Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most common liver disorder worldwide, with an estimated global prevalence of more than 31%. Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a progressive form of MASLD characterized by hepatic steatosis, inflammation, and fibrosis. This review aims to provide a comprehensive analysis of the extrahepatic manifestations of MASH, focusing on chronic diseases related to the cardiovascular, muscular, and renal systems. A systematic review of published studies and literature was conducted to summarize the findings related to the systemic impacts of MASLD and MASH. The review focused on the association of MASLD and MASH with metabolic comorbidities, cardiovascular mortality, sarcopenia, and chronic kidney disease. Mechanistic insights into the concept of lipotoxic inflammatory "spill over" from the MASH-affected liver were also explored. MASLD and MASH are highly associated (50%-80%) with other metabolic comorbidities such as impaired insulin response, type 2 diabetes, dyslipidemia, hypertriglyceridemia, and hypertension. Furthermore, more than 90% of obese patients with type 2 diabetes have MASH. Data suggest that in middle-aged individuals (especially those aged 45-54), MASLD is an independent risk factor for cardiovascular mortality, sarcopenia, and chronic kidney disease. The concept of lipotoxic inflammatory "spill over" from the MASH-affected liver plays a crucial role in mediating the systemic pathological effects observed. Understanding the multifaceted impact of MASH on the heart, muscle, and kidney is crucial for early detection and risk stratification. This knowledge is also timely for implementing comprehensive disease management strategies addressing multi-organ involvement in MASH pathogenesis.

Corrigendum: Time for micro-RNAs in steatotic liver disease: a case-control study.

[This corrects the article DOI: 10.3389/fendo.2024.1349524.].

Inflammation-related miRNAs in obesity, CVD, and NAFLD.

Obesity, cardiovascular diseases (CVD), and nonalcoholic fatty liver disease (NAFLD) pose significant worldwide health challenges, characterized by complex interplay among inflammatory pathways that underlie their development. In this review, we examine the contribution of inflammation and associated signaling molecules to the pathogenesis of these conditions, while also emphasizing the significant participation of non-coding RNAs (ncRNAs) in modulating inflammatory pathways. In the context of obesity, aberrant expression patterns of inflammatory-associated miRNAs play a contributory role in adipose tissue inflammation and insulin resistance, thereby exacerbating disturbances in metabolic homeostasis. Similarly, in CVD, dysregulated miRNA expression alters inflammatory reactions, disrupts endothelial function, and induces cardiac remodeling, thereby impacting the advancement of the disease. Moreover, in the context of NAFLD, inflammatory-associated miRNAs are implicated in mediating hepatic inflammation, lipid deposition, and fibrosis, underscoring their candidacy as promising therapeutic targets. Additionally, the competing endogenous RNA (ceRNA) network has emerged as a novel regulatory mechanism in the etiology of CVD, obesity, and NAFLD, wherein ncRNAs assume pivotal roles in facilitating communication across diverse molecular pathways. Moreover, in the concluding section, we underscored the potential efficacy of directing interventions towards inflammatory-related miRNAs utilizing herbal remedies and therapies based on exosome delivery systems as a promising strategy for ameliorating pathologies associated with inflammation in obesity, CVD, and NAFLD.

Association study of NAFLD with pericoronary adipose tissue and pericardial adipose tissue: Diagnosis of stable CAD patients with NAFLD based on radiomic features.

BACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD) is prone to complicated cardiovascular disease, and we aimed to identify patients with NAFLD who are prone to developing stable coronary artery disease (CAD). METHODS AND RESULTS: We retrospectively recruited adults who underwent coronary computed tomography angiography (CTA). A total of 127 NAFLD patients and 127 non-NAFLD patients were included in this study. Clinical features and imaging parameters were analysed, mainly including pericardial adipose tissue (PAT), pericoronary adipose tissue (PCAT), and radiomic features of 6792 PCATs. The inflammatory associations of NAFLD patients with PAT and PCAT were analysed. Clinical features (model 1), CTA parameters (model 2), the radscore (model 3), and a composite model (model 4) were constructed to identify patients with NAFLD with stable CAD. The presence of NAFLD resulted in a greater inflammatory involvement in all three coronary arteries (all P < 0.01) and was associated with increased PAT volume (r = 0.178**, P < 0.05). In the presence of NAFLD, the mean CT value of the PAT was significantly correlated with the fat attenuation index (FAI) in all three vessels and had the strongest correlation with the RCA FAI (r = 0.55, p < 0.001). A total of 9 radiomic features were screened by LASSO regression to calculate radiomic scores. In the model comparison, model 4 had the best performance of all models (AUC 0.914 [0.863-0.965]) and the highest overall diagnostic value of the model (sensitivity: 0.814, specificity: 0.941). CONCLUSIONS: NAFLD correlates with PAT volume and PCAT inflammation. Furthermore, combining clinical features, CTA parameters, and radiomic scores can improve the efficiency of early diagnosis of stable CAD in patients with NAFLD.

Acute-on-chronic liver failure in metabolic dysfunction-associated fatty liver disease patients: a disease multiplier.

Acute-on-chronic liver failure (ACLF) is a syndrome of liver failure due to an acute hepatic insult leading to liver failure with or without extra-hepatic organ failure in a patient of chronic liver disease (CLD) with or without cirrhosis presenting for the first time. The definition is still with controversy; hence, homogeneity and clarity of the case is an unmet need. There is a paradigm shift noted as far as the etiology of CLD is concerned with rise in metabolic dysfunction-associated fatty liver disease (MAFLD) and ethanol as the dominant cause even in developing countries. MAFLD is the change in nomenclature from NAFLD to justify the metabolic derangement in these group of patients. The shift from an exclusion-based criteria to one that has evolved to a diagnosis that requires positive criteria has profound significance. Clearly there is a difference in terms of its prevalence, disease progression, and liver-related events, as well as management of metabolic risk factors and MAFLD itself which requires further understanding. In tandem with the global rise in MAFLD, the incidence of MAFLD-ACLF is increasing. Excessive alcohol consumption causes metabolic and toxic injury to the liver resulting in nearly similar pathway of fatty liver, hepatitis, and cirrhosis. The interaction of MAFLD as an additional underlying chronic liver injury in ACLF patients is complex due to the presence of metabolic risk factors that are unique to MAFLD. There is lack of clarity on how MAFLD affects the clinical course of ACLF due to scarcity of this specific data. This narrative review aims to understand the unique effects, consequences, and management of MAFLD as the chronic liver injury component in ACLF.

Effects of exercise on bone marrow adipose tissue in children with overweight/obesity: role of liver fat.

CONTEXT: Exercise reduces adiposity, but its influence on bone marrow fat fraction (BMFF) is unknown; nor is it known whether a reduction in liver fat content mediates this reduction. OBJECTIVES: (i) To determine whether incorporating exercise into a lifestyle program reduces the lumbar spine (LS)-BMFF, and (ii), to investigate whether changes in liver fat mediate any such effect. DESIGN: Ancillary analysis of a two-arm, parallel, non-randomized clinical trial. SETTING: Primary care centres in Vitoria-Gasteiz (Spain). PARTICIPANTS: A total of 116 children with overweight/obesity were assigned to a 22-week family-based lifestyle program (control group [n=57]) or the same program plus an exercise intervention (exercise group [n=59]. INTERVENTIONS: The compared interventions consisted of a family-based lifestyle program (two 90-minute sessions/month) and the same program plus supervised exercise (three 90-minute sessions/week). MAIN OUTCOMES AND MEASURES: The primary outcome examined was the change in LS-BMFF between baseline and 22 weeks, as estimated by MRI. The effect of changes in hepatic fat on LS-BMFF were also recorded. RESULTS: Mean weight loss difference between groups was 1.4±0.5 kg favour of the exercise group. Only the children in the exercise group experienced a reduction in LS-BMFF (effect size [Cohen d] -0.42, CI: -0.86, -0.01). Importantly, 40.9% of the reductions in LS-BMFF were mediated by changes in percentage hepatic fat (indirect effect: ß=-0.104, 95%CI=-0.213, -0.019). The impact of changes in hepatic fat on LS-BMFF was independent of weight loss. CONCLUSIONS AND RELEVANCE: The addition of exercise to a family-based lifestyle program designed to reduce cardiometabolic risk improves bone health by reducing LS-BMFF in children with overweight or obesity. This beneficial effect on bone marrow appears to be mediated by reductions in liver fat.

Associations of very low Lipoprotein(a) levels with risks of new-onset diabetes and non-alcoholic liver disease.

Background and aims: We aimed to study the association of very low serum Lipoprotein(a) [Lp(a)] concentrations with new-onset type 2 diabetes (T2D) and non-alcoholic liver disease (NAFLD) in the context of statin usage in the UK Biobank, a large prospective population cohort. Methods: Using an extended biomarker dataset, we identified 47,362 participants with very low Lp(a) concentrations (<3.8 nmol/L) from a total of 451,479 participants. With a median follow-up of 12.3 years, we assessed the risk of new-onset cardiometabolic diseases in participants stratified by statin usage with Cox proportional hazards models. We performed two-sample Mendelian randomization MR analyses to test causal relationship between genetically predicted Lp(a) and T2D and NAFLD. Results: Taking the participants with Lp(a) within reportable range as the reference group, the hazard ratios (HR) for T2D were 1.07 (95 % confidence interval, CI 1.01-1.13) and for NAFLD 1.30 (95 % CI 1.20-1.41) respectively for participants with very low Lp(a) (<3.8 nmol/L). The risk for new-onset T2D was higher in participants using statins (adjusted HR 1.15; 95 % CI 1.05-1.27). The risk estimates for new-onset NAFLD were comparable in the analysis stratified by statin use. There was no evidence for causal links between genetically predicted Lp(a) and T2D nor NAFLD in two-sample MR analyses. Conclusions: Very low Lp(a) was associated with higher risks of T2D and NAFLD in a prospective analysis of the UK Biobank. The association with T2D was influenced by lipid lowering medication usage. MR analyses did not support causality for these inverse associations.

Metabolic dysfunction-associated steatotic liver disease (SLD) and alcohol-associated liver disease, but not SLD without metabolic dysfunction, are independently associated with new onset of chronic kidney disease during a 10-year follow-up period.

AIMS: The new nomenclature of steatotic liver disease (SLD) including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) has recently been proposed. We aimed to elucidate the relationship between each category of SLD and chronic kidney disease (CKD). METHODS: We investigated the effects of various SLDs on the development of CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or positive for urinary protein, during a 10-year period in 12 138 Japanese subjects (men / women, 7984/4154; mean age, 48 years) who received annual health examinations including abdominal ultrasonography. RESULTS: The prevalences of SLD without metabolic dysfunction (SLD-MD[-]), MASLD, MetALD, and ALD were 1.7%, 26.3%, 4.9%, and 1.9%, respectively. During the follow-up period, 1963 subjects (16.2%) (men / women, 1374 [17.2%]/589 [14.2%]) had new onset of CKD. Multivariable Cox proportional hazard model analyses after adjustment of age, sex, eGFR, current smoking habit, diabetes mellitus, hypertension, and dyslipidemia showed that the hazard ratios (HR [95% confidence interval]) for the development of CKD in subjects with MASLD (1.20 [1.08-1.33], p = 0.001) and those with ALD (1.41 [1.05-1.88], p = 0.022), but not those with MetALD (1.11 [0.90-1.36], p = 0.332), were significantly higher than the HR in subjects with non-SLD. Interestingly, subjects with SLD-MD[-] had a significantly lower HR (0.61 [0.39-0.96], p = 0.034) than that in subjects with non-SLD. The addition of the novel classification of SLDs into traditional risk factors for the development of CKD significantly improved the discriminatory capacity. CONCLUSIONS: MASLD and ALD, but not SLD-MD[-], are independently associated with the development of CKD.

Treatment with 1.25% cholesterol enriched diet produces severe fatty liver disease characterized by advanced fibrosis and inflammation and impaired autophagy in mice.

Non-alcoholic fatty liver disease (NAFLD) is reaching pandemic proportions due to overnutrition. The understanding of advanced stages that recapitulate the human pathology is of great importance to get a better mechanistic insight. We hypothesized that feeding of WT (C57BL) mice with a diet containing a high content of fat (21%), sugar (41.5%) and 1.25% of cholesterol (called from now on high fat, sucrose and cholesterol diet, HFSCD) will reproduce the characteristics of disease severity. Analysis of 16 weeks HFSCD-fed mice demonstrated increased liver weight and plasmatic liver damage markers compared with control diet (CD)-fed mice. HFSCD-fed mice developed greater hepatic triglyceride, cholesterol and NEFA content, inflammation and NAFLD activity score (NAS) indicating an advanced disease. HFSCD-fed mice displayed augmented hepatic total CD3+ T and Th9 lymphocytes, as well as reduced Th2 lymphocytes and CD206 anti-inflammatory macrophages. Moreover, T cells and anti-inflammatory macrophages correlated positively and inversely, respectively, with intrahepatic cholesterol content. Consistently, circulating cytotoxic CD8+ T lymphocytes, Th1, and B cell levels were elevated in HFSCD-fed WT mice. Hepatic and adipose tissue expression analysis demonstrated changes in fibrotic and metabolic genes related with cholesterol, triglycerides, and fatty acid synthesis in HFSCD-fed WT. These mice also exhibited reduced antioxidant capacity and autophagy and elevated ERK signaling pathway activation and CHOP levels. Our results indicate that the feeding with a cholesterol-enriched diet in WT mice produces an advanced NAFLD stage with fibrosis, characterized by deficient autophagy and ER stress along with inflammasome activation partially via ERK pathway activation.

Between-Visit Reproducibility of Shear Wave Viscoelastography in Volunteers and Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease.

OBJECTIVE: To assess the reproducibility of six ultrasound (US)-determined shear wave (SW) viscoelastography parameters for assessment of mechanical properties of the liver in volunteers and patients with biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH). METHODS: This prospective, cross-sectional, institutional review board-approved study included 10 volunteers and 20 patients with MASLD or MASH who underwent liver US elastography twice, at least 2 weeks apart. SW speed (SWS), Young's modulus (E), shear modulus (G), SW attenuation (SWA), SW dispersion (SWD), and viscosity were computed from radiofrequency data recorded on a research US scanner. Linear mixed models were used to consider the sonographer on duty as a confounder. The reproducibility of measurements was assessed by intraclass correlation coefficient (ICC), coefficient of variation (CV), reproducibility coefficient (RDC), and Bland-Altman analyses. RESULTS: The sonographer performing the exam had no impact on viscoelastic parameters (P > .05). ICCs of SWS, E, G, SWA, SWD, and viscosity were, respectively, 0.89 (95% confidence intervals [CI]: 0.79-0.95), 0.81 (95% CI: 0.79-0.95), 0.90 (95% CI: 0.80-0.95), 0.96 (95% CI: 0.93-0.98), 0.78 (95% CI: 0.60-0.89), and 0.90 (95% CI: 0.80-0.95); CVs were 11.9, 23.3, 24.2, 10.1, 29.0, and 32.2%; RDCs were 33.0, 64.5, 66.9, 27.7, 80.3, and 89.2%, and Bland-Altman mean biases and 95% limits of agreement were -0.05 (-0.45, 0.35) m/s, -0.61 (-5.33, 4.10) kPa, -0.25 (-2.06, 1.56) kPa, -0.01 (-0.27, 0.26) Np/m/Hz, -0.09 (-7.09, 6.91) m/s/kHz, and -0.33 (-2.60, 1.94) Pa/s, between the two visits. CONCLUSION: US-determined viscoelastography parameters can be measured with high reproducibility and consistency between two visits 2 weeks apart on the same ultrasound machine.

Global burden of adult non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) has been steadily increasing over the past decades and is expected to persist in the future.

Background: At present, there is a dearth of comprehensive data at the global, national, and regional levels regarding the adult non-alcoholic fatty liver disease (NAFLD) prevalence. This cross-sectional study aims at ascertaining the prevalence of NAFLD and non-alcoholic steatohepatitis (NASH), utilizing body mass index (BMI) as a determining factor. Methods: Based on the NHANES database, sigmoidal fitting curves were generated to establish the relationship between BMI and the risk of NAFLD/NASH. Utilizing BMI data from the NCD Risk Factor Collaboration (NCD-RisC) database at both global and regional levels, the prevalence of NAFLD/NASH among adults was estimated from 1975 to 2016, encompassing global, regional, and national perspectives. Additionally, projections were made to forecast the prevalence of adult NAFLD/NASH from 2017 to 2030. Results: In 2016, the global prevalence of NAFLD was 41.12% for males and 37.32% for females, while the global prevalence of NASH was 15.79% for males and 16.48% for females. The prevalence of NAFLD/NASH increased with higher BMI in both genders. Over the period from 1975 to 2016, there has been a gradual increase in the global prevalence of NAFLD/NASH in adults, and this trend is expected to continue between 2017 and 2030. In males, the prevalence of adult NAFLD/NASH was found to be highest in High-income Western countries, while it was highest in Central Asia, Middle East, and North African countries after 1995. Conclusions: The prevalence of adult NAFLD/NASH has been observed to increase annually, with significant variations in burden across different countries and regions.

Global prevalence of nonalcoholic fatty liver disease: an updated meta-analysis on 78 million population over 38 countries.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a global health challenge, with a rising rate in line with other metabolic diseases. We aimed to assess the global prevalence of NAFLD in adult and pediatric populations. METHODS: PubMed, Scopus and Web of Science databases were systematically searched up to May 2023. Heterogeneity was assessed using Cochran's Q test and I2 statistics, and random-effects model was used for meta-analysis. Analyses were performed using STATA version 18. RESULTS: A total of 479 studies with 78,001,755 participants from 38 countries were finally included. The global prevalence of NAFLD was estimated to be 30.2% (95% CI: 28.7-31.7%). Regionally, the prevalence of NAFLD was as follows: Asia 30.9% (95% CI: 29.2-32.6%), Australia 16.1% (95% CI: 9.0-24.8%), Europe 30.2% (95% CI: 25.6-35.0%), North America 29% (95% CI: 25.8-32.3%), and South America 34% (95% CI: 16.9-53.5%). Countries with a higher human development index (HDI) had significantly lower prevalence of NAFLD (coefficient = -0.523, p = 0.005). Globally, the prevalence of NAFLD in men and women was 36.6% (95% CI: 34.7-38.4%) and 25.5% (95% CI: 23.9-27.1%), respectively. The prevalence of NAFLD in adults, adults with obesity, children, and children with obesity was 30.2% (95% CI: 28.8-31.7%), 57.5% (95% CI: 43.6-70.9%), 14.3% (95% CI: 10.3-18.8%), and 38.0% (95% CI: 31.5-44.7%), respectively. CONCLUSION: The prevalence of NAFLD is remarkably high, particularly in countries with lower HDI. This substantial prevalence in both adults and children underscores the need for disease management protocols to reduce the burden.

Genetics of MASLD: The State of Art Update.

Recent advances in the genetics of metabolic dysfunction-associated steatotic liver disease (MASLD) are gradually revealing the mechanisms underlying the heterogeneity of the disease and have shown promising results in patient stratification. Genetic characterization of the disease has been rapidly developed using genome wide association studies (GWAS), exome wide association studies (EWAS), phenome wide association studies (Phewas), and whole exome sequencing (WES). These advances have been powered by the increase in the computational power, the development of new analytical algorithms, including some based on artificial intelligence (AI), and the recruitment of large and well-phenotype cohorts. This review presents an update on genetic studies that emphasize new biological insights from next-generation sequencing approaches. Additionally, we discuss innovative methods for discovering new genetic loci for MASLD, including rare variants. To comprehensively manage MASLD, it is important to stratify risks. Therefore, we present an update on Phewas associations, including extreme phenotypes. Additionally, we discuss whether polygenic risk scores and targeted sequencing are ready for clinical use. With particular focus on precision medicine, we introduce concepts such as the interplay between genetics and the environment in modulating genetic risk with lifestyle or standard therapies. A special chapter is dedicated to gene-based therapeutics. The limitations of approved pharmacological approaches are discussed, and the potential of gene-related mechanisms in therapeutic development is reviewed, including the decision to perform genetic testing in patients with MASLD.

Role of Nonalcoholic Fatty Liver Disease in Periodontitis: A Bidirectional Relationship.

Nonalcoholic fatty liver disease (NAFLD) and periodontitis share common risk factors such as obesity, insulin resistance (IR), and dyslipidemia, which contribute to systemic inflammation. It has been suggested that a bidirectional relationship exists between NAFLD and periodontitis, indicating that one condition may exacerbate the other. NAFLD is characterized by excessive fat deposition in the liver and is associated with low-grade chronic inflammation. There are several risk factors for the development of NAFLD, including gender, geriatric community, race, ethnicity, poor sleep quality and sleep deprivation, physical activity, nutritional status, dysbiosis gut microbiota, increased oxidative stress, overweight, obesity, higher body mass index (BMI), IR, type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), dyslipidemia (hypercholesterolemia), and sarcopenia (decreased skeletal muscle mass). This systemic inflammation can contribute to the progression of periodontitis by impairing immune responses and exacerbating the inflammatory processes in the periodontal tissues. Furthermore, individuals with NAFLD often exhibit altered lipid metabolism, which may affect oral microbiota composition, leading to dysbiosis and increased susceptibility to periodontal disease. Conversely, periodontitis has been linked to the progression of NAFLD through mechanisms involving systemic inflammation and oxidative stress. Chronic periodontal inflammation can release pro-inflammatory cytokines and bacterial toxins into the bloodstream, contributing to liver inflammation and exacerbating hepatic steatosis. Moreover, periodontitis-induced oxidative stress may promote hepatic lipid accumulation and IR, further aggravating NAFLD. The interplay between NAFLD and periodontitis underscores the importance of comprehensive management strategies targeting both conditions. Lifestyle modifications such as regular exercise, a healthy diet, and proper oral hygiene practices are crucial for preventing and managing these interconnected diseases. Additionally, interdisciplinary collaboration between hepatologists and periodontists is essential for optimizing patient care and improving outcomes in individuals with NAFLD and periodontitis.

Advances in clinical research on glucagon.

We are now celebrating the 100th anniversary of the discovery of an important pancreatic hormone, glucagon. Glucagon is historically described as a diabetogenic hormone elevating glucose levels via increases in insulin resistance and hepatic gluconeogenesis. The more recently identified actions of glucagon include not only its pathophysiologic effects on glucose metabolism but also its significant roles in amino-acid metabolism in the liver. The possibility that abnormalities in α-cells' secretion of glucagon in metabolic disorders are a compensatory adaptation for the maintenance of metabolic homeostasis is another current issue. However, the clinical research concerning glucagon has been considerably behind the advances in basic research due to the lack of suitable methodology for obtaining precise measurements of plasma glucagon levels in humans. The precise physiology of glucagon secretory dynamics in individuals with metabolic dysfunction (including diabetes) has been clarified since the development in 2014 of a quantitative measurement technique for glucagon. In this review, we summarize the advances in the clinical research concerning glucagon, including those of our studies and the relevant literature.

Vinpocetine and Lactobacillus improve fatty liver in rats: role of adiponectin and gut microbiome.

Therapeutics that interfere with the damage/pathogen-associated molecular patterns (DAMPs/PAMPs) have evolved as promising candidates for hepatic inflammation like that occurring in non-alcoholic fatty liver disease (NAFLD). In the current study, we examined the therapeutic impact of the phosphodiesterase-1 inhibitor vinpocetine (Vinpo), alone or when combined with Lactobacillus, on hepatic abnormalities caused by a 13-week high-fat diet (HFD) and diabetes in rats. The results show that Vinpo (10 and 20 mg/kg/day) dose-dependently curbed HFD-induced elevation of liver injury parameters in serum (ALT, AST) and tissue histopathology. These effects were concordant with Vinpo's potential to ameliorate HFD-induced fibrosis (Histological fibrosis score, hydroxyproline, TGF-ß1) and oxidative stress (MDA, NOx) alongside restoring the antioxidant-related parameters (GSH, SOD, Nrf-2, HO-1) in the liver. Mechanistically, Vinpo attenuated the hepatocellular release of DAMPs like high mobility group box (HMGB)1 alongside lowering the overactivation of the pattern recognition receptors including, toll-like receptor (TLR)4 and receptor for advanced glycation end-products (RAGE). Consequently, there was less activation of the transcription factor nuclear factor-kappa B that lowered production of the proinflammatory cytokines TNF-α and IL-6 in Vinpo-treated HFD/diabetes rats. Compared to Vinpo treatment alone, Lactobacillus probiotics as adjunctive therapy with Vinpo significantly improved the disease-associated inflammation and oxidative stress injury, as well as the insulin resistance and lipid profile abnormalities via enhancing the restoration of the symbiotic microbiota. In conclusion, combining Vinpo and Lactobacillus probiotics may be a successful approach for limiting NAFLD in humans.

Efficacy of Ultrasound for the Detection of Possible Fatty Liver Disease in Children.

Pediatric MASLD (previously referred to as NAFLD) incidence has continued to rise along with the obesity pandemic. Pediatric MASLD increases the risk of liver fibrosis and cirrhosis in adulthood. Early detection and intervention can prevent and reduce complications. Liver biopsy remains the gold standard for diagnosis, although imaging modalities are increasingly being used. We performed a retrospective study of 202 children seen in a pediatric gastroenterology clinic with a complaint of abdominal pain, elevated liver enzymes or MASLD, or a combination of the three to evaluate screening methods for MASLD. A total of 134 of the 202 patients included in the study underwent laboratory testing and abdominal ultrasound. Ultrasound images were reviewed with attention to liver size and echotexture by a fellowship-trained pediatric radiologist for liver size and echotexture. Overall, 76.2% of the initial radiology reports correctly identified hepatomegaly based on age and 75.4% of the initial radiology reports correctly described hepatic echogenicity that was consistent with increased hepatic fat deposition. Use of screening ultrasound in concert with other clinical evaluations can be helpful to identify children at risk of MASLD. Utilizing ranges for liver span according to age can help to diagnose hepatomegaly, and understanding how to identify hepatic echogenicity is important for identifying possible hepatic steatosis.

Current and experimental pharmacotherapy for the management of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with its incidence increasing in parallel with the global prevalence of obesity and type 2 diabetes mellitus. Despite our steadily increasing knowledge of its pathogenesis, there is as yet no available pharmacotherapy specifically tailored for NAFLD. To define the appropriate management, it is important to clarify the context in which the disease appears. In the case of concurrent metabolic comorbidities, NAFLD patients are treated by targeting these comorbidities, such as diabetes and obesity. Thus, GLP-1 analogs, PPAR, and SGLT2 inhibitors have recently become central to the treatment of NAFLD. In parallel, randomized trials are being conducted to explore new agents targeting known pathways involved in NAFLD progression. However, there is an imperative need to intensify the effort to design new, safe drugs with biopsy-proven efficacy. Of note, the main target of the pharmacotherapy should be directed to the regression of fibrotic NASH, as this histologic stage has been correlated with increased overall as well as liver-related morbidity and mortality. Herein we discuss the drugs currently at the forefront of NAFLD treatment.

Manifestation and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease in a Predominately African American Population at a Multi-Specialty Healthcare Organization.

African Americans (AA) have a high incidence of risk factors associated with MASLD (metabolic dysfunction-associated steatotic liver disease); the AA population has a lower incidence of MASLD and MASH (metabolic-associated steatotic hepatitis) than Caucasian and Hispanic Americans (non-AA). We investigated if underlying risk factor variation between AA and non-AA individuals could provide a rationale for the racial diversity seen in MASLD/MASH. Using ICD-10 codes, patients from 2017 to 2020 with MASLD/MASH were identified and confirmed to have either MASLD or MASH. Despite the large (>80%) AA population in our clinics, only 54% of the MASLD/MASH patients were African American. When the non-invasive NAFLD Fibrosis Scores (NFS) evaluated at early diagnosis were compared to the most recent values, the only increase in fibrosis score by NFS over time was in non-AA MASH patients. The increase in fibrosis only in non-AA MASLD patients is consistent with racial disparity in the disease progression in non-AA as compared to AA patients. Even with the large proportion of AA patients in our study, there was no significant racial disparity in the earliest assessment of either risk factors, laboratory values, or fibrosis scores that would account for racial disparity in the development and progression of MASLD.

Unveiling structural determinants for FXR antagonism in 1,3,4-trisubstituted-Pyrazol amide derivatives: A multi-scale in silico modelling approach.

Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern due to its potential to progress into severe liver diseases. Targeting the bile acid receptor FXR has emerged as a promising strategy for managing NAFLD. Building upon our previous research on FXR partial agonism, the present study investigates a series of 1,3,4-trisubstituted-pyrazol amide derivatives as FXR antagonists, aiming to delineate the structural features for antagonism. By means of 2D-QSAR (quantitative structure-activity relationships) modelling techniques, we elucidated the key structural elements responsible for the antagonistic properties of these derivatives. We then employed QPhAR, an open-access software, to identify key molecular features within the compounds that enhance their antagonistic activity. Additionally, 3D-QSAR modelling allowed us to analyse the steric and electrostatic fields of aligned 3D structures, further refining our understanding of structure-activity relationships. Subsequent molecular dynamics simulations provided insights into the binding mode interactions between the compounds and FXR, with varying potencies, confirming and complementing the findings from 2D-QSAR, pharmacophore, and 3D-QSAR modelling. Particularly, our study highlighted the significance of hydrophobic interactions in conferring potent antagonism by the 1,3,4-trisubstituted-pyrazol amide derivatives against FXR. Overall, this work underscores the potential of 1,3,4-trisubstituted-pyrazol amides as FXR antagonists for NAFLD treatment. Notably, our reliance on open-access software fosters reproducibility and broadens the accessibility of our findings.