Metabolic dysfunction-associated steatotic liver disease is a prevalent disease that affects nearly one-third of the global population. Recent genome-wide association studies revealed that a common missense variant in the gene encoding mitochondrial amidoxime reducing component 1 (mARC1) is associated with protection from metabolic dysfunction-associated steatotic liver disease, all-cause cirrhosis, and liver-related mortality suggesting a role for mARC1 in liver pathophysiology; however, little is known about its function in the liver. In this study, we aimed to evaluate the impact of mARC1 hepatoprotective variants on protein function, the effect of loss of mARC1 on cellular lipotoxic stress response, and the effect of global or hepatocyte-specific loss of mARC1 in various mouse models of metabolic dysfunction-associated steatohepatitis and liver fibrosis.

Expression and characterization of mARC1 hepatoprotective variants in cells and mouse liver revealed that the mARC1 p.A165T exhibited lower protein levels but maintained its mitochondrial localization. In cells, the knockdown of mARC1 improved cellular bioenergetics and decreased mitochondrial superoxide production in response to lipotoxic stress. Global genetic deletion and hepatocyte-specific knockdown of mARC1 in mice significantly reduced liver steatosis and fibrosis in multiple mouse models of metabolic dysfunction-associated steatohepatitis and liver fibrosis. Furthermore, RNA-seq analysis revealed that the pathways involved in extracellular matrix remodeling and collagen formation were downregulated in the liver, and the plasma lipidome was significantly altered in response to the loss of mARC1 in mice.

Overall, we have demonstrated that loss of mARC1 alters hepatocyte response to lipotoxic stress and protects mice from diet-induced MASH and liver fibrosis consistent with findings from human genetics.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a pressing public health issue associated with adverse outcomes such as cirrhosis, malignancy, transplantation, and mortality. Lifestyle modifications constitute the most effective and fundamental management approach, but they often pose challenges in sustaining long-term clinical benefits. Hence, there is a critical need to enhance our understanding through pharmacological management, which unfortunately remains limited. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a leading treatment in the fields of diabetes and obesity, with recent preclinical and clinical studies indicating significant benefits in the management and treatment of MASLD. Our article begins by reviewing the beneficial therapeutic components of GLP-1RAs in MASLD. Subsequently, from a clinical research perspective, we concluded with the liver outcomes of current primary GLP-1RAs and co-agonists. Finally, we presented our insights on clinical concerns such as appropriate trial endpoints, management of comorbidities, and future developments. In conclusion, the benefits of GLP-1RAs in MASLD are promising, and background therapy involving metabolic modulation may represent one of the future therapeutic paradigms.

This study aims to evaluate the association between hypertension and the risk of fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, as well as to investigate the impact of hypertension on the progression of liver fibrosis within this population.

We utilized data from the NHANES 2017 to March 2020. Multivariate logistic regression models were employed to control for sociodemographic and metabolic factors to determine the associations between hypertension, MASLD, and fibrosis.

Of the total cohort (N = 5,967) 57.92% had hypertension, 38.8% had MASLD, 25.88% had both MASLD and hypertension. Patients with MASLD were more likely to have hypertension (64.24% vs. 44.80%). There was a significant association between stage I (OR1.70, 95% CI: 1.15-2.53) and stage II hypertension (OR1.98, 95% CI: 1.38-2.85) and an increased risk of SF. After adjusting for multiple confounding factors, stage I (OR1.59, 95% CI: 1.09-2.24) and stage II hypertension (OR1.48, 95% CI: 1.06-2.06) remained significantly associated with the risk of SF. Patients with both MASLD and hypertension had higher rates of SF at 14.83% and AF at 7.47%. After adjusting for sociodemographic factors, those patients still had an 8.02-fold increased risk of SF (OR8.02, 95% CI: 4.47-14.39) and a 15.13-fold increased risk of AF (OR15.13, 95% CI: 7.09-32.3). Further adjustment for metabolic factors, those patients still had a significantly higher risk of SF (OR3.07, 95% CI: 1.83-5.14) and AF (OR4.01, 95% CI: 1.48-10.89).

MASLD and hypertension are at risk for fibrosis, and the coexistence of the two has a more significant impact on the risk of fibrosis.

Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is a broad condition characterized by lipid accumulation in the liver tissue, which can progress to fibrosis and cirrhosis if left untreated. Traditionally, liver biopsy is the gold standard for evaluating fibrosis. However, non-invasive biomarkers of liver fibrosis are developed to assess the fibrosis without the risk of biopsy complications. Novel serum biomarkers have emerged as a promising tool for non-invasive assessment of liver fibrosis in MAFLD patients. Several studies have shown that elevated levels of Mac-2 binding protein glycosylation isomer (M2BPGi) are associated with increased liver fibrosis severity in MAFLD patients. This suggests that M2BPGi could serve as a reliable marker for identifying individuals at higher risk of disease progression. Furthermore, the use of M2BPGi offers a non-invasive alternative to liver biopsy, which is invasive and prone to sampling errors. Overall, the usage of M2BPGi in assessing liver fibrosis in MAFLD holds great promise for improving risk stratification and monitoring disease progression in affected individuals. Further research is needed to validate its utility in clinical practice and establish standardized protocols for its implementation.

The relationship between plasmatic fatty acid (FA) composition and liver fibrosis remains scarce in people living with HIV/AIDS (PLWHA). We aimed to evaluate the association of plasmatic FAs and liver fibrosis in HIV mono-infected individuals.

This case-control study included PLWHA with liver fibrosis (cases) and randomly selected subjects without fibrosis (controls) from the PROSPEC-HIV study (NCT02542020). Participants with viral hepatitis, abusive alcohol consumption and lipid supplements use were excluded. Liver fibrosis was defined using transient elastography (TE) by liver stiffness measurement (LSM) ≥ 7.1 kPa or ≥ 6.2 kPa with M or XL probe, respectively. All HIV mono-infected participants with liver fibrosis identified at the baseline PROSPEC-HIV visit were included. Controls (1:1) were randomly selected among those HIV mono-infected participants without liver fibrosis. Plasmatic FA profile, dietary lipid intake, anthropometric measures, and blood samples were assessed. Plasmatic fatty acid was analyzed using gas chromatography and intake of fats lipids were assessed by two 24-h dietary recall (24-HDR). Multivariate logistic regression models adjusted by age, sex at birth and duration of antiretroviral therapy (ART) were performed.

A total of 142 participants (71 cases and 71 controls) [62 % female, median age = 46 (IQR, 37-53) years, 14.8 % with diabetes, median CD4 count = 655 cells/mm3, 96.5 % under ART] were included. Higher percentages of plasmatic palmitc acid (16:0) and saturated fatty acids (SFA) were observed in participants with liver fibrosis (cases) compared to those without (controls). Presence of higher percentage of plasmatic palmitc acid (16:0) was associated with an increased odds for liver fibrosis [adjusted OR = 1.23 (95%CI 1.04-1.46); p = 0.02] in multivariate models.

This study showed the potential role of the plasmatic FA composition in the pathogenesis of liver fibrosis in PLWHA.

This study aims to conduct a comprehensive quantitative analysis of various nonalcoholic fatty liver disease (NAFLD) therapeutics, utilizing magnetic resonance (MR)-detected liver fat content (LFC) as the efficacy endpoint, and to identify biomarkers correlated with changes in LFC based on published literature.

We performed a systematic search of public databases for placebo-controlled randomized trials on NAFLD up to September 29, 2023. A random-effects meta-analysis was employed to assess efficacy differences between drugs with various mechanisms and placebo. Initial Pearson correlation analysis explored the relationships between biomarkers and LFC. For biomarkers showing significant correlations with LFC, further modeling analysis was conducted to examine their relationship characteristics.

Our analysis included 36 studies with 3222 subjects and 33 investigational drugs, which were categorized into 6 mechanistic groups. Drugs such as fibroblast growth factor agonists, and those targeting adipocytes, inflammation, or fibrosis, showed greater efficacy in reducing LFC compared to Resmetirom, which has an efficacy of reducing LFC by 5.2%. From the 121 biomarkers analyzed, alanine aminotransferase and aspartate aminotransferase demonstrated moderate correlations with LFC; specifically, changes of -5.9 U/L in alanine aminotransferase or -3.3 U/L in aspartate aminotransferase were associated with an additional 1% reduction in LFC.

The results of this study provide valuable insights for the clinical development of future NAFLD therapeutics, highlighting the efficacy of specific drug mechanisms and the potential of certain biomarkers as surrogate endpoints.

Glucose metabolism status (GMS) is linked to non-alcoholic fatty liver disease (NAFLD). Higher levels of advanced glycation end products (AGEs) are observed in people with type 2 diabetes mellitus (T2DM) and NAFLD. We examined the association between GMS, non-invasive tests and AGEs, with liver steatosis and fibrosis.

Data from The Maastricht Study, a population-based cohort, were analysed. Participants with alcohol overconsumption or missing data were excluded. GMS was determined via an oral glucose tolerance test. AGEs, measured by skin autofluorescence (SAF), were assessed using an AGE Reader. Associations of GMS and SAF with the fibrosis-4 score (FIB-4), Forns index (FI) and fatty liver index (FLI) were investigated using multivariable linear regression, adjusted for sociodemographic, lifestyle and clinical variables.

1955 participants (56.6%) were analysed: 598 (30.6%) had T2DM, 264 (13.5%) had pre-diabetes and 1069 (54.7%) had normal glucose metabolism. Pre-diabetes was significantly associated with FLI (standardised regression coefficient (Stβ) 0.396, 95% CI 0.323 to 0.471) and FI (Stβ 0.145, 95% CI 0.059 to 0.232) but not FIB-4. T2DM was significantly associated with FLI (Stβ 0.623, 95% CI 0.552 to 0.694) and FI (Stβ 0.307, 95% CI 0.226 to 0.388) but not FIB-4. SAF was significantly associated with FLI (Stβ 0.083, 95% CI 0.036 to 0.129), FI (Stβ 0.106, 95% CI 0.069 to 0.143) and FIB-4 (Stβ 0.087, 95% CI 0.037 to 0.137).

The study showed that adverse GMS and higher glycaemia are positively associated with steatosis. FI, but not FIB-4, was related to adverse GMS concerning fibrosis. This study is the first to demonstrate that SAF is positively associated with steatosis and fibrosis.

This review discussed experimental mouse models used in the pre-clinical study of liver fibrosis regression, a pivotal process in preventing the progression of metabolic dysfunction-associated steatohepatitis to irreversible liver cirrhosis. These models provide a valuable resource for understanding the cellular and molecular processes underlying fibrosis regression in different contexts. The primary focus of this review is on the most commonly used models with diet- or hepatotoxin-induced fibrosis, but it also touches upon genetic models and mouse models with biliary atresia or parasite-induced fibrosis. In addition to emphasizing in vivo models, we briefly summarized current in vitro approaches designed for studying fibrosis regression and provided an outlook on evolving methodologies that aim to refine and reduce the number of experimental animals needed for these studies. Together, these models contribute significantly to unraveling the underlying mechanisms of liver fibrosis regression and offer insights into potential therapeutic interventions. By presenting a comprehensive overview of these models and highlighting their respective advantages and limitations, this review serves as a roadmap for future research.

The global incidence of nonalcoholic fatty liver disease (NAFLD) is escalating considerably. NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis, which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix, leading to fibrosis. Hepatocyte ballooning is a key catalyst for fibrosis progression, potentially advancing to cirrhosis and its decompensated state. Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD; therefore, those with substantial fibrosis require timely intervention. Although liver biopsy is the most reliable method for fibrosis detection, it is associated with certain risks and limitations, particularly in routine screening. Consequently, various noninvasive diagnostic techniques have been introduced. This review examines the increasing prevalence of NAFLD, evaluates the noninvasive diagnostic techniques for fibrosis, and assesses their efficacy in staging the disease. In addition, it critically appraises current and emerging antifibrotic therapies, focusing on their mechanisms, efficacy, and potential in reversing fibrosis. This review underscores the urgent need for effective therapeutic strategies, given the dire consequences of advanced fibrosis.

To evaluate comprehensive bone health among young Indian women, including bone mass, microarchitecture, and turnover, in relation to their non-alcoholic fatty liver disease (NAFLD) status.

This cross-sectional study (May 2018-November 2019) recruited women with a history of gestational diabetes mellitus (GDM) and normoglycemia in their index pregnancy, who were at least 6 months postpartum. All participants underwent abdominal ultrasonography for determination of NAFLD status (grades 2 and 3: severe NAFLD) and transient elastography (FibroScan) for hepatic fibrosis (LSM >6 kPa). Bone mass was assessed by DXA, bone microarchitecture with trabecular bone score {TBS} (low TBS ≤ 1.310) and bone turnover with markers of bone formation (osteocalcin and P1NP), and resorption (CTX).

Bone mineral density (BMD) at femoral neck (p = 0.026) and total hip (p = 0.007) was significantly higher among women with NAFLD (n = 170) compared to those without (n = 124). There was no significant difference in bone turnover markers between the two groups. The presence of NAFLD [adjusted OR: 1.82 (1.07, 3.11)] was associated with low TBS, with a greater strength of association among women with severe NAFLD [adjusted OR: 2.97 (1.12, 7.88)]. However, these associations were attenuated and no longer significant after additionally adjusting for BMI. Women with NAFLD and hepatic fibrosis manifested significantly higher BMD at lumbar spine, femoral neck, and total hip (p < 0.001 for all) and significantly lower bone turnover markers (osteocalcin, p = 0.009 and CTX, p = 0.029), however, the association with low TBS was not observed.

Among young Indian women, NAFLD is associated with increased bone mass and impaired bone microarchitecture, and hepatic fibrosis with increased bone mass and reduced bone turnover.

This study investigated the efficacy of a new chrysin-loaded calixarene-cyclodextrin ternary drug delivery system (DDS) in reversing liver fibrosis in a mouse model of chronic diabetes. The system was designed to enhance the solubility and bioavailability of chrysin (CHR) and calixarene 0118 (OTX008). Adult male CD1 mice received streptozotocin (STZ) injections to induce diabetes. After 20 weeks, they underwent intraperitoneal treatments twice weekly for a two-week period. Histological analyses revealed that long-term hyperglycaemia increased liver fibrosis and altered hepatic ultrastructure, characterized by lipid accumulation, hepatic stellate cell activation, and collagen deposition. The treatment with the chrysin-loaded DDS restored liver structure closely to normal levels, as opposed to the minimal impact observed with sulfobutylated β-cyclodextrin (SBECD) alone. The treatment significantly decreased serum activities of alanine /aspartate transaminases and reduced the gene expression of collagen type I (Col-I). It also modulated the transforming growth factor beta 1 (TGF-β1)/Smad signalling pathway, inhibiting the activation and proliferation of hepatic stellate cells. The treatment led to a downregulation of the TGF-β1 gene and its receptors TGFβR1 and TGFβR2, together with a decrease in Smad 2 and 3 mRNA levels. Conversely, Smad 7 mRNA expression was increased by the DDS. Furthermore, it downregulated galectin-1 (Gal-1) gene and protein levels, which correlated with fibrotic markers. In conclusion, the chrysin-loaded calixarene-cyclodextrin ternary DDS presents a promising therapeutic approach for diabetic liver fibrosis, effectively targeting fibrotic pathways and restoring hepatic function and structure.

Melatonin signaling via melatonin receptor type 1 (MT1) and type 2 (MT2) plays an important role in the regulation of several physiological functions. Studies in rodents and humans have demonstrated that disruption of melatonin signaling may affect glucose metabolism, insulin sensitivity, and leptin levels. Accumulating experimental evidence also indicates that in rodents the administration of exogenous melatonin has a beneficial effect on the blood lipid levels. However, the molecular mechanism by which melatonin signaling may regulate lipids is still unclear. In addition, most of the studies with mice have been performed in melatonin-deficient mice by administering exogenous melatonin at supraphysiological doses. Hence the results of these studies may be greatly affected by these two factors. In this study, we report the effects of melatonin signaling removal on the liver biology and transcriptome using melatonin-proficient mice (C3H-f+/f+) in which MT1 or MT2 have been genetically ablated. Our data indicate that the absence of MT1 or MT2 signaling leads to disruption of the blood lipids profile and an increase in lipids deposition in the liver. These effects were more pronounced in the mice lacking MT1 than MT2. The gene expression profiles obtained with RNA-seq from the livers of the three genotypes revealed that removal of MT1 affected the transcription of 4255 genes (i.e., 40.6%). Conversely, the removal of MT2 affected the transcription of 1864 transcripts (i.e., 17.2%). Finally, we identified a group of 13 genes involved in lipids biology that may play a key role in the accumulation of lipids in the liver when melatonin signaling is disrupted. In conclusion, our study indicates that melatonin signaling is an important modulator of liver physiology and metabolism. Our study also indicated that the removal of MT1 signaling is more deleterious than MT2 removal.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, continues to rise with rapid economic development and poses significant challenges to human health. No effective drugs are clinically approved. MASLD is regarded as a multifaceted pathological process encompassing aberrant lipid metabolism, insulin resistance, inflammation, gut microbiota imbalance, apoptosis, fibrosis, and cirrhosis. In recent decades, herbal medicines have gained increasing attention as potential therapeutic agents for the prevention and treatment of MASLD, due to their good tolerance, high efficacy, and low toxicity. In this review, we summarize the pathological mechanisms of MASLD; emphasis is placed on the anti-MASLD mechanisms of Chinese herbal formula (CHF), especially their effects on improving lipid metabolism, inflammation, intestinal flora, and fibrosis. Our goal is to better understand the pharmacological mechanisms of CHF to inform research on the development of new drugs for the treatment of MASLD.

Polyunsaturated fatty acids (PUFAs) have potentially beneficial effects on the liver tissue. Noninvasive biomarkers, including imaging techniques and blood-based biomarkers, are important tools for assessing liver fibrosis. This study aims to investigate the relationship between dietary intake of PUFAs and noninvasive biomarkers for liver fibrosis in the general population.

The National Health and Nutrition Examination Survey 2017-2018 (NHANES 2017-2018) datasets were used. Fibrosis-4 index (FIB-4), FIB-8, and Fatty Liver Index (FLI) were calculated for each subject. The fibrosis groups were compared based on their intake of PUFA. The correlation between each score and PUFA intake was calculated. Correlation analysis was performed.

A total of 5087 subjects (50.36% female) with a mean age of 49.37 ± 12.14 were evaluated. The mean of median liver stiffness measurement (LSM) was 5.92 ± 5.20 kPa (kPa). The mean PUFA intake was reported as 20.2 ± 13.9 gm. Fibrosis (F) grouping revealed that 190 subjects had F3, and 154 F4. HDL had a significant correlation with Docosapentaenoic acid (DPA) intake (r = -0.038, p = 0.007). Moreover, AST and ALT had a significant correlation with Docosahexaenoic acid (DHA) intake (r = 0.033 and 0.059, p = 0.019 and < 0.001, respectively). FIB-4 and FIB-8 had no correlation with PUFA intake. FLI had a significant correlation with DPA acid (r = 0.062, p < 0.001).

A significant correlation between FLI, and PUFA intake suggests that increasing PUFA consumption could have a positive impact on liver health.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation, steatosis and fibrosis. Sympathetic nerves play a critical role in maintaining hepatic lipid homeostasis and regulating fibrotic progression through adrenergic receptors expressed by hepatocytes and hepatic stellate cells; however, the use of sympathetic nerve-focused strategies for the treatment of NAFLD is still in the infancy. Herein, a biomimetic nanoplatform with ROS-responsive and ROS-scavenging properties was developed for the codelivery of retinoic acid (RA) and the adrenoceptor antagonist labetalol (LA). The nanoplatform exhibited improved accumulation and sufficient drug release in the fibrotic liver, thereby achieving precise codelivery of drugs. Integration of adrenergic blockade effectively interrupted the vicious cycle of sympathetic nerves with hepatic stellate cells (HSCs) and hepatocytes, which not only combined with RA to restore HSCs to a quiescent state but also helped to reduce hepatic lipid accumulation. We demonstrated the excellent ability of the biomimetic nanoplatform to ameliorate liver inflammation, fibrosis and steatosis. Our work highlights the tremendous potential of a sympathetic nerve-focused strategy for the management of NAFLD and provides a promising nanoplatform for the treatment of NAFLD.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is one of the most prevalent chronic liver diseases worldwide. Thermal imaging combined with advanced image-processing and machine learning analysis accurately classified disease status in a study on mice; this study aimed to develop this tool for humans. This prospective study included 46 patients who underwent liver biopsy. Liver thermal imaging was performed on the same day as liver biopsy. We developed an image-processing algorithm that measured the relative spatial thermal variation across the skin covering the liver. The texture parameters obtained from the thermal images were input into the machine learning algorithm. Patients were diagnosed with MASLD and stratified according to nonalcoholic fatty liver disease activity score (NAS) and fibrosis stage using the METAVIR score. Twenty-one of 46 patients were diagnosed with MASLD. Using thermal imaging followed by processing, detection accuracy for patients with NAS >4 was 0.72.

Diagnosis of early hepatic steatosis would allow timely intervention. B-mode ultrasound imaging was in question for detecting early steatosis, especially with a variety of concomitant parenchymal disease. This study aimed to use the surgical specimen as a reference standard to elucidate the clinical performance of ultrasonic echogenicity and backscatter parametric and nonparametric statistics in real-world scenarios. Ultrasound radio-frequency (RF) signals of right liver lobe and patient data were collected preoperatively. Surgical specimen was then used to histologically determine staging of steatosis. A backscatter nonparametric statistic (h), a known backscatter parametric statistic, i.e., the Nakagami parameter (m), and a quantitative echo intensity (env) were calculated. Among the 236 patients included in the study, 93 were grade 0 (<5% fat) and 143 were with steatosis. All the env, m and h statistics had shown significant discriminatory power of steatosis grades (AUC = 0.643-0.907 with p-value < 0.001). Mann-Whitney U tests, however, revealed that only the backscatter statistics m and h were significantly different between the groups of grades 0 and 1 steatosis. The two-way ANOVA showed a significant confounding effect of the elevated ALT on env (p-value = 0.028), but no effect on m or h. Additionally, the severe fibrosis was found to be a significant covariate for m and h. Ultrasonic signals acquired from different scanners were found linearly comparable.

In this editorial, we offer commentary on the article published by Chen et al in a recent issue of the World Journal of Gastroenterology (2024; 30: 1346-1357). The study highlights a noteworthy association between persistently elevated, yet high-normal levels of alanine transaminase (ALT) and an escalated cumulative risk of developing metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD has emerged as a globally prevalent chronic liver condition, whose incidence is steadily rising in parallel with improvements in living standards. Left unchecked, MAFLD can progress from hepatic steatosis to liver fibrosis, cirrhosis, and even hepatocellular carcinoma, underscoring the importance of early screening and diagnosis. ALT is widely recognized as a reliable biomarker for assessing the extent of hepatocellular damage. While ALT levels demonstrate a significant correlation with the severity of fatty liver disease, they lack specificity. The article by Chen et al contributes to our understanding of the development of MAFLD by investigating the long-term implications of high-normal ALT levels. Their findings suggest that sustained elevation within the normal range is linked to an increased likelihood of developing MAFLD, emphasizing the need for closer monitoring and potential intervention in such cases.

Nonalcoholic fatty liver disease (NALFD) represents a complex condition ranging from simple steatosis (nonalcoholic fatty liver, NAFL) to inflammation, and fibrosis is one of the main features of nonalcoholic steatohepatitis (NASH). The pathogenesis of NAFLD is not well established but involves several factors (i.e., predisposition of genetic variants, obesity, and unhealthy lifestyle as unbalanced diets) that lead to an alteration of lipid homeostasis and consequently to an abnormal accumulation of triglycerides and other lipids in the liver parenchyma. Currently, no resolutive pharmacological treatment for NAFLD is available, and the only therapeutic approach is a healthy diet and physical exercise. In this study, we investigated the potential beneficial effect of GprA, a new synthetic agonist of G-protein-coupled receptor 120/free fatty acid receptor 4 (GPR120/FFAR4), in the progression of NAFL/NASH in mice fed for different periods (26 weeks and 30 weeks), with a high-fat (40% kcal) and high-carbohydrate diet, also called a Western-style diet (WSD). In our experimental model, the histological, protein, and transcriptomic analyses highlighted that the GprA can reduce signs of steatosis in WSD-fed mice. Furthermore, in 30 week-treated mice, GprA is also effective in the reduction of collagen deposition and fibrosis development. Altogether, our data validate the central role of FFAR4 in the context of NAFL/NASH onset and progression and reveal that GprA could represent an interesting candidate for the development of a new therapeutic approach in NAFLD treatment.

Liver fibrosis, a major global health issue, is marked by excessive collagen deposition that impairs liver function. Noninvasive methods for the direct visualization of collagen content are crucial for the early detection and monitoring of fibrosis progression. This study investigates the potential of spectral photoacoustic imaging (sPAI) to monitor collagen development in liver fibrosis. Utilizing a novel data-driven superpixel photoacoustic unmixing (SPAX) framework, we aimed to distinguish collagen presence and evaluate its correlation with fibrosis progression. We employed an established diethylnitrosamine (DEN) model in rats to study liver fibrosis over various time points. Our results revealed a significant correlation between increased collagen photoacoustic signal intensity and advanced fibrosis stages. Collagen abundance maps displayed dynamic changes throughout fibrosis progression. These findings underscore the potential of sPAI for the noninvasive monitoring of collagen dynamics and fibrosis severity assessment. This research advances the development of noninvasive diagnostic tools and personalized management strategies for liver fibrosis.

In this in vitro study, for the first time, we evaluate the effects of simvastatin-loaded liposome nanoparticles (SIM-LipoNPs) treatment on fibrosis-induced liver microtissues, as simvastatin (SIM) has shown potential benefits in the non-alcoholic fatty liver disease process. We developed multicellular liver microtissues composed of hepatic stellate cells, hepatoblastoma cells and human umbilical vein endothelial cells. The microtissues were supplemented with a combination of palmitic acid and oleic acid to develop fibrosis models. Subsequently, various groups of microtissues were exposed to SIM and SIM-LipoNPs at doses of 5 and 10 mg/mL. The effectiveness of the treatments was evaluated by analysing cell viability, production of reactive oxygen species (ROS) and nitric oxide (NO), the expression of Kruppel-like factor (KLF) 2, and pro-inflammatory cytokines (interleukin(IL)-1 α, IL-1 β, IL-6 and tumour necrosis factor-α), and the expression of collagen I. Our results indicated that SIM-LipoNPs application showed promising results. SIM-LipoNPs effectively amplified the SIM-klf2-NO pathway at a lower dosage compatible with a high dosage of free SIM, which also led to reduced oxidative stress by decreasing ROS levels. SIM-LipoNPs administration also resulted in a significant reduction in pro-inflammatory cytokines and Collagen I mRNA levels, as a marker of fibrosis. In conclusion, our study highlights the considerable therapeutic potential of using SIM-LipoNPs to prevent liver fibrosis progress, underscoring the remarkable properties of SIM-LipoNPs in activating the KLF2-NO pathway and anti-oxidative and anti-inflammatory response.

With around one billion of the world's population affected, the era of the metabolic-associated fatty liver disease (MAFLD) pandemic has entered the global stage. MAFLD is a chronic progressive liver disease with accompanying metabolic disorders such as type 2 diabetes mellitus and obesity which can progress asymptomatically to liver cirrhosis and subsequently to hepatocellular carcinoma (HCC), and for which to date there are almost no approved pharmacologic options. Because MAFLD has a very complex etiology and it also affects extrahepatic organs, a multidisciplinary approach is required when it comes to finding an effective and safe active substance for MAFLD treatment. The optimal drug for MAFLD should diminish steatosis, fibrosis and inflammation in the liver, and the winner for MAFLD drug authorisation seems to be the one that significantly improves liver histology. Saroglitazar (Lipaglyn®) was approved for metabolic-dysfunction-associated steatohepatitis (MASH) in India in 2020; however, the drug is still being investigated in other countries. Although the pharmaceutical industry is still lagging behind in developing an approved pharmacologic therapy for MAFLD, research has recently intensified and many molecules which are in the final stages of clinical trials are expected to be approved in the coming few years. Already this year, the first drug (Rezdiffra™) in the United States was approved via accelerated procedure for treatment of MAFLD, i.e., of MASH in adults. This review underscores the most recent information related to the development of drugs for MAFLD treatment, focusing on the molecules that have come furthest towards approval.

Primary sclerosing cholangitis (PSC) is a rare, progressive disease, characterized by inflammation and fibrosis of the bile ducts, lacking reliable prognostic biomarkers for disease activity. Machine learning applied to broad proteomic profiling of sera allowed for the discovery of markers of disease presence, severity, and cirrhosis and the exploration of the involvement of CCL24, a chemokine with fibro-inflammatory activity. Sera from 30 healthy controls and 45 PSC patients were profiled with proximity extension assay, quantifying the expression of 2870 proteins, and used to train an elastic net model. Proteins that contributed most to the model were tested for correlation to enhanced liver fibrosis (ELF) score and used to perform pathway analysis. Statistical modeling for the presence of cirrhosis was performed with principal component analysis (PCA), and receiver operating characteristics (ROC) curves were used to assess the useability of potential biomarkers. The model successfully predicted the presence of PSC, where the top-ranked proteins were associated with cell adhesion, immune response, and inflammation, and each had an area under receiver operator characteristic (AUROC) curve greater than 0.9 for disease presence and greater than 0.8 for ELF score. Pathway analysis showed enrichment for functions associated with PSC, overlapping with pathways enriched in patients with high levels of CCL24. Patients with cirrhosis showed higher levels of CCL24. This data-driven approach to characterize PSC and its severity highlights potential serum protein biomarkers and the importance of CCL24 in the disease, implying its therapeutic potential in PSC.

Chronic Kidney Disease (CKD) and Metabolic dysfunction-associated steatohepatitis (MASH) are metabolic fibroinflammatory diseases. Combining single-cell (scRNAseq) and spatial transcriptomics (ST) could give unprecedented molecular disease understanding at single-cell resolution. A more comprehensive analysis of the cell-specific ligand-receptor (L-R) interactions could provide pivotal information about signaling pathways in CKD and MASH. To achieve this, we created an integrative analysis framework in CKD and MASH from two available human cohorts.

The analytical framework identified L-R pairs involved in cellular crosstalk in CKD and MASH. Interactions between cell types identified using scRNAseq data were validated by checking the spatial co-presence using the ST data and the co-expression of the communicating targets. Multiple L-R protein pairs identified are known key players in CKD and MASH, while others are novel potential targets previously observed only in animal models.

Our study highlights the importance of integrating different modalities of transcriptomic data for a better understanding of the molecular mechanisms. The combination of single-cell resolution from scRNAseq data, combined with tissue slide investigations and visualization of cell-cell interactions obtained through ST, paves the way for the identification of future potential therapeutic targets and developing effective therapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are a growing health burden across a significant portion of the global patient population. However, these conditions seem to have disparate rates and outcomes between different ethnic populations. The combination of MASLD/MASH and type 2 diabetes increases the risk of hepatocellular carcinoma (HCC), and Hispanic patients experience the greatest burden, particularly those in South Texas.

To compare outcomes between Hispanic and non-Hispanic patients in the United States, while further focusing on the Hispanic population within Southeast Texas to determine whether the documented disparity in outcomes is a function of geographical circumstance or if there is a more widespread reason that all clinicians must account for in prognostic consideration.

This cohort analysis was conducted with data obtained from TriNetX, LLC ("TriNetX"), a global federated health research network that provides access to deidentified medical records from healthcare organizations worldwide. Two cohort networks were used: University of Texas Medical Branch (UTMB) hospital and the United States national database collective to determine whether disparities were related to geographic regions, like Southeast Texas.

This study findings revealed Hispanics/Latinos have a statistically significant higher occurrence of HCC, type 2 diabetes mellitus, and liver fibrosis/cirrhosis in both the United States and the UTMB Hispanic/Latino groups. All-cause mortality in Hispanics/Latinos was lower within the United States group and not statistically elevated in the UTMB cohort.

This would appear to support that Hispanic patients in Southeast Texas are not uniquely affected compared to the national Hispanic population.

Currently, staging the degree of liver fibrosis predominantly relies on liver biopsy, a method fraught with potential risks, such as bleeding and infection. With the rapid development of medical imaging devices, quantification of liver fibrosis through image processing technology has become feasible. Stacking technology is one of the effective ensemble techniques for potential usage, but precise tuning to find the optimal configuration manually is challenging. Therefore, this paper proposes a novel EVO-MS model-a multiple stacking ensemble learning model optimized by the energy valley optimization (EVO) algorithm to select most informatic features for fibrosis quantification. Liver contours are profiled from 415 biopsied proven CT cases, from which 10 shape features are calculated and inputted into a Support Vector Machine (SVM) classifier to generate the accurate predictions, then the EVO algorithm is applied to find the optimal parameter combination to fuse six base models: K-Nearest Neighbors (KNNs), Decision Tree (DT), Naive Bayes (NB), Extreme Gradient Boosting (XGB), Gradient Boosting Decision Tree (GBDT), and Random Forest (RF), to create a well-performing ensemble model. Experimental results indicate that selecting 3-5 feature parameters yields satisfactory results in classification, with features such as the contour roundness non-uniformity (Rmax), maximum peak height of contour (Rp), and maximum valley depth of contour (Rm) significantly influencing classification accuracy. The improved EVO algorithm, combined with a multiple stacking model, achieves an accuracy of 0.864, a precision of 0.813, a sensitivity of 0.912, a specificity of 0.824, and an F1-score of 0.860, which demonstrates the effectiveness of our EVO-MS model in staging the degree of liver fibrosis.

Halophyte species represent valuable reservoirs of natural antioxidants, and, among these, Salicornia europaea stands out as a promising edible plant. In this study, young and old S. europaea leaves were compared for the content of bioactive compounds and antioxidant activity to assess changes in different growth phases; then, the potential protective effects against low-dose CCl4-induced toxicant-associated fatty liver disease (TAFLD) were investigated by administering an aqueous suspension of young leaves to rats daily for two weeks. Quantification of total and individual phenolic compounds and in vitro antioxidant activity assays (DPPH, FRAP, and ORAC) showed the highest values in young leaves compared to mature ones. Salicornia treatment mitigated CCl4-induced hepatic oxidative stress, reducing lipid peroxidation and protein carbonyl levels, and preserving the decrease in glutathione levels. Electronic paramagnetic resonance (EPR) spectroscopy confirmed these results in the liver and evidenced free radicals increase prevention in the brain. Salicornia treatment also attenuated enzymatic disruptions in the liver's drug metabolizing system and Nrf2-dependent antioxidant enzymes. Furthermore, histopathological examination revealed reduced hepatic lipid accumulation and inflammation. Overall, this study highlights Salicornia's potential as a source of bioactive compounds with effective hepatoprotective properties capable to prevent TAFLD.

It is unclear what biopsychosocial factors influence the impact of NAFLD on health-related quality of life (HRQoL), and if these factors are equally important predictors between different nationalities.

HRQoL (CLDQ) was measured in both Southern European (Spain, n = 513) and Northern European (United Kingdom -UK-, n = 224) cohorts of patients with NAFLD in this cross-sectional study. For each cohort, participant data were recorded on histological grade of steatohepatitis, stage of fibrosis and biopsychosocial variables. Regression analysis was used to explore which of these variables predicted HRQoL. Moderated mediation models were conducted using SPSS PROCESS v3.5 macro.

Participants with severe fibrosis reported more fatigue, systemic symptoms and worry, and lower HRQoL than those with none/mild fibrosis, regardless of place of origin. In addition, body mass index (BMI) and gender were found to be significant predictors of HRQoL in both Spanish and UK participants. Female gender was associated with worse emotional function, higher BMI and more fatigue, which predicted lower participants' HRQoL. UK participants showed more systemic symptoms and worry than Spanish participants, regardless of liver severity. The negative effects of gender on HRQoL through emotional function, BMI and fatigue were reported to a greater degree in UK than in Spanish participants.

UK participants showed a greater impairment in HRQoL as compared to Spanish participants. Higher fibrosis stage predicted lower HRQoL, mainly in the Spanish cohort. Factors such as female gender or higher BMI contributed to the impact on HRQoL in both cohorts of patients and should be considered in future multinational intervention studies in NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease, affecting 25-30% of the general population globally. The condition is even more prevalent in individuals with obesity and is frequently linked to the metabolic syndrome. Given the known associations between the metabolic syndrome and common mental health issues, it is likely that such a relationship also exists between NAFLD and mental health problems. However, studies in this field remain limited. Accordingly, the aim of this systematic review and meta-analysis was to explore the prevalence of one or more common mental health conditions (i.e., depression, anxiety, and/or stress) in adults with NAFLD.

PubMed, EBSCOhost, ProQuest, Ovid, Web of Science, and Scopus were searched in order to identify studies reporting the prevalence of depression, anxiety, and/or stress among adults with NAFLD. A random-effects model was utilized to calculate the pooled prevalence and confidence intervals for depression, anxiety and stress.

In total, 31 studies were eligible for inclusion, involving 2,126,593 adults with NAFLD. Meta-analyses yielded a pooled prevalence of 26.3% (95% CI: 19.2 to 34) for depression, 37.2% (95% CI: 21.6 to 54.3%) for anxiety, and 51.4% (95% CI: 5.5 to 95.8%) for stress among adults with NAFLD.

The present findings suggest a high prevalence of mental health morbidity among adults with NAFLD. Given the related public health impact, this finding should prompt further research to investigate such associations and elucidate potential associations between NAFLD and mental health morbidity, exploring potential shared underlying pathophysiologic mechanisms.

https://www.crd.york.ac.uk/prospero/, identifier CRD42021288934.

The utilization of evolutive models and algorithms for predicting the evolution of hepatic steatosis holds immense potential benefits. These computational approaches enable the analysis of complex datasets, capturing temporal dynamics and providing personalized prognostic insights. By optimizing intervention planning and identifying critical transition points, they promise to revolutionize our approach to understanding and managing hepatic steatosis progression, ultimately leading to enhanced patient care and outcomes in clinical settings. This paradigm shift towards a more dynamic, personalized, and comprehensive approach to hepatic steatosis progression signifies a significant advancement in healthcare. The application of evolutive models and algorithms allows for a nuanced characterization of disease trajectories, facilitating tailored interventions and optimizing clinical decision-making. Furthermore, these computational tools offer a framework for integrating diverse data sources, creating a more holistic understanding of hepatic steatosis progression. In summary, the potential benefits encompass the ability to analyze complex datasets, capture temporal dynamics, provide personalized prognostic insights, optimize intervention planning, identify critical transition points, and integrate diverse data sources. The application of evolutive models and algorithms has the potential to revolutionize our understanding and management of hepatic steatosis, ultimately leading to improved patient outcomes in clinical settings.

Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11), has been identified as a key player in various biological processes, including embryonic development, aging, metabolic disorders and cancers. GDF11 has also emerged as a critical component in liver development, injury and fibrosis. However, the effects of GDF11 on liver physiology and pathology have been a subject of debate among researchers due to conflicting reported outcomes. While some studies suggest that GDF11 has anti-aging properties, others have documented its senescence-inducing effects. Similarly, while GDF11 has been implicated in exacerbating liver injury, it has also been shown to have the potential to reduce liver fibrosis. In this narrative review, we present a comprehensive report of recent evidence elucidating the diverse roles of GDF11 in liver development, hepatic injury, regeneration and associated diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma. We also explore the therapeutic potential of GDF11 in managing various liver pathologies.

Hepatic fibrosis exacerbates mortality and complications in progressive metabolic dysfunction-associated steatohepatitis (MASH). The role of the adenosine 2A receptor (A2aAR) in hepatic fibrosis within the context of MASH remains uncertain. This study aims to elucidate the involvement of the A2aAR signaling pathway and the efficacy of a novel potent A2aAR antagonist in treating hepatic fibrosis in MASH-induced mice fed a chlorine-deficient, L-amino acid-defined, high fat diet (CDAHFD). A2aAR overexpression in LX-2 cells increased fibrosis markers, whereas the known A2aAR antagonist, ZM241385, decreased these markers. A novel A2aAR antagonist, RAD11, not only attenuated fibrosis progression but also exhibited greater inhibition of the A2aAR signaling pathway compared to ZM241385 in mice with MASH, activated primary hepatocytes, and LX-2 cells. RAD11 exhibited a dual antifibrotic mechanism by targeting both activated HSCs and hepatocytes. Its superior antifibrotic efficacy over ZM241385 in the MASH condition stems from its ability to suppress A2aAR-mediated signaling, inhibit HSC activation, reduce hepatic lipogenesis in hepatocytes, and mitigate lipid accumulation-induced oxidative stress-mediated liver damage. This study has shed light on the relationship between A2aAR signaling and hepatic fibrosis, presenting RAD11 as a potent therapeutic agent for managing MASH and hepatic fibrosis.

Portal hypertension (PH) has traditionally been observed as a consequence of significant fibrosis and cirrhosis in advanced non-alcoholic fatty liver disease (NAFLD). However, recent studies have provided evidence that PH may develop in earlier stages of NAFLD, suggesting that there are additional pathogenetic mechanisms at work in addition to liver fibrosis. The early development of PH in NAFLD is associated with hepatocellular lipid accumulation and ballooning, leading to the compression of liver sinusoids. External compression and intra-luminal obstacles cause mechanical forces such as strain, shear stress and elevated hydrostatic pressure that in turn activate mechanotransduction pathways, resulting in endothelial dysfunction and the development of fibrosis. The spatial distribution of histological and functional changes in the periportal and perisinusoidal areas of the liver lobule are considered responsible for the pre-sinusoidal component of PH in patients with NAFLD. Thus, current diagnostic methods such as hepatic venous pressure gradient (HVPG) measurement tend to underestimate portal pressure (PP) in NAFLD patients, who might decompensate below the HVPG threshold of 10 mmHg, which is traditionally considered the most relevant indicator of clinically significant portal hypertension (CSPH). This creates further challenges in finding a reliable diagnostic method to stratify the prognostic risk in this population of patients. In theory, the measurement of the portal pressure gradient guided by endoscopic ultrasound might overcome the limitations of HVPG measurement by avoiding the influence of the pre-sinusoidal component, but more investigations are needed to test its clinical utility for this indication. Liver and spleen stiffness measurement in combination with platelet count is currently the best-validated non-invasive approach for diagnosing CSPH and varices needing treatment. Lifestyle change remains the cornerstone of the treatment of PH in NAFLD, together with correcting the components of metabolic syndrome, using nonselective beta blockers, whereas emerging candidate drugs require more robust confirmation from clinical trials.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to some metabolic disorders, such as central obesity and type 2 diabetes (T2D). Glucagon-like peptide 1 receptor agonists (GLP-1RAs), such as semaglutide, may have therapeutic roles in MASLD associated with T2D. This study aims to investigate the molecular mechanisms underlying the effectiveness of semaglutide on MASLD in terms of progression from liver steatosis to fibrosis. We characterized exosomes from ten patients with type 2 diabetes (T2D) before (T0) and after 12 months (T12) of treatment with once-weekly subcutaneous semaglutide. Six of ten patients were considered responders to therapy (R) based on MASLD severity downgrading by at least one class according to a validated ultrasonographic (US) score. Normal hepatocytes (HEPA-RG) and stellate (LX-2) cells were challenged with exosomes from R and NR patients, isolated before and after 12 months of therapy. Exosomes from both R and NR patients isolated at T0 significantly affected LX-2 viability. After 12 months of treatment, only those isolated from R patients restored cell viability, whereas those from NR patients did not. No effects were observed on HEPA-RG cells. Exosomes at T12 from R but not from NR patients significantly decreased the production of α-SMA, a marker of LX-2 activation, a liver stellate cell model, and ph-SMAD2 and CTGF, involved in fibrosis processes. TGF-β1 was not modulated by the exosomes of R and NR patients. As a downstream effect, Vimentin, Collagen 1A1, and Fibronectin extracellular matrix components were also downregulated, as measured by droplets digital PCR. In conclusion, these results shed light on the potential effectiveness of semaglutide in improving liver fibrosis in MASLD.

Cirrhosis is becoming one of the most common diseases worldwide. Abnormal upregulation of transforming growth factor β (TGF-β) signaling plays a pivotal role in the excess activation of hepatic stellate cells. However, an efficient countermeasure against abnormal hepatic stellate cell activation is yet to be established because TGF-β signaling is involved in several biological processes. Herein, we demonstrated the antifibrotic effect of miR-12135, a microRNA with unknown function upregulated by isoflavone. Comprehensive transcriptome assay demonstrated that miR-12135 suppressed Integrin Subunit Alpha 11 (ITGA11) and that ITGA11 expression is correlated with alpha smooth muscle actin expression in patients with cirrhosis. miR-12135 suppressed the expression level of ITGA11 and liver fibrosis. Importantly, ITGA11 is overexpressed in activated hepatic stellate cells, whereas ITGA11 knockout mice are viable and fertile. In conclusions, the miR-12135/ITGA11 axis can be an ideal therapeutic target to suppress fibrosis by precisely targeting abnormally upregulated TGF-β signaling in hepatic stellate cells.