Metabolic dysfunction associated steatotic liver disease (MASLD) is the predominant cause of chronic liver disease, with dysregulation of bile acid (BA) metabolism and intestinal microbiota being intricately associated with MASLD progression. In this study, we investigated the role of ileal FXR in MASLD progression and BA metabolism in portal blood.

Sprague-Dawley rats were fed a typical western diet for 20 weeks, followed by local perfusion of AAV2-shNr1h4 to downregulate Nr1h4 expression in ileum tissue. To investigate the effect of ileal FXR on BA reabsorption and gut microbiota, portal blood and cecal fecal samples were collected from MASLD rats injected with AAV2-Ctrl or AAV2-shNr1h4 for metabolomics targeting BAs and 16S rRNA sequencing analysis.

Our results showed that hepatic steatosis and inflammation were alleviated, whereas the reabsorption of secondary BAs and unconjugated BAs into the portal blood was enhanced when ileal FXR was knocked down. Furthermore, knockdown of ileal FXR resulted in a significant alteration in composition of the cecal microbiota, characterized by an increasing abundance of microbes involved in secondary BA production, including Escherichia, Adlercreutzia, Eubacterium, and Clostridium.

These findings suggest that downregulation of ileal FXR ameliorates the progression of MASLD in rats by modulating BA metabolism mediated by the gut microbiota, indicating that ileal FXR might be a potential therapeutic target for the treatment of MASLD.

Chronic diseases such as obesity, hypertension, and metabolic syndrome are major health concerns worldwide. Ursodeoxycholic acid (UDCA) is a bile acid that is naturally produced in the liver and has been used for the treatment of various liver disorders. In this systematic review and meta-analysis, we investigated how UDCA might affect inflammation, blood pressure, and obesity.

Five major databases were searched from inception to August 2024. The investigated outcomes included body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). A random effect was carried out to estimate pooled weighted mean difference (WMD) with 95% confidence intervals (CI). The registration code is CRD42023428064.

Of the 7912 articles in the initial search, 12 were included in the systematic review and meta-analysis. UDCA consumption significantly decreased BMI (WMD: -0.29 kg/m2, 95% CI: -0.58, -0.01, P = 0.044), and DBP (WMD: -2.16 mmHg, 95% CI: -3.66, -0.66, P = 0.005). It also increased SBP (WMD: 5.50 mmHg, 95% CI: 3.65, 7.35, P < 0.001); however, it was not associated with weight loss (WMD: -0.3 kg, 95% CI: -1.3, 0.71, P = 0.561). Our systematic review showed that UDCA consumption has no effect on IL-6 and TNF-α.

This systematic review and meta-analysis suggest that UDCA supplementation may improve BMI and DBP, whereas it may increase SBP and have no effect on weight or inflammation. Further long-term and well-designed RCTs are needed to further assess and confirm these results.

Non-alcohol fatty liver disease (NAFLD) is a metabolic disorder that represents the hepatic manifestation of systemic process, and is a strong risk factor for diabetes Meletus, whereas the presence of DM increases the severity of NAFLD/NASH and its progression. Data on the impact of diabetes on NASH phenotype is sparse from northern India. We studied and compared the clinical profile of NALFD in the presence and absence of DM and the effect of diabetes on NASH.

We did a cross-sectional analysis of data from NAFLD patients (n = 90) who were divided into diabetic and non-diabetic cohorts and their respective demographic, biochemical, imaging and histological features were recorded and compared.

Out of 90 patients, 53.3% were females with a mean age of 44 ± 12 years. The mean BMI and WHR of the study cohort were 28.9 ± 3.4 and 1.01 ± 0.15, respectively. The current study showed that 35.8% were diabetics. The mean age and WHR were 52 ± 11 years vs 40 ± 10 years and 1.1 ± 0.17 vs 0.99 ± 0.09, respectively, in diabetic and non-diabetic NAFLD patients. Non-invasive fibrosis scores, including BARD (2.8 vs 1.73), FIB-4 (3.4 vs 2.2) and NFS (0.97 vs -1.13), were significantly higher in diabetic NAFLD compared to non-diabetic NAFLD (P < 0.03). The histological grade of steatosis and fibrosis as depicted by the mean NAS score (5.7 ± 1.2 vs 4.63 ± 0.8) was higher in diabetic NAFLD vs non-diabetic NAFLD; however, only the fibrosis stage was statistically significant between the groups (P < 0.001).

Despite the small no of cases, we should conclude that there is a bidirectional relationship between NAFLD and DM where the progression of one increases the rate of progression of other. Diabetic patients have higher risk of NASH and hence increased risk of liver related mortality and should be screened early for NAFLD/NASH.

We explored the changes in metabolic dysfunction-associated steatotic liver disease (MASLD) severity over time by analyzing data from the placebo arms of randomized controlled trials (RCTs), focusing on the presence of diabetes.

RCTs on MASLD that included a placebo arm were identified using a systematic search of the literature. Primary outcomes were changes in hepatic steatosis and fibrosis.

The meta-analysis included 8 RCTs involving 386 patients without diabetes and 24 RCTs involving 637 patients with diabetes. The pooled estimate of mean change in steatosis grade was - 0.1 in patients without diabetes, and - 0.37 in patients with diabetes (P = 0.066). The mean change in fibrosis stage was 0.05 in patients without diabetes, and - 0.03 in patients with diabetes (P = 0.359). The mean change in nonalcoholic fatty liver disease activity score was - 0.55 in patients without diabetes, and - 1.50 in patients with diabetes (P = 0.100). The mean change in ALT and AST were significantly larger in patients without diabetes compared to those with diabetes (P < 0.05).

Placebo treatment had a greater effect in improving liver steatosis in patients with diabetes compared to those without. These findings highlight the importance of tailored treatment strategies in MASLD, particularly considering diabetes status.

The study aimed to investigate the alterations in gut microbiota among nonobese individuals with nonalcoholic fatty liver disease (NAFLD) and their response to treatment with ursodeoxycholic acid (UDCA). A total of 90 patients diagnosed with NAFLD and 36 healthy subjects were recruited to participate in this study. Among them, a subgroup of 14 nonobese nonalcoholic steatohepatitis (NASH) were treated with UDCA. Demographic and serologic data were collected for all participants, while stool samples were obtained for fecal microbiome analysis using 16S sequencing. In nonobese NAFLD patients, the alpha diversity of intestinal flora decreased (Shannon index, p < 0.05), and the composition of intestinal flora changed (beta diversity, p < 0.05). The abundance of 20 genera, including Fusobacterium, Lachnoclostridium, Klebsiella, etc., exhibited significant changes (p < 0.05). Among them, nine species including Fusobacterium, Lachnoclostridium, Klebsiella, etc. were found to be associated with abnormal liver enzymes and glucolipid metabolic disorders. Among the 14 NASH patients treated with UDCA, improvements were observed in terms of liver enzymes, CAP values, and E values (p < 0.05), however, no improve the glucolipid metabolism. While the alpha diversity of intestinal flora did not show significant changes after UDCA treatment, there was a notable alteration in the composition of intestinal flora (beta diversity, p < 0.05). Furthermore, UCDA treatment led to an improvement in the relative abundance of Alistipes, Holdemanella, Gilisia, etc. among nonobese NASH patients (p < 0.05). Nonobese NAFLD patients exhibit dysbiosis of the intestinal microbiota. UDCA can ameliorate hepatic enzyme abnormalities and reduce liver fat content in nonobese NASH patients, potentially through its ability to restore intestinal microbiota balance.

On March 14, 2024, after more than 25 years of intense research and a long series of failures, the Food and Drug Administration approved resmetirom as first drug for the treatment of non-alcoholic steatohepatitis (NASH) with fibrosis (now Metabolic-Associated Steatotic Liver Disease - MASLD). The present review covers this difficult process, finally providing a drug to complement lifestyle intervention, that has long been the sole approved therapeutic intervention. However, the availability of a drug shown to reduce disease progression in advanced stages of diseases opens a series of questions that deserve even more intense research. How to continue ongoing trials? How to generate an appropriate use of resmetirom in the community, limiting treatment according to predefined criteria and according to individual risk assessment? How to guarantee that both hepatic and non-hepatic comorbidities are appropriately targeted? How to define cost-effective strategies that might prevent the generation of unacceptable differences within the population, given the high costs of novel drugs and the extremely high numbers of candidates to treatment? Only a close surveillance of drug use in the real world, generated by insurance databases and national healthcare system registries, might provide adequate answers to these compelling questions.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.

BAR502, a bile acid analogue, is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. In this paper we report the synthesis and the biological evaluation of a library of hybrid compounds prepared by combining, through high-yield condensation reaction, some fibrates with BAR502.The activity of the new conjugates was evaluated towards FXR, GPBAR1 and PPARα receptors, employing transactivation or cofactor recruitment assays. Compound 1 resulted as the most promising of the series and was subjected to further pharmacological investigation, together with stability evaluation and cell permeation assessment. We have proved by LCMS analysis that compound 1 is hydrolyzed in mice releasing clofibric acid and BAR505, the oxidized metabolite of BAR502, endowed with retained dual FXR/GPBAR1 activity.

Non-alcoholic fatty liver disease (NAFLD), spanning from non-alcoholic steatohepatitis (NASH) to liver fibrosis, poses a global health challenge amid rising obesity and metabolic syndrome rates. Effective pharmacological treatments for NASH and liver fibrosis are limited.

This study systematically reviews and meta-analyzes the safety and efficacy of resmetirom, a selective thyroid hormone receptor-β agonist, in NASH and liver fibrosis treatment. By analyzing data from clinical trials, we aim to offer evidence-based recommendations for resmetirom's use in managing these conditions and identify avenues for future research.

Electronic databases (PubMed, Scopus, Science Direct, Google Scholar, ClinicalTrials.gov, and Cochrane CENTRAL) were systematically searched, supplemented by manual screening of relevant sources. Only English-language randomized controlled trials were included. Data extraction, risk of bias assessment, pooled analyses, and meta-regression were performed.

Three randomized controlled trials involving 2231 participants were analyzed. Resmetirom demonstrated significant reductions in hepatic fat fraction [standardized mean difference (SMD) -4.61, 95% CI -6.77 to -2.44, P < 0.0001], NASH resolution without worsening fibrosis [risk ratio (RR) 2.51, 95% CI 1.74-3.64, P = 0.00001), and liver fibrosis improvement (RR 2.31, 95% CI 1.20-4.44, P = 0.01). Secondary outcomes showed significant improvements in lipid profiles, liver enzymes, and NASH biomarkers with resmetirom treatment. Meta-regression revealed associations between covariates and primary outcomes.

Resmetirom exhibits promising efficacy in reducing hepatic fat, improving NASH resolution, and ameliorating liver fibrosis with a favorable safety profile. Further research is warranted to validate findings and optimize therapeutic strategies for NASH and liver fibrosis management.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid commonly used for treating cholestatic liver disease. However, its efficacy on non-alcoholic steatohepatitis (NASH) was controversial. This study aimed to investigate the impact of a high dosage of UDCA on a mouse model of NASH. Forty 6-week-old mice were fed a high-fat high-cholesterol (HFHC) diet for 12 weeks to establish a mouse model of NASH, and then divided into four groups: two groups transitioned to a normal diet, and the other two groups maintained the HFHC diet. Each group was administered a daily dosage of 300 mg/kg of UDCA or saline for a period of 8 weeks. The 16 s ribosomal RNA genes extracted from mice fecal pellets were sequenced using next-generation sequencing techniques. Serum bile acid profiles were quantified using liquid chromatography electrospray ionization tandem mass spectrometry method. The results showed that UDCA treatment ameliorated liver inflammation, without affecting liver fibrosis. UDCA treatment reduced the relative abundance of the genera Bacteroides, Parabacteroides, and Intestinimonas, whereas increased the relative abundance of the genera norank_f_Muribaculaceae and Parasutterella in the HFHC-maintaining groups. The serum levels of total bile acids and total primary bile acids increased, whereas those of endogenous primary bile acids decreased after UDCA treatment. Correlation analysis showed that primary bile acids were negatively correlated with the genera norank_f_Christensenellaceae and unclassified_f_Ruminococcaceae. In conclusion, a high dosage of UDCA can alleviate liver inflammation, probably by modifying the composition of gut microbiota and serum bile acid profiles in NASH mice.

Nonalcoholic steatohepatitis (NASH) has been the second most common cause of liver transplantation in the United States. To date, NASH pathogenesis has not been fully elucidated but is multifactorial, involving insulin resistance, obesity, metabolic disorders, diet, dysbiosis, and gene polymorphism. An effective and approved therapy for NASH has also not been established. Bile acid is long known to have physiological detergent function in emulsifying and absorbing lipids and lipid-soluble molecules within the intestinal lumen. With more and more in-depth understandings of bile acid, it has been deemed to be a pivotal signaling molecule, which is capable of regulating lipid and glucose metabolism, liver inflammation, and fibrosis. In recent years, a plethora of studies have delineated that disrupted bile acid homeostasis is intimately correlated with NASH disease severity.

The review aims to clarify the role of bile acid in hepatic lipid and glucose metabolism, liver inflammation, as well as liver fibrosis, and discusses the safety and efficacy of some pharmacological agents targeting bile acid and its associated pathways for NASH.

Bile acid has a salutary effect on hepatic metabolic disorders, which can ameliorate liver fat accumulation and insulin resistance mainly through activating Takeda G-protein coupled receptor 5 and farnesoid X receptor. Moreover, bile acid also exerts anti-inflammation and anti-fibrosis properties. Furthermore, bile acid has great potential in nonalcoholic liver disease stratification and treatment of NASH.

Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD) is a disease spectrum encompassing liver injury with progressive severity, tightly connected to the metabolic syndrome. Management of MASLD mostly relies on lifestyle change aiming at improving metabolic homeostasis and insulin resistance. A Mediterranean-like dietary pattern and individualized lifestyle interventions are the cornerstone of MASLD treatment. A careful evaluation of alcohol intake and active treatment of all metabolic co-morbidities are recommended. In the MASLD spectrum, the population with liver inflammation and enhanced fibrogenesis (MASH - Metabolic-dysfunction associated steatohepatitis) can progress to advanced liver disease and has been addressed as "at-risk MASH", eligible to pharmacological treatment according to FDA and EMA. Currently there is a robust therapeutic pipeline across a variety of new targets to resolve MASH or reverse fibrosis, or both. Some of these therapies have beneficial effects that extend beyond the liver, such as effects on glycaemic control, lipid profile and weight loss. For "at-risk" MASH, reversal of fibrosis by one stage or resolution of MASH with no worsening in fibrosis as a surrogate end-point will need to be accompanied by overall survival benefits. In this review, we summarize the current evidence on lifestyle interventions in MASLD as well as pharmacological approaches for fibrosing MASH that have progressed to phase II and phase III clinical trials.

Nonalcoholic fatty liver disease (NAFLD), currently referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 38% of the world's population, yet no pharmacological therapies have been approved for treatment. We conducted a traditional and network meta-analysis to comprehensively assess the effectiveness of drug regimens on NAFLD, and continued to use the old terminology for consistency.

Randomized, placebo-controlled trials (RCTs) investigating drug therapy in an adult population diagnosed with NAFLD with or without diabetes mellitus were included. We assessed the quality of RCTs via the Risk of Bias 2 (ROB 2) tool. When I2 < 50%, we chose a random-effects model, otherwise a fixed-effects model was selected. A random effects model was applied in the network meta-analysis. The odds ratio (OR), weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence interval (CI) were used for outcome evaluation. The primary endpoint was the resolution of nonalcoholic steatohepatitis (NASH) without the worsening of liver fibrosis. Other endpoints included histological findings and metabolic changes. The PROSPERO Registration ID was CRD42023404309.

Thiazolidinediones (TZDs), vitamin E plus pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists and fibroblast growth factor-21 (FGF-21) analogue had a higher surface under the cumulative ranking curve (SUCRA = 76.6, 73.0, 72.0 and 71.6) regarding NASH resolution. Improvement of liver fibrosis stage (≥ 1) was observed with obeticholic acid 25 mg/day (OR 2.01, 95% CI 1.35-2.98), lanifibranor 1200 mg/day (OR 2.39, 95% CI 1.19-4.82) and silymarin (OR 4.54, 95% CI 1.18-17.43) in traditional meta-analysis.

The results of the comprehensive analysis suggested hypoglycemic drug therapy as an effective intervention for NAFLD, with or without diabetes mellitus. A prioritized selection of TZDs, vitamin E plus pioglitazone, GLP-1 receptor agonists and FGF-21 analogue may be considered for NASH resolution. Obeticholic acid, lanifibranor and silymarin could be considered for the improvement of liver fibrosis. Each medication was relatively safe compared with placebo.

Non-alcoholic fatty liver disease (NAFLD) is a global metabolic disease with high prevalence in both adults and children. Importantly, NAFLD is becoming the main cause of hepatocellular carcinoma (HCC). Berberine (BBR), a naturally occurring plant component, has been demonstrated to have advantageous effects on a number of metabolic pathways as well as the ability to kill liver tumor cells by causing cell death and other routes. This permits us to speculate and make assumptions about the value of BBR in the prevention and defense against NAFLD and HCC by a global modulation of metabolic disorders. Herein, we briefly describe the etiology of NAFLD and NAFLD-related HCC, with a particular emphasis on analyzing the potential mechanisms of BBR in the treatment of NAFLD from aspects including increasing insulin sensitivity, controlling the intestinal milieu, and controlling lipid metabolism. We also elucidate the mechanism of BBR in the treatment of HCC. More significantly, we provided a list of clinical studies for BBR in NAFLD. Taking into account our conclusions and perspectives, we can make further progress in the treatment of BBR in NAFLD and NAFLD-related HCC.

Bile salts have an established role in the emulsification and intestinal absorption of dietary lipids, and their homeostasis is tightly controlled by various transporters and regulators in the enterohepatic circulation. Notably, emerging evidence points toward bile salts as major modulators of cardiometabolic disease (CMD), an umbrella disease of disorders affecting the heart and blood vessels that is caused by systemic metabolic diseases such as Type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), the latter encompassing also metabolic dysfunction-associated steatohepatitis (MASH). The underlying mechanisms of protective effects of bile salts are their hormonal properties, enabling them to exert versatile metabolic effects by activating various bile salt-responsive signaling receptors with the nuclear farnesoid X receptor (FXR) and the Takeda G-protein-coupled receptor 5 (TGR5) as most extensively investigated. Activation of FXR and TGR5 is involved in the regulation of glucose, lipid and energy metabolism, and inflammation. Bile salt-based therapies directly targeting FXR and TGR5 signaling have been evaluated for their therapeutic potential in CMD. More recently, therapeutics targeting bile salt transporters thereby modulating bile salt localization, dynamics, and signaling, have been developed and evaluated in CMD. Here, we discuss the current knowledge on the contribution of bile salt signaling in the pathogenesis of CMD and the potential of bile salt-based therapies for the treatment of CMD.

This meta-analysis's objective was to assess the effectiveness of ursodeoxycholic acid (UDCA) in the management of nonalcoholic fatty liver disease (NAFLD).

Electronic databases like PubMed, Embase, Scopus, and Cochrane Library were thoroughly looked for randomized controlled trials determining ursodeoxycholic acid's (UDCAs) effectiveness on the serum liver function tests in NAFLD patients. After screening, seven randomized controlled trials were incorporated overall. Utilizing a fixed effects model, quantitative data synthesis was performed in R version 4.3.1.

The meta-analysis showed significant reductions in alanine transaminase (ALT) (p ≤ 0.0001), aspartate transaminase (p = 0.0009), and gamma-glutamyl transferase (GGT) (p ≤ 0.0001) after UDCA therapy. However, significant reductions in bilirubin (p = 0.6989) and alkaline phosphatase (ALP) (p = 0.1172) levels were not noted. Sensitivity analysis by removing the studies with some concerns of bias was successful in demonstrating a remarkable reduction in heterogeneity for aspartate transaminase and ALP, which was also observed while performing the subgroup analyses via dosage.

Ursodeoxycholic acid was beneficial in patients diagnosed with NAFLD as it significantly reduced aspartate transaminase, ALT and GGT levels. However, more randomized controlled trials are required to be conducted in the future to increase the certainty of the evident findings.

This meta-analysis strengthens the evidence about the reductions in AST, ALT, and GGT levels observed with ursodeoxycholic acid therapy in NAFLD patients by pooling the data together from the latest RCTs thus proving its hepatoprotective effects which can be beneficial in preventing the associated complications.

Patel VS, Mahmood SF, Bhatt KH, et al. Ursodeoxycholic Acid's Effectiveness in the Management of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Euroasian J Hepato-Gastroenterol 2024;14(1):92-98.

In recent decades, the global prevalence of metabolic syndrome has surged, posing a significant public health challenge. Metabolic disorders, encompassing diabetes, obesity, nonalcoholic fatty liver disease, and polycystic ovarian syndrome, have been linked to alterations in the gut microbiota. Nonetheless, the connection between gut microbiota and host metabolic diseases warrants further investigation. In this review, we delve into the associations between various metabolic disorders and the gut microbiota, focusing on immune responses and bile acid (BA) metabolism. Notably, T helper cells, innate lymphoid cells, macrophages, and dendritic cells have been shown to modulate host metabolism through interactions with intestinal microorganisms and the release of cytokines. Furthermore, secondary BA metabolites, derived from the microbiota, are involved in the pathogenesis of metabolic diseases via the farnesoid X receptor and Takeda G protein-coupled receptor 5. By covering both aspects of this immune system-microorganism axis, we present a comprehensive overview of the roles played by the gut microbiota, microbiota-derived BA metabolites, and immune responses in metabolic diseases, as well as the interplay between these systems.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide, ranging from liver steatosis to nonalcoholic steatohepatitis, which ultimately progresses to fibrosis, cirrhosis, and hepatocellular carcinoma. Individuals with NAFLD have a higher risk of developing cardiovascular and extrahepatic cancers. Despite the great progress being made in understanding the pathogenesis and the introduction of new pharmacological targets for NAFLD, no drug or intervention has been accepted for its management. Recent evidence suggests that NAFLD may be a mitochondrial disease, as mitochondrial dysfunction is involved in the pathological processes that lead to NAFLD. In this review, we describe the recent advances in our understanding of the mechanisms associated with mitochondrial dysfunction in NAFLD progression. Moreover, we discuss recent advances in the efficacy of mitochondria-targeted compounds (e.g., Mito-Q, MitoVit-E, MitoTEMPO, SS-31, mitochondrial uncouplers, and mitochondrial pyruvate carrier inhibitors) for treating NAFLD. Furthermore, we present some medications currently being tested in clinical trials for NAFLD treatment, such as exercise, mesenchymal stem cells, bile acids and their analogs, and antidiabetic drugs, with a focus on their efficacy in improving mitochondrial function. Based on this evidence, further investigations into the development of mitochondria-based agents may provide new and promising alternatives for NAFLD management.

Recently the roles of gut microbiota are highly regarded in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The intestinal bacteria regulate the metabolism of bile acids depending on bile salt hydrolase (BSH), 7-dehydroxylation, hydroxysteroid dehydrogenase (HSDH), or amide conjugation reaction, thus exerting effects on NAFLD development through bile acid receptors such as farnesoid X receptor (FXR), Takeda G-protein-coupled bile acid protein 5 (TGR5), and vitamin D receptor (VDR), which modulate nutrient metabolism and insulin sensitivity via interacting with downstream molecules. Reversely, the composition of gut microbiota is also affected by the level of bile acids in turn. We summarize the mutual regulation between the specific bacteria and bile acids in NAFLD and the latest clinical research based on microbiota and bile acids, which facilitate the development of novel treatment modalities in NAFLD.

Paralleling the rise in obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) is now the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, may progress to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Despite its public health treat, no approved pharmacotherapies for NAFLD/NASH currently exist. Although the armamentarium of therapies for NASH is limited, current treatment options include life-style modification and the use of medications to treat metabolic comorbidities. This review addresses current approaches to the treatment of NAFLD/NASH, including the impact of diet, exercise, and available pharmacotherapies on the histologic features of liver injury.

Nonalcoholic fatty liver disease (NAFLD) is a rapidly growing multisystem disease with extrahepatic manifestations, including effects on the cardiovascular (CV) system. The leading cause of death in NAFLD is of cardiac etiology being ischemic heart disease.

NAFLD is associated with several CV complications including cardiac structural and functional alterations. However, there are no current approved pharmacotherapies for treating NAFLD, leading to increased CV risk with an increasing morbidity and mortality.

We summarize the currently available therapeutic strategies in managing NAFLD and their cardioprotective effects according to recently published data, guidelines, and practice guidance recommendations.

Several therapeutic modalities evaluated in NAFLD include nonpharmacological strategies, pharmacotherapies and surgical management. Nonpharmacological strategies are recommended in early stages of NAFLD and include weight loss, physical activity, and dietary changes. Personalized management strategies with nonpharmacological lifestyle modifications are associated with reduced CV risk, improved liver enzyme levels, in addition to liver fat content, injury, and fibrosis. Several pharmacotherapies including lipid-lowering agents and antidiabetic drugs such as insulin sensitizers and incretin mimetics, in addition to antioxidants, ursodeoxycholic acid, semi-synthetic bile acid analogue, acetylsalicylic acid, and renin-angiotensin system inhibitors have been evaluated in the current literature. Despite promising results of several drugs in NAFLD with cardioprotective effects, we currently remain with no approved medical drugs for treating NAFLD. Although bariatric surgery was demonstrated to be associated with CV risk reduction and improvements in hepatic steatosis, inflammation, and fibrosis, it remains of limited use because of its invasiveness.

Management of NAFLD necessitates a multidisciplinary team with a patient-centered and individualized medicine approach. Early lifestyle modifications are essential in NAFLD to reduce CV risk. Experimental studies are required to confirm hepatic and cardioprotective effects associated with several drugs. Bariatric surgery remains of limited use.

Nonalcoholic fatty liver disease (NAFLD), a chronic liver condition affects a large number of people around the world with a frequency of 25% of all the chronic liver disease worldwide. Several targets viz. anti-inflammatory, anti-apoptotic and, anti-fibrotic factors, anti-oxidant and insulin-sensitizing pathways, metabolic regulators as well as repurposing traditional medications have been studied for the pharmacologic therapy of NAFLD. Newer pharmacotherapies like caspases blockade, agonists of PPAR and farnesoid X receptor agonists are currently being investigated in treating human NAFLD. However, NAFLD has no FDA-approved pharmacological therapy, therefore there is a considerable unmet therapy need. Apart from the conventional treatment regime, the current approaches to treating NAFLD include lifestyle interventions including healthy diet with adequate nutrition and physical activity. Fruits are known to play a key role in the well-being of human health. Fruits are loaded with a repertoire of bioactive phytoconstituents like catechins, phytosterols, proanthocyanidin, genestin, daidzen, resveratrol, magiferin found in fruits like pear, apricot, strawberries, oranges, apples, bananas, grapes, kiwi, pineapple, watermelon, peach, grape seed and skin, mango, currants, raisins, dried dates, passion fruit and many more. These bioactive phytoconstituents are reported to demonstrate promising pharmacological efficacy like reduction in fatty acid deposition, increased lipid metabolism, modulation of insulin signaling pathway, gut microbiota and hepatic inflammation, inhibition of histone acetyltransferase enzymatic activity to name a few. Not only fruits, but their derivatives like oils, pulp, peel, or their preparations are also found to be equally beneficial in various liver diseases like NAFLD, NASH. Although most of the fruits contains potent bioactive phytoconstituents, however, the presence of sugar in fruits put a question mark on the ameliorative property of the fruits and there has been contrasting reports on the glycemic control post fruit consumption in type 2 diabetic patients. This review is an attempt to summarize the beneficial effects of fruit phytoconstituents on NAFLD based on epidemiological, clinical and experimental evidence, focusing especially on their mechanisms of action.

Nonalcoholic fatty liver disease (NAFLD) is one of the world's most common chronic liver diseases. However, its pathogenesis remains unclear. With the deepening of research, NAFLD is considered a metabolic syndrome associated with the environment, heredity, and metabolic disorders. Recently, the close relationship between the intestinal microbiome and NAFLD has been discovered, and the theory of the "gut-liver axis" has been proposed. In short, the gut bacteria directly reach the liver via the portal vein through the damaged intestinal wall or indirectly participate in the development of NAFLD through signaling pathways mediated by their components and metabolites. This review focuses on the roles of microbiota-derived lipopolysaccharide, DNA, peptidoglycan, bile acids, short-chain fatty acids, endogenous ethanol, choline and its metabolites, indole and its derivatives, and bilirubin and its metabolites in the progression of NAFLD, which may provide significative insights into the pathogenesis, diagnosis, and treatment for this highly prevalent liver disease.

Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids are signaling molecules acting on two main receptors the Farnesoid-x-receptor (FXR) and G protein coupled receptor GPB AR1. Clinical trials have shown that FXR agonism might result in side effects along with lack of efficacy in restoring liver histopathology. For these reasons a multi-targets therapy combined FXR agonists with agent targeting additional molecular mechanisms might have improved efficacy over selective FXR agonists. In the present study we have compared the effects of BAR502, a dual FXR/GPBAR1 ligand) alone or in combination with ursodeoxycholic acid (UDCA) in a model of NAFLD/NASH induced by feeding mice with a Western diet for 10 weeks. The results demonstrated that while BAR502 and UDCA partially protected against liver damage caused by Western diet, the combination of the two, reversed the pro-atherogenic lipid profile and completely reversed the histopathology damage, attenuating liver steatosis, ballooning, inflammation and fibrosis. Additionally, while both agents increased insulin sensitivity and bile acid signaling, the combination of the two, modulated up top 85 genes in comparison of mice feed a Western diet, strongly reducing expression of inflammatory markers such as chemokines and cytokines. Additionally, the combination of the two agents redirected the bile acid metabolism toward bile acid species that are GPBAR1 agonist while reduced liver bile acid content and increased fecal excretion. Together, these data, highlight the potential role for a combinatorial therapy based on BAR502 and UDCA in treating of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, associated with a high risk of progression to NASH, liver cirrhosis and hepatocarcinoma. Its prevalence is closely related to obesity (understood as adipose-based disease and insulin resistance), which makes that at present NAFLD can be considered a metabolic dysfunction hallmark, regardless of the body mass index. Despite being such a prevalent condition, with such severe consequences, at present there are no reliable biomarkers for its diagnosis or specific treatment. Significant and sustained weight loss, as well as some antidiabetic treatments, has shown promising results for NAFLD but data needs confirmation in larger clinical trials and longer follow-up. Efforts should be made for a better and more accurate baseline diagnosis (including large-scale genetics), identification of patients at higher risk for progression to NASH as well as adequate treatment, to allow us to offer a personalized approach in NAFLD in the context of precision medicine.

Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids play an essential role in regulating liver metabolism, and several bile acids-based therapy are currently investigated for their potential therapeutic efficacy in NAFLD/NASH. Bile acids exert their functions, at least in part, by modulating two main receptors the Farnesoid-x-receptor (FXR) and the G protein-coupled receptor, GPBAR1. In the present study we have compared the pharmacological effects of two bile acids, the ursodeoxycholic acid (UDCA) and its derivative norUDCA, in a model of NAFLD/NASH induced by feeding mice with a Western diet for 12 weeks. The results of these studies demonstrated that both UDCA and norUDCA protected against development of steatosis and fibrosis, but did not reduce the hepatocytes ballooning nor the development of a pro-atherogenic lipid profile. Both agents reduced liver lipogenesis and ameliorated insulin sensitivity and adipocytes signaling as shown by increased expression of adiponectin. Mechanistically, UDCA acts as weak GPBAR1 agonist, while norUDCA exerted no effect on both GPBAR1 and FXR. In vivo administration of UDCA resets bile acid synthesis and promotes a shift toward bile acids species that are GPBAR1 agonists, UDCA, TUDCA and hyodeoxycholic acid, and increases GLP1 expression in the ileum. In contrast norUDCA is poorly metabolized exerting a minimal impact on GPBAR1 signaling. Together, these data, highlight the potential role of UDCA and norUDCA in treating of NAFLD, though these beneficial effects are supported by different mechanisms.

Numerous studies show a modification of the gut microbiota in patients with obesity or diabetes. Animal studies have also shown a causal role of gut microbiota in liver metabolic disorders including steatosis whereas the human situation is less clear. Patients with metabolic dysfunction associated fatty liver disease (MAFLD) also have a modification in their gut microbiota composition but the changes are not fully characterized. The absence of consensus on a precise signature is probably due to disease heterogeneity, possible concomitant medications and different selection or evaluation criteria. The most consistent changes were increased relative abundance of Proteobacteria, Enterobacteriaceae and Escherichia species and decreased abundance of Coprococcus and Eubacterium. Possible mechanisms linking the microbiota and MAFLD are increased intestinal permeability with translocation of microbial products into the portal circulation, but also changes in the bile acids and production of microbial metabolites such as ethanol, short chain fatty acids and amino acid derivatives able to modulate liver metabolism and inflammation. Several interventional studies exist that attempt to modulate liver disease by administering antibiotics, probiotics, prebiotics, synbiotics, postbiotics or fecal transplantation. In conclusion, there are both gaps and hopes concerning the interest of gut microbiome evaluation for diagnosis purposes of MAFLD and for new therapeutic developments that are often tested on small size cohorts.

The bile acid receptor FXR has emerged as a bona fide drug target for chronic cholestatic and metabolic liver diseases, ahead of all non-alcoholic fatty liver disease (NAFLD). FXR is highly expressed in the liver and intestine and activation at both sites differentially contributes to its desired metabolic effects. Unrestricted FXR activation, however, also comes along with undesired effects such as a pro-atherogenic lipid profile, pruritus and hepatocellular toxicity under certain conditions. Several pre-clinical studies have confirmed the potency of FXR activation for cholestatic and metabolic liver diseases, but overall it remains still open whether selective activation of intestinal FXR is advantageous over pan-FXR activation and whether restricted or modulated FXR activation can limit some of the side effects. Even more, FXR antagonist also bear the potential as intestinal-selective drugs in NAFLD models. In this review we will discuss the molecular prerequisites for FXR activation, pan-FXR activation and intestinal FXR in/activation from a therapeutic point of view, different steroidal and non-steroidal FXR agonists, ways to restrict FXR activation and finally what we have learned from pre-clinical models and clinical trials with different FXR therapeutics.

Bile acids (BAs) can regulate their own metabolism and transport as well as other key aspects of metabolic homeostasis via dedicated (nuclear and G protein-coupled) receptors. Disrupted BA transport and homeostasis results in the development of cholestatic disorders and contributes to a wide range of liver diseases, including nonalcoholic fatty liver disease and hepatocellular and cholangiocellular carcinoma. Furthermore, impaired BA homeostasis can also affect the intestine, contributing to the pathogenesis of irritable bowel syndrome, inflammatory bowel disease, and colorectal and oesophageal cancer. Here, we provide a summary of the role of BAs and their disrupted homeostasis in the development of gastrointestinal and hepatic disorders and present novel insights on how targeting BA pathways might contribute to novel treatment strategies for these disorders.

The global burden of chronic liver disease (CLD) is substantial. Due to the limited indication of and accessibility to antiviral therapy in viral hepatitis and lack of effective pharmacological treatment in nonalcoholic fatty liver disease, the beneficial effects of antidiabetics and non-antidiabetics in clinical practice have been continuously investigated in patients with CLD. In this narrative review, we focused on non-antidiabetic drugs, including ursodeoxycholic acid, silymarin, dimethyl4,4'-dimethoxy-5,6,5',6'-dimethylenedixoybiphenyl-2,2'-dicarboxylate, L-ornithine L-aspartate, branched chain amino acids, statin, probiotics, vitamin E, and aspirin, and summarized their beneficial effects in CLD. Based on the antioxidant, anti-inflammatory properties, and regulatory functions in glucose or lipid metabolism, several non-antidiabetic drugs have shown beneficial effects in improving liver histology, aminotransferase level, and metabolic parameters and reducing risks of hepatocellular carcinoma and mortality, without significant safety concerns, in patients with CLD. Although the effect as the centerpiece management in patients with CLD is not robust, the use of these non-antidiabetic drugs might be potentially beneficial as an adjuvant or combined treatment strategy.

Previous studies have demonstrated that ursodeoxycholic acid (UDCA) possesses anti-inflammatory, antioxidant, and anti-fibrotic properties, and it may reduce the degree of liver damage caused by nonalcoholic steatohepatitis (NASH). However, the effectiveness of UDCA in improving liver function and histology in cases of NASH remains unclear. Therefore, we performed a meta-analysis to assess the efficacy of UDCA in the treatment of NASH.

PubMed, Web of Science, Embase, Cochrane, and other databases were searched for randomized controlled trials (RCTs) published before 1 January 2022, in which UDCA was used to treat patients with NASH.

A total of 8 studies with 655 participantsmet the criteria for inclusion in this meta-analysis. The forest plot displayed that UDCA treatment significantly reduced blood concentrations of alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT). However, the pooled effect size results did not suggest any significant effect of UDCA on anthropometric characteristics or hepatic histology.

UDCA therapy can effectively reduce serum levels of ALT and GGT in patients with NASH but has no significant effects on physical characteristics or liver histology. Further large-scale and dose-response clinical studies are needed to evaluate the clinical potential of UDCA in treating NASH.

Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the past years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato, the Società Italiana di Diabetologia and the Società Italiana dell'Obesità reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure and Istituto Superiore di Sanità. Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources.Level of evidence Level of evidence of recommendations for each PICO question were reported according to available evidence.

The evaluation of the natural history of NASH has been limited. Currently, liver biopsy remains the gold standard in the assessment of NASH. Placebo-controlled trials represent a controlled environment with paired biopsies for the evaluation of NASH. This meta-analysis thus seeks to quantify the change severity of NASH over time, with patients on placebo arms from randomized controlled trials (RCTs) to examine the natural history of NASH.

A search was conducted to include NASH RCTs with placebo treatment arms. Primary outcomes were (1) the resolution of NASH without worsening of fibrosis, (2) two-point reduction in NAFLD activity score without worsening of fibrosis, and (3) at least one-point reduction in fibrosis. Generalized linear mix model was used to estimate pooled proportion and mean differences.

This meta-analysis of 43 RCTs included 2649 placebo-treated patients. The pooled estimate of NASH resolution and two-point NAFLD activity score reduction without worsening of fibrosis was 11.65% (95% CI: 7.98-16.71) and 21.11% (95% CI: 17.24-25.57). The rate of ≥1 stage reduction and progression of fibrosis was 18.82% (95% CI: 15.65-22.47) and 22.74% (CI: 19.63-26.17), respectively. Older age and African American ethnicity was associated with lower NASH resolution rate in placebo-treated patients.

Despite the absence of any pharmacological interventions, a significant proportion of patients in the placebo arm demonstrated improvements in liver histology, highlighting the possibility that NASH is a disease that can not only progress but regress spontaneously over time. Additionally, histologic response in placebo-treated patients is helpful in future design of phase 2B and phase 3 trials.

Non-alcoholic steatohepatitis (NASH) is the most common cause of liver disease. However, there is lack of comparison of efficacy between different NASH drug classes. We conducted a network meta-analysis evaluating drug classes through comparing histological outcomes and targets of drugs.

Medline, EMBASE and CENTRAL were searched for randomised controlled trials evaluating NASH drugs in biopsy-proven NASH patients. Primary outcomes included NASH resolution without worsening of fibrosis, at least 2-point reduction in Non-alcoholic fatty liver disease Activity Score (NAS) without worsening of fibrosis and at least 1-point reduction in fibrosis. Treatments were classified into inflammation, energy, bile acid and fibrosis modulators. The analysis was conducted with Bayesian network model and surface under the cumulative ranking curve (SUCRA) analysis. Among 49 included trials, treatments modulating energy (Risk ratio (RR): 1.92, Credible intervals (Crl): 1.59-2.34) were most likely to achieve NASH resolution followed by treatments modulating fibrosis (RR 1.66, Crl: 0.65-4.50), bile acids (RR: 1.37, Crl: 0.99-1.92) and inflammation (RR: 1.00, Crl: 0.75-1.33). Energy and bile acids modulation were effective in at least 2-point NAS reduction without worsening of fibrosis (RR: 1.52, Crl 1.30-1.77; RR: 1.69, Crl 1.41-2.03) and at least 1-point reduction in fibrosis (RR: 1.26, Crl:1.05-1.49; RR: 1.54, Crl: 1.20-1.97).

This network analysis demonstrates the relative superiority of drugs modulating energy pathways and bile acids in NASH treatment. This guides the development and selection of drugs for combination therapies.

Nonalcoholic fatty liver disease (NAFLD), a series of liver metabolic disorders manifested by lipid accumulation within hepatocytes, has become the primary cause of chronic liver diseases worldwide. About 20%-30% of NAFLD patients advance to nonalcoholic steatohepatitis (NASH), along with cell death, inflammation response and fibrogenesis. The pathogenesis of NASH is complex and its development is strongly related to multiple metabolic disorders (e.g. obesity, type 2 diabetes and cardiovascular diseases). The clinical outcomes include liver failure and hepatocellular cancer. There is no FDA-approved NASH drug so far, and thus effective therapeutics are urgently needed. Bile acids are synthesized in hepatocytes, transported into the intestine, metabolized by gut bacteria and recirculated back to the liver by the enterohepatic system. They exert pleiotropic roles in the absorption of fats and regulation of metabolism. Studies on the relevance of bile acid disturbance with NASH render it as an etiological factor in NASH pathogenesis. Recent findings on the functional identification of bile acid receptors have led to a further understanding of the pathophysiology of NASH such as metabolic dysregulation and inflammation, and bile acid receptors are recognized as attractive targets for NASH treatment. In this review, we summarize the current knowledge on the role of bile acids and the receptors in the development of NAFLD and NASH, especially the functions of farnesoid X receptor (FXR) in different tissues including liver and intestine. The progress in the development of bile acid and its receptors-based drugs for the treatment of NASH including bile acid analogs and non-bile acid modulators on bile acid metabolism is also discussed.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease with no decisive treatment. The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin was developed as a new oral hypoglycemic drug, which can improve NASH via an insulin-independent glucose-lowering effect by inhibiting glucose reabsorption in the renal proximal tubules. However, ipragliflozin appears to modulate steatosis or inflammation via different pathways. To elucidate the new mechanism of ipragliflozin for the treatment of NASH, we evaluated its effects in a NASH mouse model (STAM mice) with beta cell depletion, and compared the expression of microRNAs (miRNAs) in STAM mice treated with or without ipragliflozin (16.7 μg/day for 5 weeks). Ipragliflozin reduced aspartate transaminase and alanine aminotransferase levels, along with reduced hepatic steatosis, hepatocyte ballooning, lobular inflammation, and liver fibrosis. In addition, ipragliflozin upregulated mitochondrial transport-related and antioxidant defensive system-related genes in the liver. Among 2555 mouse miRNA probes, miR-19b-3p was commonly differentially expressed with ipragliflozin treatment for 5 weeks in both the liver and serum but in different directions, with a decrease in the liver and increase in the serum. Therefore, ipragliflozin can improve NASH development likely through the antioxidative stress pathway and by regulating miR-19b-3p.

Ursodeoxycholic acid (UDCA) is a safe bile acid effective in reducing hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). However, the mechanism of action linked to this effect is poorly defined. In the present study, we identified that UDCA acted as a free fatty acid receptor 4 (FFA4) agonist with EC50 of 10.4 ± 0.7 μM, and its activity was determined by dynamic mass redistribution, fluorometric imaging plate reader, inositol monophosphate and bioluminescence resonance energy transfer assays. Moreover, UDCA showed FFA4 selectivity over eleven other G protein-coupled receptors. Real-Time PCR and immunocytochemistry analyses showed that FFA4 was abundantly expressed in human hepatocytes HuH-7 cells. In an in vitro model of NAFLD induced by oleic acid (OA), UDCA downregulated lipid accumulation in HuH-7 cells and suppressed sterol-regulatory element binding protein-1c (SREBP-1c) mRNA expression. This suppression of SREBP-1c was restored when FFA4 expression was knocked down in siRNA assay. In a mouse model of hepatic steatosis, db/db mice were exposed to a high-fat diet (HFD), and treatment of UDCA or docosahexaenoic acid (DHA, an endogenous FFA4 agonist) effectively prevented body weight gain and hepatic fat deposition and reduced triglyceride (TG) levels in serum and liver. This study not only identified a new skeleton of FFA4 agonists, but also demonstrated that FFA4 signal was accounting for the protective effects of UDCA in the NAFLD treatment.

Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell'Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources. Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.