Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a significant hepatic manifestation of metabolic syndrome, with its prevalence increasing globally alongside the epidemics of obesity and diabetes. MAFLD represents a continuum of liver damage, spanning from uncomplicated steatosis to metabolic dysfunction-associated steatohepatitis (MASH). This condition can advance to more severe outcomes, including fibrosis and cirrhosis. Fibroblast growth factor receptors (FGFRs) are a family of four receptor tyrosine kinases (FGFR1-4) that interact with both paracrine and endocrine fibroblast growth factors (FGFs). This interaction activates the phosphorylation of tyrosine kinase residues, thereby triggering downstream signaling pathways, including RAS-MAPK, JAK-STAT, PI3K-AKT, and PLCγ. In the context of MAFLD, paracrine FGF-FGFR signaling is predominantly biased toward the development of liver fibrosis and carcinogenesis. In contrast, endocrine FGF-FGFR signaling is primarily biased toward regulating the metabolism of bile acids, carbohydrates, lipids, and phosphate, as well as maintaining the overall balance of energy metabolism in the body. The interplay between these biased signaling pathways significantly influences the progression of MAFLD. This review explores the critical functions of FGFR signaling in MAFLD from three perspectives: first, it examines the primary roles of FGFRs relative to their structure; second, it summarizes FGFR signaling in hepatic lipid metabolism, elucidating mechanisms underlying the occurrence and progression of MAFLD; finally, it highlights recent advancements in drug development aimed at targeting FGFR signaling for the treatment of MAFLD and its associated diseases.

Gallstones, a global hepatobiliary disorder, are linked to systemic inflammation, lipid disturbances, and metabolic-associated fatty liver disease (MAFLD). This population-based study aims to investigate the association of the novel inflammation-lipid composite biomarker high-sensitivity C-reactive protein-to-HDL cholesterol ratio (CHR) with gallstones and evaluate whether MAFLD mediates this relationship.

This cross-sectional analysis utilized data from the National Health and Nutrition Examination Survey (NHANES, 2021-2023) to assess the correlation between the CHR and gallstone prevalence through weighted logistic regression. To evaluate potential nonlinear relationships and assess heterogeneity across key demographics, restricted cubic splines (RCS) were employed to model the association, complemented by subgroup analyses stratified by age, sex, and other covariates. A mediation analysis was used for elucidating the mediating effects of MAFLD.

Among 4,078 participants, 432 (10.60%) had gallstones. After adjusting for confounders, each unit increase in CHR was associated with a 165% increased risk of gallstones (OR: 2.65, 95% CI: 1.43-4.93, P = 0.006). The RCS curve demonstrated a nonlinear association between the CHR and gallstones (Poverall < 0.001, Pnonlinear < 0.001). Mediation analysis indicated that MAFLD explained 27.1% of this association.

CHR is positively associated with gallstones, with MAFLD partially mediating this relationship. Managing CHR levels and preventing MAFLD may reduce gallstone incidence.

Visceral adipose tissue (VAT) accumulation in obesity has been implicated as a key factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Apart from lifestyle change interventions, there is no effective therapy against MASLD. In this study, the effect of a novel microbial therapy along with dietary change on VAT and VAT-liver crosstalk was evaluated in a MASLD mouse model.

MASLD was induced by feeding eighteen C57BL/6J male mice with the American Lifestyle-Induced Obesity diet for fourteen weeks. Subsequently, during the following seven weeks, all mice were switched to standard diet and the intervention group received single gelatine cubes containing 109 CFU each of aldafermin-expressing Escherichia coli Nissle (EcNA, n = 6); while the control groups received either 109 CFU/gelatine cube of non-modified Escherichia coli Nissle (EcN, n = 6) or gelatin cube with no treatment (CTRL, n = 6). The effect of EcNA on epididymal visceral adipose tissue (eVAT) morphology was evaluated by histology and the gene expression profile in eVAT and liver by RNA-sequencing analysis.

After seven weeks of intervention, EcNA, when compared to CTRL group, induced smaller adipocytes (p-value = 0.0217 for diameter, p-value = 0.0386 for area). Gene Set Enrichment Analysis in eVAT showed significant upregulation of fatty acid metabolism (FDR-adjusted p-value = 0.001), oxidative phosphorylation (FDR-adjusted p-value < 2.2e-16), peroxisome (FDR-adjusted p-value = 0.0185), and thermogenesis (FDR-adjusted p-value = 0.0199) pathways when EcNA was compared to EcN group. In addition, the impact of EcNA in eVAT-liver gene expression crosstalk was underlined by the upregulation of Bcl6 and Cnst expression in both tissues when EcNA was compared to CTRL and EcN groups.

These results support the beneficial effects of EcNA, along with dietary change intervention, in obesity-associated MASLD. This microbial therapy could potentially boost the improvements induced by dietary change in eVAT metabolism and its crosstalk with the liver.

Circadian rhythm is critical to maintaining the whole-body metabolic homeostasis of an organism. Chronic disruption of circadian rhythm by shift work is an important risk factor for metabolic diseases. Fibroblast growth factor 15/19 (FGF15/19), a key component in the liver-gut axis, potently suppresses bile acid (BA) synthesis and improves insulin sensitivity. FGF15/19 emerges as a novel pharmaceutical target for prevention and treatment of metabolic diseases. The nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin 1 (SIRT1) deacetylase plays an important role in the maintenance of hepatic homeostasis by linking hepatic metabolism to circadian rhythm. Here, our clinical study identified that circadian rhythmicity and levels of plasma FGF19 and BA profiling, and cellular NAD+-dependent SIRT1 signaling were disturbed in night shift (NS, n = 10) compared to day shift (DS, n = 12) nurses. Our in vitro data showed that recombinant FGF19 protein rescued cellular circadian rhythm disrupted by SIRT1 inhibitors. Furthermore, we determined the effect of FGF15 on circadian rhythm and hepatic metabolism in wild-type (WT), Fgf15 knockout (KO), and Fgf15 transgenic (TG) mice. The expressions of circadian-controlled genes (CCGs) involved in SIRT1 signaling, BA and lipid metabolism, and inflammation were disrupted in Fgf15 KO compared to WT and/or Fgf15 TG mice. Moreover, systemic FGF15 deficiency led to the circadian disturbance of NAD+-dependent SIRT1 signaling and significant reduction during nighttime in mice. These findings suggest that FGF15/19 regulates the circadian energy metabolism, which warrants further studies as a putative prognostic biomarker and pharmaceutical target for preventing against metabolic diseases associated with chronic shift work.

Non-alcoholic fatty liver disease (NAFLD) presents a pervasive global pandemic, affecting approximately 25 % of the world's population. This grave health issue not only demands urgent attention but also stands as a significant economic concern on a global scale. The genesis of NAFLD can be primarily attributed to unhealthy dietary habits and a sedentary lifestyle, albeit certain genetic factors have also been recorded to contribute to its occurrence. NAFLD is characterized by fat accumulation in more than 5 % of hepatocytes according to histological analysis, or >5.6 % of lipid volume fraction in total liver weight in patients. The pathophysiology of NAFLD/non-alcoholic steatohepatitis (NASH) is multifactorial and the mechanisms underlying the progression to advanced forms remain unclear, thereby representing a challenge to disease therapy. Despite the substantial efforts from the scientific community and the large number of pre-clinical and clinical trials performed so far, only one drug was approved by the Food and Drug Administration (FDA) to treat NAFLD/NASH specifically. This review provides an overview of available information concerning emerging molecular targets and drug candidates tested in clinical studies for the treatment of NAFLD/NASH. Improving our understanding of NAFLD pathophysiology and pharmacotherapy is crucial not only to explore new molecular targets, but also to potentiate drug discovery programs to develop new therapeutic strategies. This knowledge endeavours scientific efforts to reduce the time for achieving a specific and effective drug for NAFLD or NASH management and improve patients' quality of life.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) represents the most frequent cause of hepatic disorder, and its progressive form defined as Metabolic Dysfunction-Associated Steatohepatitis (MASH) contributes to the development of fibrosis/cirrhosis and hepatocellular carcinoma (HCC). Today effective therapeutic strategies addressing MASH-related comorbidities, inflammation, and fibrosis are needed. The fibroblast growth factor (FGF) 19 and 21 and their fibroblast growth factor receptor/β-Klotho (KLB) complexes have recently emerged as promising druggable targets for MASLD. However, less is known regarding the causative association between KLB activity and advanced stages of liver disease. In the present narrative review, we aimed to provide an up-to-date picture of the role of the KLB co-receptor in MASLD development and progression. We performed a detailed analysis of recently published preclinical and clinical data to decipher the molecular mechanisms underlying KLB function and to correlate the presence of inherited or acquired KLB aberrancies with the predisposition towards MASLD. Moreover, we described ongoing clinical trials evaluating the therapeutic approaches targeting FGF19-21/FGFR/KLB in patients with MASLD and discussed the challenges related to their use. We furtherly described that KLB exhibits protective effects against metabolic disorders by acting in an FGF-dependent and independent manner thus triggering the hypothesis that KLB soluble forms may play a critical role in preserving liver health. Therefore, targeting KLB may provide promising strategies for treating MASLD, as supported by experimental evidence and ongoing clinical trials.

Metabolic dysfunction-associated steatohepatitis (MASH) represents a global health threat. MASH pathophysiology involves hepatic lipid accumulation and progression to severe conditions like cirrhosis and, eventually, hepatocellular carcinoma. Fibroblast growth factor (FGF)-19 has emerged as a key regulator of metabolism, offering potential therapeutic avenues for MASH and associated disorders. We evaluated the therapeutic potential of non-mitogenic (NM)-FGF19 mRNA formulated in liver-targeted lipid nanoparticles (NM-FGF19-mRNAs-LNPs) in C57BL/6NTac male mice with diet-induced obesity and MASH (DIO-MASH: 40% kcal fat, 20% kcal fructose, 2% cholesterol). After feeding this diet for 21 weeks, NM-FGF19-mRNAs-LNPs or control (C-mRNA-LNPs) were administered (0.5 mg/kg, i.v.) weekly for another six weeks, in which diet feeding continued. NM-FGF19-mRNAs-LNPs treatment in DIO-MASH mice resulted in reduced body weight, adipose tissue depots, and serum transaminases, along with improved insulin sensitivity. Histological analyses confirmed the reversal of MASH features, including steatosis reduction without worsening fibrosis. NM-FGF19-mRNAs-LNPs reduced total hepatic bile acids (BAs) and changed liver BA composition, markedly influencing cholesterol homeostasis and metabolic pathways as observed in transcriptomic analyses. Extrahepatic effects included the down-regulation of metabolic dysfunction-associated genes in adipose tissue. This study highlights the potential of NM-FGF19-mRNA-LNPs therapy for MASH, addressing both hepatic and systemic metabolic dysregulation. NM-FGF19-mRNA demonstrates efficacy in reducing liver steatosis, improving metabolic parameters, and modulating BA levels and composition. Given the central role played by BA in dietary fat absorption, this effect of NM-FGF19-mRNA may be mechanistically relevant. Our study underscores the high translational potential of mRNA-based therapies in addressing the multifaceted landscape of MASH and associated metabolic perturbations.

Dysregulation of bile acids (BAs), as important signalling molecules in regulating lipid and glucose metabolism, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, static BA profiles during fasting may obscure certain pathogenetic aspects. In this study, we investigate the dynamic alterations of BAs in response to an oral glucose tolerance test (OGTT) among children with NAFLD.

We recruited 230 subjects, including children with overweight/obesity, or complicated with NAFLD, and healthy controls. Serum BAs, 7-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19) were quantified during OGTT. Clinical markers related to liver function, lipid metabolism and glucose metabolism were assessed at baseline or during OGTT.

Conjugated BAs increased while unconjugated ones decreased after glucose uptake. Most BAs were blunted in response to glucose in NAFLD (p > .05); only glycine and taurine-conjugated chenodeoxycholic acid (CDCA) and cholic acid (CA) were responsive (p < .05). Primary BAs were significantly increased while secondary BAs were decreased in NAFLD. C4 and FGF19 were significantly increased while their ratio FGF19/C4 ratio was decreased in NAFLD. The dynamic pattern of CDCA and taurine-conjugated hyocholic acid (THCA) species was closely correlated with glucose (correlation coefficient r = .175 and -.233, p < .05), insulin (r = .327 and -.236, p < .05) and c-peptide (r = .318 and -.238, p < .05). Among which, CDCA was positively associated with liver fat content in NAFLD (r = .438, p < .05). Additionally, glycochenodeoxycholic acid (GCDCA), CDCA and THCA were potential biomarkers to discriminate paediatric NAFLD from healthy controls and children with obesity.

This study provides novel insights into the dynamics of BAs during OGTT in paediatric NAFLD. The observed variations in CDCA and HCA species were associated with liver dysfunction, dyslipidaemia and dysglycaemia, highlighting their potential roles as promising diagnostic and therapeutic targets in NAFLD.

Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which therapeutic options are limited, with an unmet need to identify new therapeutic targets. IPF is thought to be the consequence of repeated microlesions of the alveolar epithelium, leading to aberrant epithelial-mesenchymal communication and the accumulation of extracellular matrix proteins. The reactivation of developmental pathways, such as Fibroblast Growth Factors (FGFs), is a well-described mechanism during lung fibrogenesis. Secreted FGFs with local paracrine effects can either exert an anti-fibrotic or a pro-fibrotic action during this pathological process through their FGF receptors (FGFRs) and heparan sulfate residues as co-receptors. Among FGFs, endocrine FGFs (FGF29, FGF21, and FGF23) play a central role in the control of metabolism and tissue homeostasis. They are characterized by a low affinity for heparan sulfate, present in the cell vicinity, allowing them to have endocrine activity. Nevertheless, their interaction with FGFRs requires the presence of mandatory co-receptors, alpha and beta Klotho proteins (KLA and KLB). Endocrine FGFs are of growing interest for their anti-fibrotic action during liver, kidney, or myocardial fibrosis. Innovative therapies based on FGF19 or FGF21 analogs are currently being studied in humans during liver fibrosis. Recent data report a similar anti-fibrotic action of endocrine FGFs in the lung, suggesting a systemic regulation of the pulmonary fibrotic process. In this review, we summarize the current knowledge on the protective effect of endocrine FGFs during the fibrotic processes, with a focus on pulmonary fibrosis.

Nonalcoholic fatty liver disease (NAFLD) emerges as the most predominant cause of liver disease, tightly linked to metabolic dysfunction. Bile acids (BAs), initially synthesized from cholesterol in the liver, undergo further metabolism by gut bacteria. Increasingly acknowledged as critical modulators of metabolic processes, BAs have been implicated as important signaling molecules. In this review, we will focus on the mechanism of BAs signaling involved in glucose homeostasis, lipid metabolism, energy expenditure, and immune regulation and summarize their roles in the pathogenesis of NAFLD. Furthermore, gut microbiota dysbiosis plays a key role in the development of NAFLD, and the interactions between BAs and intestinal microbiota is elucidated. In addition, we also discuss potential therapeutic strategies for NAFLD, including drugs targeting BA receptors, modulation of intestinal microbiota, and metabolic surgery.

Steatotic liver disease (SLD) displays a dynamic and complex disease phenotype. Consequently, the metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) therapeutic pipeline is expanding rapidly and in multiple directions. In parallel, noninvasive tools for diagnosing and monitoring responses to therapeutic interventions are being studied, and clinically feasible findings are being explored as primary outcomes in interventional trials. The realization that distinct subgroups exist under the umbrella of SLD should guide more precise and personalized treatment recommendations and facilitate advancements in pharmacotherapeutics. This review summarizes recent updates of pathophysiology-based nomenclature and outlines both effective pharmacotherapeutics and those in the pipeline for MASLD/MASH, detailing their mode of action and the current status of phase 2 and 3 clinical trials. Of the extensive arsenal of pharmacotherapeutics in the MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, have shown only marginal benefits and are now being tested as part of combination therapies, yet others are still in development as monotherapies. Although the Food and Drug Administration (FDA) has recently approved resmetirom, additional therapeutic approaches in development will ideally target MASH and fibrosis while improving cardiometabolic risk factors. Due to the urgent need for the development of novel therapeutic strategies and the potential availability of safety and tolerability data, repurposing existing and approved drugs is an appealing option. Finally, it is essential to highlight that SLD and, by extension, MASLD should be recognized and approached as a systemic disease affecting multiple organs, with the vigorous implementation of interdisciplinary and coordinated action plans. SIGNIFICANCE STATEMENT: Steatotic liver disease (SLD), including metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, is the most prevalent chronic liver condition, affecting more than one-fourth of the global population. This review aims to provide the most recent information regarding SLD pathophysiology, diagnosis, and management according to the latest advancements in the guidelines and clinical trials. Collectively, it is hoped that the information provided furthers the understanding of the current state of SLD with direct clinical implications and stimulates research initiatives.

Formula feeding, obesity and the gut microbiota are closely related. The present investigation explored the profiles of the intestinal microbiota in obese children over 5 years old with formula feeding in early life. We identified functional bacteria with anti-obesity potential through in vitro and in vivo experiments, elucidating their mechanisms. The results indicated that, in the group of children over 5 years old who were fed formula in early life, obese children exhibited distinct gut microbiota, which were characterized by diminished species diversity and reduced Bifidobacterium levels compared to normal-weight children. As a result, Lactobacillus acidophilus H-68 (H-68) was isolated from the feces of the N-FF group and recognized as a promising candidate. H-68 demonstrated the ability to stimulate cholecystokinin (CCK) secretion in STC-1 cells and produce bile salt hydrolase. In vivo, H-68 promoted CCK secretion, suppressing food intake, and regulated bile acid enterohepatic circulation, leading to increased deoxycholic acid and lithocholic acid levels in the ileum and liver. This regulation effectively inhibited the diet-induced body weight and body fat gain, along with the liver fat deposition. In conclusion, H-68 was recognized for its prospective anti-obesity impact, signifying an auspicious pathway for forthcoming interventions targeted at averting pediatric obesity in formula-fed children.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 25%. Patients with NAFLD are more likely to suffer from advanced liver disease, cardiovascular disease, or type II diabetes. However, unfortunately, there is still a shortage of FDA-approved therapeutic agents for NAFLD. Lian-Mei-Yin (LMY) is a traditional Chinese medicine formula used for decades to treat liver disorders. It has recently been applied to type II diabetes which is closely related to insulin resistance. Given that NAFLD is another disease involved in insulin resistance, we hypothesize that LMY might be a promising formula for NAFLD therapy. Herein, we verify that the LMY formula effectively reduces hepatic steatosis in diet-induced zebrafish and NAFLD model mice in a time- and dose-dependent manner. Mechanistically, LMY suppresses Yap1-mediated Foxm1 activation, which is crucial for the occurrence and development of NAFLD. Consequently, lipogenesis is ameliorated by LMY administration. In summary, the LMY formula alleviates diet-induced NAFLD in zebrafish and mice by inhibiting Yap1/Foxm1 signaling-mediated NAFLD pathology.

Nonalcoholic fatty liver disease (NAFLD) affects approximately 25% of the adult population worldwide. This pathology can progress into end-stage liver disease with life-threatening complications, and yet no pharmacologic therapy has been approved. NAFLD is commonly characterized by excessive fat accumulation in the liver and is in closely associated with insulin resistance and metabolic disorders, which suggests that NAFLD is the hepatic manifestation of metabolic syndrome. Regarding treatment options, the current validated strategy relies on lifestyle modifications (exercise and diet restrictions). Although there are no approved drug-based treatments, several clinical trials are ongoing. Novel targets are being discovered, and the repurposing of drugs that show promising effects in NAFLD is starting to gain more interest. The field of nanotechnology has been growing at an increasing rate, with new and more efficient drug delivery strategies being developed for NAFLD treatment. Nanocarriers can easily encapsulate drugs that need to be better protected from the organism to exert their effect or that need help at reaching their target, thereby helping achieve a better bioavailability. Drug delivery systems can also be designed to target the site of the disease, in this case, the liver. In this review, we focus on the current knowledge of NAFLD pathology, the targets being considered for clinical trials, and the current guidelines and ongoing clinical trials, with a specific focus on potential oral treatments for NAFLD using promising drug delivery strategies.

Nonalcoholic fatty liver disease (NAFLD), as a multisystemic disease, is the most prevalent chronic liver disease characterized by extremely complex pathogenic mechanisms and multifactorial etiology, which often develops as a consequence of obesity, metabolic syndrome. Pathophysiological mechanisms involved in the development of NAFLD include diet, obesity, insulin resistance (IR), genetic and epigenetic determinants, intestinal dysbiosis, oxidative/nitrosative stress, autophagy dysregulation, hepatic inflammation, gut-liver axis, gut microbes, impaired mitochondrial metabolism and regulation of hepatic lipid metabolism. Some of the new drugs for the treatment of NAFLD are introduced here. All of them achieve therapeutic objectives by interfering with certain pathophysiological pathways of NAFLD, including fibroblast growth factors (FGF) analogues, peroxisome proliferator-activated receptors (PPARs) agonists, glucagon-like peptide-1 (GLP-1) agonists, G protein-coupled receptors (GPCRs), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), farnesoid X receptor (FXR), fatty acid synthase inhibitor (FASNi), antioxidants, etc. This review describes some pathophysiological mechanisms of NAFLD and established targets and drugs.

Better screening tools for paediatric NAFLD are needed. We tested the hypothesis that the postprandial triglyceride (TG) and fibroblast growth factor 19 (FGF19) response to an abbreviated fat tolerance test (AFTT) could differentiate adolescents with NAFLD from peers with obesity and normal weight.

Fifteen controls with normal weight (NW), 13 controls with obesity (OB) and 9 patients with NAFLD completed an AFTT. Following an overnight fast, participants consumed a high-fat meal. TG and FGF19 were measured at baseline and 4 h post-meal. Liver steatosis and fibrosis were measured via Fibroscan.

Fasting TG and FGF19 did not differ among groups; 4 h TG in the NAFLD and OB groups were greater (197 ± 69 mg/dL; 157 ± 72 mg/dL, respectively) than NW (105 ± 45 mg/dL; p < 0.05) and did not differ from one another. Within the entire cohort, 4 h TG were stratified by high and low steatosis. Adolescents with high steatosis had 98% greater 4 h TG than adolescents with low steatosis. 4 h FGF19, but not fasting FGF19, was higher in children with low steatosis compared with high steatosis (p < 0.05). Using area under the receiver operating curve (AUROC), the only biochemical outcome with diagnostic accuracy for NAFLD was 4 h TG (0.77 [95% CI: 0.60-0.94; p = 0.02]).

The postprandial TG response is increased in adolescents with obesity with hepatic steatosis, with or without NAFLD. Our preliminary analysis demonstrates 4 h TG differentiate patients with NAFLD from those without, supporting a role for the AFTT as a screening tool for paediatric NAFLD.

Nonalcoholic fatty liver disease (NAFLD), a chronic condition associated with metabolic dysfunction and obesity, has reached epidemic proportions worldwide. Although early NAFLD can be treated with lifestyle changes, the treatment of advanced liver pathology, such as nonalcoholic steatohepatitis (NASH), remains a challenge. There are currently no FDA-approved drugs for NAFLD. Fibroblast growth factors (FGFs) play essential roles in lipid and carbohydrate metabolism and have recently emerged as promising therapeutic agents for metabolic diseases. Among them, endocrine members (FGF19 and FGF21) and classical members (FGF1 and FGF4) are key regulators of energy metabolism. FGF-based therapies have shown therapeutic benefits in patients with NAFLD, and substantial progress has recently been made in clinical trials. These FGF analogs are effective in alleviating steatosis, liver inflammation, and fibrosis. In this review, we describe the biology of four metabolism-related FGFs (FGF19, FGF21, FGF1, and FGF4) and their basic action mechanisms, and then summarize recent advances in the biopharmaceutical development of FGF-based therapies for patients with NAFLD.

Steatosis is a common feature of intestinal failure-associated liver disease (IFALD) in adult and older pediatric patients receiving long-term parenteral nutrition (PN). There are limited clinical data concerning steatosis in infants with short bowel syndrome (SBS). We investigated early histopathological steatosis and its association to PN.

In this retrospective study, 31 patients with SBS had a diagnostic liver biopsy taken at the median age of 5 (IQR 3-8) months. Follow-up biopsy was available for 24 patients at the median age of 29 (IQR 14-52) months. We evaluated the biopsies for steatosis and other histopathological signs of IFALD and compared results with patient characteristics, PN composition, and liver biochemistry.

Diagnostic biopsies revealed steatosis in 8 (26%) patients. At the age of 3 months, patients with steatosis had received higher amounts of parenteral glucose: median 15.1 (IQR 12.4-17.2) vs 12.3 (8.7-14.4) g/kg/d (P = 0.04), amino acids: 2.9 (2.5-3.4) vs 2.2 (1.6-2.7) g/kg/d (P = 0.03), and energy: 87 (80-98) vs 73 (54-79) kcal/kg/d (P = 0.01) than those without steatosis. We detected no significant differences in parenteral lipid intake between the groups. Steatosis also associated with increased serum bile acid (P = 0.02), alanine aminotransferase (P = 0.0002), and aspartate aminotransferase (P = 0.001) levels.

In this cohort, high parenteral glucose, amino acid, and energy provision associated with liver steatosis in infants with SBS. We recommend monitoring of bile acid and transaminase levels while aiming for PN with balanced macronutrient supply according to current recommendations to protect the liver from steatosis.

Our understanding of nonalcoholic steatohepatitis (NASH) pathophysiology continues to advance rapidly. Given the complexity of the pathogenesis of NASH, the field has moved from describing the single pathogenesis of NASH to deeply phenotyping with a description of the multi-mechanism and multi-target pathogenesis that includes glucose, lipid and cholesterol metabolism, fibrotic progression, inflammation, immune reaction and apoptosis. To make the picture more complex, the pathogenesis of NASH involves pathological connections between the liver and several organs such as the adipose, pancreas, kidney and gut. Numerous pharmacologic candidates have been tested in clinical trials and have generated some positive results. Importantly, PPAR as triglyceride synthesis inhibitor and FXR as bile acids synthesis inhibitor have displayed beneficial effects on candidates for lipid and cholesterol metabolism. Although the efficacy of these drugs has been affirmed, serious side effects hinder their further development. It is a particularly important task to carry out the in-depth long-term research. Additionally, drug combination increases response rate and reduces side effects of a single drug. Mastering the advantages and limitations of clinical candidate drugs and continuous improvement and innovation are necessary to formulate a new strategy for the future treatment of NASH.

The objective of this study was to investigate the effect of dietary fatty acid (FA) composition on bile acid (BA) metabolism in a pig model of NAFLD, by using a multiomics approach combined with histology and serum biochemistry. Thirty 20-day-old Iberian pigs pair-housed in pens were randomly assigned to receive 1 of 3 hypercaloric diets for 10 wk: 1) lard-enriched (LAR; n = 5 pens), 2) olive oil-enriched (OLI; n = 5), and 3) coconut oil-enriched (COC; n = 5). Animals were euthanized on week 10 after blood sampling, and liver, colon, and distal ileum (DI) were collected for histology, metabolomics, and transcriptomics. Data were analyzed by multivariate and univariate statistics. Compared with OLI and LAR, COC increased primary and secondary BAs in liver, plasma, and colon. In addition, both COC and OLI reduced circulating fibroblast growth factor 19, increased hepatic necrosis, composite lesion score, and liver enzymes in serum, and upregulated genes involved in hepatocyte proliferation and DNA repair. The severity of liver disease in COC and OLI pigs was associated with increased levels of phosphatidylcholines, medium-chain triacylglycerides, trimethylamine-N-oxide, and long-chain acylcarnitines in the liver, and the expression of profibrotic markers in DI, but not with changes in the composition or size of BA pool. In conclusion, our results indicate a role of dietary FAs in the regulation of BA metabolism and progression of NAFLD. Interventions that aim to modify the composition of dietary FAs, rather than to regulate BA metabolism or signaling, may be more effective in the treatment of NAFLD.NEW & NOTEWORTHY Bile acid homeostasis and signaling is disrupted in NAFLD and may play a central role in the development of the disease. However, there are no studies addressing the impact of diet on bile acid metabolism in patients with NAFLD. In juvenile Iberian pigs, we show that fatty acid composition in high-fat high-fructose diets affects BA levels in liver, plasma, and colon but these changes were not associated with the severity of the disease.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the predominant cause of chronic liver injury worldwide. Bile acids and their receptors are profoundly implicated in the pathogenesis of NAFLD and its progression to nonalcoholic steatohepatitis and cirrhosis.

We conducted extensive literature search using PubMed database, and we summarized the relevant literature. We provided an overview of the fibroblast growth factor 19 (FGF-19)-farnesoid X receptor (FXR) axis and summarized the latest findings derived from animal and human studies concerning the impact of FGF-19 on NAFLD.

FGF-19, a nutritionally regulated endocrine post-prandial hormone, governs bile acid metabolism, lipid oxidation, lipogenesis, and energy homeostasis. As no approved medication for NAFLD exists, FGF-19 seems to be a propitious therapeutic opportunity for NAFLD, since its administration was associated with ameliorated results in hepatic steatosis, liver inflammation and fibrosis. Furthermore, promising results have been derived from clinical trials concerning the beneficial efficacy of FGF-19 on histological findings and laboratory parameters of NAFLD. However, we should bear in mind the pleiotropic effects of FGF-19 on various metabolically active tissues along with its potential tumorigenic reservoir. Further clinical research is required to determine the clinical application of FGF-19-based therapies on NAFLD.

In humans, aging, triggers increased plasma concentrations of triglycerides, cholesterol, low-density lipoproteins and lower capacity of high-density lipoproteins to remove cellular cholesterol. Studies in rodents showed that aging led to cholesterol accumulation in the liver and decrease in the brain with reduced cholesterol synthesis and increased levels of cholesterol 24-hydroxylase, an enzyme responsible for removing cholesterol from the brain. Liver diseases are also related to brain aging, inducing changes in cholesterol metabolism in the brain and liver of rats. It has been suggested that late onset Alzheimer's disease is associated with metabolic syndrome. Non-alcoholic fatty liver is associated with lower total brain volume in the Framingham Heart Study offspring cohort study. Furthermore, disorders of cholesterol homeostasis in the adult brain are associated with neurological diseases such as Niemann-Pick, Alzheimer, Parkinson, Huntington and epilepsy. Apolipoprotein E (apoE) is important in transporting cholesterol from astrocytes to neurons in the etiology of sporadic Alzheimer's disease, an aging-related dementia. Desmosterol and 24S-hydroxycholesterol are reduced in ApoE KO hypercholesterolemic mice. ApoE KO mice have synaptic loss, cognitive dysfunction, and elevated plasma lipid levels that can affect brain function. In contrast to cholesterol itself, there is a continuous uptake of 27- hydroxycholesterol in the brain as it crosses the blood-brain barrier and this flow can be an important link between intra- and extracerebral cholesterol homeostasis. Not surprisingly, changes in cholesterol metabolism occur simultaneously in the liver and nervous tissues and may be considered possible biomarkers of the liver and nervous system aging.

Human fibroblast growth factor 19 (FGF19) has become a potential therapeutic target for metabolic-related diseases. However, the effects of FGF19 on obesity-induced bone loss have not been completely elucidated. The aim of this study was to investigate the protective effects of FGF19 in high-fat diet (HFD)-fed obese mice and palmitic acid (PA)-treated osteoblasts and to further explore its underlying mechanisms. In vivo, we found that FGF19 alleviated the decreased bone mineral density (BMD) induced by HFD. Micro-CT analysis of femur samples and histological analysis indicated that FGF19 alleviated HFD-induced loss of bone trabeculae and damage to the bone trabecular structure. In vitro, the results suggested that FGF19 ameliorated the PA-induced decline in osteoblast proliferation, increased cell death and impaired cell morphology. Additionally, FGF19 protected against the decline in activation of alkaline phosphatase (ALP) and protein expression of Collagen-1, Runx-2, and osteopontin (OPN) induced by PA. Furthermore, FGF19 might enhance osteogenic differentiation via the Wnt/β-catenin pathway and inhibit osteoclastogenesis by regulating the osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) axis, thus attenuating the negative effect of PA in osteoblasts. In conclusion, our results suggested that FGF19 might promote osteogenic differentiation partially through activation of the Wnt/β-catenin pathway and alleviate obesity-induced bone loss.

Fibrotic remodelling is a highly conserved protective response to tissue injury and it is essential for the maintenance of structural and functional tissue integrity. Also hepatic fibrosis can be considered as a wound-healing response to liver injury, reflecting a balance between liver repair and scar formation. In contrast, pathological fibrosis corresponds to impaired wound healing. Usually, the liver regenerates after acute injury. However, if the damaging mechanisms persist, the liver reacts with progressive and uncontrolled accumulation of extracellular matrix proteins. Eventually, excessive fibrosis can lead to cirrhosis and hepatic failure. Furthermore, cirrhosis is the major risk factor for the development of hepatocellular cancer (HCC). Therefore, hepatic fibrosis is the most critical pathological factor that determines the morbidity and mortality of patients with chronic liver disease. Still, no effective anti-fibrogenic therapies exist, despite the very high medical need. The regulation of fibroblast growth factor (FGF) signalling is a prerequisite for adequate wound healing, repair and homeostasis in various tissues and organs. The FGF family comprises 22 proteins that can be classified into paracrine, intracrine and endocrine factors. Most FGFs signal through transmembrane tyrosine kinase FGF receptors (FGFRs). Although FGFRs are promising targets for the treatment of HCC, the expression and function of FGFR-ligands in hepatic fibrosis is still poorly understood. This review summarizes the latest advances in our understanding of FGF signalling in hepatic fibrosis. Furthermore, the potential of FGFs as targets for the treatment of hepatic fibrosis and remaining challenges for the field are discussed.