animal studies have shown that platelets directly activate hepatic stellate cells to promote liver fibrosis, whereas anti-platelet agents decrease liver fibrosis. It is unknown whether platelet inhibition by aspirin prevents liver fibrosis in humans., Aim: To examine the association between aspirin use and liver fibrosis among adults with suspected chronic liver disease., Methods: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey III. We identified 1856 individuals with suspected chronic liver disease (CLD). The degree of liver fibrosis was determined using four validated fibrosis indices and a composite index., Results: The use of aspirin was associated with a significantly lower composite liver fibrosis index calculated from FIB4, APRI, Forns and NFS [0.24 standard deviation (s.d.) units lower; 95% CI -0.42 to -0.06, P = 0.009]. The association of aspirin with lower fibrosis scores was significantly larger among those with suspected CLD compared to those without (-0.23 vs. -0.03 s.d. units; P interaction = 0.05). The negative association between aspirin use and lower fibrosis index was consistent across all four fibrosis indices (P = 0.002-0.08) in individuals with chronic viral hepatitis, suspected alcoholic liver disease and NASH. In comparison, no negative associations with liver fibrosis were seen with ibuprofen in parallel analyses., Conclusions: The use of aspirin was associated with significantly lower indices of liver fibrosis among US adults with suspected chronic liver diseases. Aspirin and other anti-platelet drugs warrant further investigation for the prevention and treatment of liver fibrosis., (© 2016 John Wiley & Sons Ltd.)

Background & Aims: We tested the putative association of the rs58542926 variant of TM6SF2, a recently described genetic determinant of nonalcoholic fatty liver disease, with steatosis and fibrosis in genotype 1(G1) chronic hepatitis C(CHC) patients., Methods: A total of 694 consecutively biopsied Caucasian G1 CHC patients were genotyped for TM6SF2 rs58542926, IL28B rs12979860 and PNPLA3 rs738409. Steatosis was classified as absent (<5%), mild-moderate(5-29%) and severe(≥30%), Fibrosis was considered severe if=F3-F4., Results: Carriers of TM6SF2 rs58542926 (6.3% of patients) exhibited lower serum levels of cholesterol (P = 0.04) and triglycerides (P = 0.01), but a similar distribution of steatosis severity (P = 0.63), compared to noncarriers. Prevalence and severity of steatosis were reduced in IL28B C allele carriers (P = 0.005) and elevated in PNPLA3 G allele carriers (P < 0.001). After adjustment for age, gender, body mass index and homoeostasis model assessment score, steatosis severity was independently associated with IL28B rs12979860 (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.55-0.86, P = 0.001) and PNPLA3 rs738409 (OR 1.84, 95% CI 1.46-2.83, P < 0.001), but not TM6SF2 rs58542926 (OR 1.48, 95% CI 0.82-2.69, P = 0.19). Variants of TM6SF2 (30.9% vs. 25%, P = 0.40), IL28B and PNPLA3 were not directly associated with fibrosis severity, although variants of IL28B and PNPLA3 promoted steatosis (OR 1.36, 95% CI 1.06-1.75, P = 0.01) that in turn is associated with severe fibrosis., Conclusions: In G1 CHC patients, TM6SF2 rs58542926 does not affect the histological severity of liver damage. However, IL28B rs12979860 and PNPLA3 rs738409 modify steatosis., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The human intestinal microbiota is a key regulator of host metabolic and immune functions and alterations in the microbiome ('dysbiosis') have been implicated in several human diseases. Because of the anatomical links between the intestines and the liver, dysbiosis may also disrupt hepatic function and thereby contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD)., Aim: To perform a comprehensive review of the medical literature investigating associations between intestinal dysbiosis and NAFLD, with a particular emphasis on studies that characterise the microbiome in NAFLD., Methods: We conducted a search of PubMed, Embase, and Web of Science using multiple search terms including: 'NAFLD, NASH, fatty liver, steatohepatitis' combined with 'metagenome, microbiom*, microbiota*, fecal flora, intestinal flora, gut bacteria'. Results were manually reviewed and studies selected based on relevance to intestinal microbiota and NAFLD. We also included studies that addressed potential mechanistic models of pathways linking the dysbiosis to NAFLD., Results: Nine studies (five human and four animal models) were identified in our search that assessed associations between specific intestinal microbiota composition and NAFLD. We reviewed and summarised the results of additional investigations that more broadly addressed the mechanisms by which the microbiome may impact NAFLD pathogenesis., Conclusions: Investigations in humans and animals demonstrate associations between intestinal dysbiosis and NAFLD; however, causality has not been proven and mechanistic links require further delineation. As the field of microbiome research matures in techniques and study design, more detailed insights into NAFLD pathogenesis and its associations with the intestinal microbiota will be elucidated., (© 2015 John Wiley & Sons Ltd.)

Background: Patients with non-alcoholic steatohepatitis (NASH) have increased intestinal permeability and small intestine bacterial overgrowth., Aims: To test the hypothesis that endotoxemia is associated with non-alcoholic fatty liver disease (NAFLD) in the general population, and to study dietary factors associated with endotoxemia., Methods: Nine hundred and twenty adults were randomly selected from the government's census database and underwent proton-magnetic resonance spectroscopy to assess hepatic steatosis. Endotoxemia was assessed using the limulus amebocyte lysate, lipopolysaccharide-binding protein (LBP) and EndoCab immunoglobulin G (IgG) assays., Results: Two hundred and sixty-three (29%) subjects had NAFLD. Subjects with NAFLD had slightly higher LBP (P < 0.001) and EndoCab IgG (P = 0.013) levels. EndoCab IgG remained an independent factor associated with intrahepatic triglycerides after adjusting for other metabolic factors. Among 565 subjects without NAFLD at baseline who had repeated assessment at a median interval of 47 months, 78 (13.8%) developed incident NAFLD and they also had higher LBP (P = 0.016). Moreover, LBP was associated with insulin resistance and dyslipidaemia, and modestly increased with the cytokeratin-18 fragment level but not liver stiffness measurement by transient elastography. Although total energy consumption and individual macronutrients were not associated with endotoxemia, current drinkers (mostly <140 g/week) had lower endotoxin, EndoCab IgG and fetuin-A levels than nondrinkers., Conclusions: Endotoxin markers are associated with NAFLD in the general population, but do not have a major effect on NASH and fibrosis. People with modest alcohol consumption have lower serum endotoxin. This may partly explain the lower risk of NAFLD and NASH in modest drinkers in previous observational studies., (© 2015 John Wiley & Sons Ltd.)

Background: Elevated fasting triglyceride is often associated with metabolic syndrome and non-alcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease. On the other hand, as liver disease progresses, patients may develop hepatocellular dysfunction that impairs triglyceride production., Aim: To test the hypothesis that lower fasting triglyceride levels may paradoxically indicate more advanced liver disease., Methods: A cross-sectional analysis of 11 947 adults aged 20 years or older without chronic viral hepatitis from the National Health and Nutrition Examination Survey 1999-2010 was performed to analyze the relationships between fasting triglyceride levels and five validated non-invasive indices of liver fibrosis, including Fibrosis 4 Score (FIB4), NAFLD Fibrosis Score (NFS), Ast-Platelet Ration Index, AST/ALT ratio and BARD., Results: Low-fasting triglyceride levels were consistently associated with elevated liver fibrosis indices. Individuals in the lowest quintile of triglycerides (TG) had an adjusted odds ratio (OR) of 3.0 (95% CI, 1.7-5.2; P < 0.001) for advanced fibrosis estimated by FIB4 score and OR of 1.8 (95% Cl, 1.2-2.7; P = 0.009) estimated by NFS, compared to individuals in the highest quintile. This association remained highly significant when restricted to individuals with abnormal LFTs from suspected NAFLD. This inverse relationship was continuous, and more pronounced among men and whites (P interaction <0.001 and 0.008 respectively), but not modified by age or body mass index. In addition, fasting TG had a stronger, more direct association with liver fibrosis indices than did albumin or total bilirubin., Conclusions: Fasting triglyceride levels were inversely associated with liver fibrosis indicators in American adults, especially among white men. Our findings suggest that sequential lipid measurements may serve as a useful disease marker in the management of chronic liver disease patients., (© 2015 John Wiley & Sons Ltd.)

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and its incidence has been increasing recently. In addition to hepatic complications, NAFLD is also recognized as an independent risk factor for cardiovascular disease. Unfortunately, the current therapies for NAFLD display variable efficacy; a novel and effective drug is urgently needed. Glucagon-like peptide-1 (GLP-1), a receptor agonist is a new drug approved for treating type 2 diabetes. Recently, these types of agents have shown a novel therapeutic effect on NAFLD. However, the mechanisms of GLP-1 receptor agonists on the treatment of NAFLD have not yet been explained precisely. Recent studies have demonstrated that GLP-1 reverses the progression of NAFLD not only indirectly through an incretin effect that improves key parameters involved in NAFLD, but also a direct effect on lipid metabolism of hepatocytes and inflammation in liver. In this review, we provided an overview of the role and mechanisms of GLP-1 in the therapy of NAFLD., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background & Aims: Notwithstanding evidences implicating the lipopolysaccharides (LPS)/toll-like receptor-4 (TLR4) axis in the pathogenesis of NAFLD, there are no studies aimed to characterize hepatic TLR4 expression in NAFLD patients. We aimed to analyse hepatic TLR4 expression and to verify its relationship with disease activity/evolution in NAFLD patients., Methods: Liver tissue from 74 patients with NAFLD and 12 controls was analysed by immunohistochemistry (IHC) for TLR4, α-smooth muscle actin (α-SMA) and cytokeratin-7. IHC for α-SMA was used to evaluate activation of fibrogenic cells (hepatic stellate cells and portal/septal myofibroblasts), that for cytokeratin-7 to count hepatic progenitor cells and bile ducts/ductules, and that for CD68, in a subgroup of 27 patients, for detecting macrophages. Serum LPS-binding protein (LBP), a sensitive marker of LPS activity, was determined in 36 patients and 32 controls., Results: As confirmed by double-labelling experiments, the highest level of TLR4 expression was observed in hepatic progenitor cells, biliary cells and portal/septal macrophages. TLR4-positive hepatic progenitor cells and bile ducts/ductules correlated with portal/interface inflammation, activity of fibrogenic cells and fibrosis (P < 0.001). Also the score of TLR4 positivity of porto-septal inflammatory infiltrate correlated with number of hepatic progenitor cells and bile ducts/ductules, activity of fibrogenic cells and fibrosis (P < 0.01). Serum LBP was increased in patients compared to controls (P < 0.001), and correlated with portal/interface inflammation, activity of portal/septal myofibroblasts and fibrosis (all P < 0.05)., Conclusions: TLR4 expression by regenerating and inflammatory cells at the porto-septal and interface level, favoured by increased LPS activity, is associated with activation of fibrogenic cells and the degree of fibrosis., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries, yet its pathophysiology is incompletely understood. Small-molecule metabolite screens may offer new insights into disease mechanisms and reveal new treatment targets., Methods: Discovery (N = 33) and replication (N = 66) of liver biopsies spanning the range from normal liver histology to non-alcoholic steatohepatitis (NASH) were ascertained ensuring rapid freezing under 30 s in patients. 252 metabolites were assessed using GC/MS. Replicated metabolites were evaluated in a murine high-fat diet model of NAFLD., Results: In a two-stage metabolic screening, hydroquinone (HQ, p(combined) = 3.0 × 10(-4)) and nicotinic acid (NA, p(combined) = 3.9 × 10(-9)) were inversely correlated with histological NAFLD severity. A murine high-fat diet model of NAFLD demonstrated a protective effect of these two substances against NAFLD: Supplementation with 1% HQ reduced only liver steatosis, whereas 0.6% NA reduced both liver fat content and serum transaminase levels and induced a complex regulatory network of genes linked to NALFD pathogenesis in a global expression pathway analysis. Human nutritional intake of NA equivalent was also consistent with a protective effect of NA against NASH progression., Conclusion: This first small-molecular screen of human liver tissue identified two replicated protective metabolites. Either the use of NA or targeting its regulatory pathways might be explored to treat or prevent human NAFLD., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Non-alcoholic fatty liver disease (NAFLD) is the accumulation of triglycerides in the hepatocytes in the absence of excess alcohol intake, and is caused by an imbalance between hepatic synthesis and breakdown of fats, as well as fatty acid storage and disposal. Liver metabolic pathways are driven by circadian biological clocks, and hepatic health is maintained by proper timing of circadian patterns of metabolic gene expression with the alternation of anabolic processes corresponding to feeding/activity during wake times, and catabolic processes characterizing fasting/resting during sleep. A number of nuclear receptors in the liver are expressed rhythmically, bind hormones and metabolites, sense energy flux and expenditure, and connect the metabolic pathways to the molecular clockwork throughout the 24-h day. In this review, we describe the role played by the nuclear receptors in the genesis of NAFLD in relationship with the circadian clock circuitry., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The purpose of this study was to evaluate the advantages of exenatide treatment on obesity and non-alcoholic fatty liver disease (NAFLD) with elevated liver enzymes in patients with type 2 diabetes (T2D)., Methods: A total of 60 newly diagnosed patients with obesity, NAFLD with elevated liver enzymes and T2D were included in the study. The patients were randomly divided into two groups. The exenatide treatment group (n = 30) were treated with exenatide and insulin glargine, and the intensive insulin therapy group (n = 30) were treated with insulin aspart and insulin glargine for 12 weeks. Selected clinical characteristics were determined, and ultrasonography was performed at both baseline and 12 weeks following treatment., Results: At baseline, the clinical characteristics were matched between the two groups. After 12 weeks, fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated haemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG) and total bilirubin levels were significantly decreased in the two groups (p < 0.001). Body weight and waist circumference were significantly decreased in the exenatide group but increased in the intensive insulin group (p < 0.001). The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyl transpeptidase (γGGT) in the exenatide group were significantly lower than in the intensive insulin group (p < 0.001). The mean body weight change correlated with the levels of ALT, AST and γGGT change (ALT, r = 0.761; AST, r = 0.733; γGGT, r = 0.752; p < 0.001). Moreover, the reversal rate of fatty liver was significantly higher in the exenatide group (93.3%) than the intensive insulin group (66.7%) (p < 0.01)., Conclusions: Exenatide has a better hepatic-protective effect than intensive insulin therapy and perhaps represents a unique option for adjunctive therapy for patients with obesity, non-alcoholic fatty liver disease with elevated liver enzymes and T2D., (Copyright © 2014 John Wiley & Sons, Ltd.)