Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes without significant alcohol consumption. It is closely associated with sedentarism, hypercaloric diets, obesity, dyslipidemia, insulin resistance, type 2 diabetes mellitus, and genetic predisposition. NAFLD comprises a spectrum of liver disorders, from simple steatosis to non-alcoholic (NASH) and liver cirrhosis. The complex etiological mechanisms include oxidative stress, inflammation, apoptosis, and fibrosis; therefore, its management is challenging. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i), a class of antidiabetic drugs, have emerged as promising therapeutic agents due to their ability to improve key metabolic parameters, including obesity, dyslipidemia, insulin resistance, and hyperglycemia. This review explores the cellular mechanisms by which SGLT2i, either as monotherapy or combined with other treatments, modulate signaling pathways involved in lipid and carbohydrate metabolism. Additionally, we examine their effects on oxidative stress, inflammation, fibrosis, and apoptosis, which are critical drivers of NAFLD progression. This review is intended to summarize the multiple benefits of SGLT2 inhibitors and to educate healthcare providers on the therapeutic potential of these drugs in order to foster their incorporation into effective NAFLD management plans.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, and its exact pathogenesis has not been fully studied. Hydrogen sulfide (H2S) is the third gas signaling molecule discovered in mammals, following nitric oxide and carbon monoxide. It has the effects of anti-inflammation, anti-apoptosis, and so on, thereby playing an important role in many diseases. However, the role and mechanism of exogenous H2S in NAFLD are not fully understood. In this study, we constructed in vitro and in vivo NAFLD models by feeding mice a high-fat diet and stimulating hepatocytes with palmitic acid, respectively, to investigate the improvement effect and mechanism of exogenous H2S on NAFLD. The results showed that NaHS (a donor of H2S) treatment alleviated lipid accumulation, inflammation, apoptosis and pyroptosis, and downregulated endoplasmic reticulum (ER) stress and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NRRP3) inflammasome in NAFLD. The activation of NLRP3 inflammasome weakened NaHS improvement of NAFLD, indicating that exogenous H2S ameliorated NAFLD by inhibiting NLRP3 inflammasome-mediated lipid synthesis, inflammation, apoptosis and pyroptosis. Similarly, the activation of ER stress weakened NaHS improvement of NAFLD and NaHS inhibition of NLRP3 inflammasome, indicating that exogenous H2S suppressed NLRP3 inflammasome by downregulating ER stress, thus improving NAFLD. Additionally, the protein expressions of NLRP3 and cleaved caspase-1 were downregulated after inhibiting the reactive oxygen species (ROS)/extracellular signal-regulated kinases (ERK) and ROS/thioredoxin-interacting protein (TXNIP) pathways, indicating that ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways. In conclusion, our results indicated that exogenous H2S inhibited NLRP3 inflammasome-mediated hepatocytes inflammation, lipid synthesis, apoptosis and pyroptosis by downregulating ER stress, thereby improving NAFLD; Furthermore, ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways in NAFLD. ER stress/NLRP3 inflammasome is expected to become a new target of H2S for treating NAFLD.

The metabolic pathway of sulfur-containing amino acids in organisms begins with methionine, which is metabolized to produce important sulfur-containing biomolecules such as adenosylmethionine, adenosylhomocysteine, homocysteine, cystine, and hydrogen sulfide (H2S). These sulfur-containing biomolecules play a wide range of physiological roles in the body, including anti-inflammation, antioxidant stress, DNA methylation, protein synthesis, etc., which are essential for maintaining cellular function and overall health. In contrast, dysregulation of the metabolic pathway of sulfur-containing amino acids leads to abnormal levels of sulfur-containing biomolecules, which produce a range of pathological consequences in multiple systems of the body, such as neurodegenerative diseases, cardiovascular diseases, and cancer. This review traces the milestones in the development of these sulfur-containing biomolecules from their initial discovery to their clinical applications and describes in detail the structure, physiochemical properties, metabolism, sulfide signaling pathway, physiopathological functions, and assays of sulfur-containing biomolecules. In addition, the paper also explores the regulatory role and mechanism of sulfur-containing biomolecules on cardiovascular diseases, liver diseases, neurological diseases, metabolic diseases and tumors. The focus is placed on donors of sulfur-containing biological macromolecule metabolites, small-molecule drug screening targeting H2S-producing enzymes, and the latest advancements in preclinical and clinical research related to hydrogen sulfide, including clinical trials and FDA-approved drugs. Additionally, an overview of future research directions in this field is provided. The aim is to enhance the understanding of the complex physiological and pathological roles of sulfur-containing biomolecules and to offer insights into developing effective therapeutic strategies for diseases associated with dysregulated sulfur-containing amino acid metabolism.

Nonalcoholic fatty liver disease (NAFLD) is a significant global health burden. It comprises a broad pathological spectrum ranging from simple liver steatosis to steatohepatitis with variable degrees of fibrosis, and liver failure. Patients with NAFLD have an increased risk of liver-related and overall mortality. While the trials to assess the efficacy of the medications are ongoing, lifestyle modification is the first line of therapy recommended. The primary aim of this review paper is to synthesize literature related to current evidence-based lifestyle interventions for preventing and managing NAFLD. The review and synthesis of the literature reveal that personalized nutritional, exercise, and behavior change interventions are effective in managing NAFLD. Evidence suggests that there are several gaps in managing NAFLD. The gaps discussed in this paper include a lack of awareness of the disease, ineffective patient-provider communication, shortage of specialists, under-recognition of the disease, and liver health disparities. This paper highlights the evidence-based opportunities to overcome those gaps, such as utilizing comprehensive models of care, clinical care pathways, and clinical practice guidelines. Primary care physicians and endocrinologists, who are the first point of contact must utilize these opportunities for diagnosing and managing patients with NAFLD.

The clinical manifestations of Cushing syndrome are variable, but an important number of patients present a metabolic syndrome, strongly associated with hepatic steatosis.

The aim of this study was to determine the prevalence of metabolic dysfunction associated steatotic liver disease (MASLD) at the diagnosis of Cushing syndrome.

We conducted a single-center retrospective study at Angers Hospital (France) between 2010 and 2020. Forty-nine patients followed for Cushing syndrome with available abdominal imaging at diagnosis were included. A mean liver/spleen density ratio < 1 on computed tomography was diagnostic of hepatic steatosis. Simple clinico-biological scores predictive of hepatic fibrosis (FIB-4, NAFLD Fibrosis Score, and eLIFT) were calculated for patients with hepatic steatosis.

Of the 49 patients, 13 (26.5%) had hepatic steatosis at diagnosis of Cushing syndrome. All 13 had MASLD. These patients had a higher prevalence of type 2 diabetes and higher triglyceride levels in multivariate analysis. There was no difference according to the intensity or duration of Cushing syndrome. Among the 13 patients with MASLD, 2 (15.4%) had a significant fibrosis predictive score. Of the 4 patients with follow-up imaging after remission of Cushing syndrome, 3 had remission of steatosis between 1 and 5 years after remission of Cushing syndrome. No patient without MASLD at diagnosis had a worsening liver/spleen ratio after remission.

We estimated the prevalence of hepatic steatosis at the diagnosis of Cushing syndrome at 26.5%. The presence of metabolic factors was associated with the occurrence of hepatic steatosis.

The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, and effective treatment is urgently needed. To understand the molecular mechanisms behind the effectiveness of bariatric surgery in treating NASH, we integrated single-cell and bulk RNA sequencing data to identify the role of liver macrophage polarization in alleviating NASH and screen possible drugs for treatment. Analysis revealed that bariatric surgery alleviates NASH by inhibiting liver M1 macrophage polarization with 12 differentially expressed M1 macrophage-related genes. Additionally, 56 potentially effective drugs were predicted for NASH treatment. These findings shed light on the effectiveness of bariatric surgery in treating NASH and offer potential drug candidates for further exploration.

Non-alcoholic fatty liver disease (NAFLD) and hyperlipidemia belong to the metabolic disorder syndromes of metabolic syndrome. They share a common pathological basis and are often complicated. Complanatoside A (CA), a flavonoid abundant in Astragali complanati semen, helps to prevent NAFLD and hyperlipidemia. However, the exact molecular mechanism is uncertain. Therefore, this study aims to explore the core mechanism. Network pharmacology was used to analyze the preventive mechanism of CA against NAFLD and hyperlipidemia. The efficacy of CA was proven in a high-fat diet-fed mouse model and a steatogenic hepatocyte model. Transcriptomic analysis, Western blot validation, and molecular docking methods were used to explore the common mechanism of CA in preventing NAFLD and hyperlipidemia. Network pharmacology revealed that the AMP-activated protein kinase (AMPK) pathway is a common mechanism leading to NAFLD and hyperlipidemia. It is also a potential pathway by which CA exerts its protective effect, which was confirmed in transcriptomics in vivo. Both in vitro and in vivo experiments showed that CA could inhibit lipid synthesis and promote fatty acid oxidation by activating the AMPK, alleviating lipid accumulation, and lipotoxic liver injury. This was demonstrated by the use of an AMPK inhibitor in vitro. Furthermore, molecular docking results showed that CA could directly interact with AMPK to regulate downstream lipid-related proteins. In conclusion, the AMPK pathway is key in developing NAFLD and hyperlipidemia. CA plays a dual preventive role in NAFLD and hyperlipidemia by activating AMPK to regulate lipid metabolism.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance, and systemic pro-inflammatory response. Thymosin β4 (Tβ4) is a bioactive polypeptide that inhibits extracellular matrix (ECM) deposition and protects the liver. It can achieve immune homeostasis by regulating the polarization of liver macrophages and is a potential treatment for NAFLD.

A dataset was used to evaluate the expression of Tβ4 in fatty and non-fatty adjacent tissues of primary hepatocellular carcinoma. NAFLD was induced in C57 mice with methionine and choline-deficient diet (MCD), siRNATβ4 was injected into the tail vein to reduce liver Tβ4, and the therapeutic effect of Tβ4 was observed by phagocytosis of macrophages with clodronate liposomes. Hematoxylin and Eosin staining (HE) staining was used to observe the inflammation of mice in each group, and oil red O staining was used to determine the lipid accumulation. Macrophage polarization was detected by immunofluorescence assay. In the extrachromosomal experiment of oil red O, human myeloid leukemia mononuclear (THP-1) cells was co-cultured with human hepatic (LO2) constructed with oleic acid to detect the changes of aspartate transaminase (AST) and alanine transaminase (ALT) in supernatant and the apoptosis of LO2 under the intervention of different concentrations of Tβ4.

Tβ4 allowed the mice to recover from NAFLD and reduce liver inflammation more effectively. Liver steatosis was more severe in sirnat4 mice. Macrophages are involved in Tβ4 treatment of NAFLD. The expression level of M1 phenotype in macrophages treated with Tβ4 decreased, and the apoptosis of hepatocytes decreased. At the same time, Tβ4 down-regulates signal transduction and activator of transcription1 (STAT1) phosphorylation and increases suppressor of cytokine signaling1/3 (SOCS1/3) expression in hepatocytes.

This study revealed the molecular mechanism of the effective effect of Tβ4 on the polarization of liver macrophages, suggesting that Tβ4 may be a potential therapeutic measure for NAFLD.

Pyroptosis is a distinct form of cell death that plays a critical role in intensifying inflammatory responses. It primarily occurs via the classical pathway, non-classical pathway, caspase-3/6/7/8/9-mediated pathways, and granzyme-mediated pathways. Key effector proteins involved in the pyroptosis process include gasdermin family proteins and pannexin-1 protein. Pyroptosis is intricately linked to the onset and progression of non-alcoholic steatohepatitis (NASH). During the development of NASH, factors such as pyroptosis, innate immunity, lipotoxicity, endoplasmic reticulum stress, and gut microbiota imbalance interact and interweave, collectively driving disease progression. This review analyzes the molecular mechanisms of pyroptosis and its role in the pathogenesis of NASH. Furthermore, it explores potential diagnostic and therapeutic strategies targeting pyroptosis, offering new avenues for improving the diagnosis and treatment of NASH.

The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.

The peroxisome proliferator-activated receptor-γ (PPARγ) serves as a pivotal regulator of lipid balance, adipogenesis, and inflammatory processes. PPARγ full agonists display strong curative effects but also serious adverse effects. Here, we found a novel 4-(cyclohexyloxy)phenyl acetate scaffold with partial PPARγ agonist activity, and its structure-activity relationship was studied. We also describe the structure-guided lead optimization of orally bioavailable SP-C01 as a dual modulator of soluble epoxide hydrolase (sEH) and partial PPARγ, which can inhibit Ser273 phosphorylation. In mice, oral administration of SP-C01 at a dose of 5 g/kg resulted in excellent safety; a significant reduction in the negative consequences of lipid accumulation and water-sodium retention; and no gastrointestinal adverse effects, weight gain, or cardiotoxicity. In addition, SP-C01 has shown a better effect than pioglitazone (Pio.) in type 2 diabetes and nonalcoholic steatohepatitis. Additionally, SP-C01 has demonstrated potent anti-inflammatory and analgesic properties in models of both neuropathic and inflammatory pain.

Metabolic dysfunction-associated steatitic liver disease (MASLD) is the predominant chronic liver disease, with its incidence increasing year by year. It has emerged as the most rapidly increasing contributor to liver-related mortality worldwide and is becoming a principal cause of end-stage liver disorders, primarily cancer of the liver and liver transplantation, hence putting a substantial economic burden on public health. The approval of Resmetirom signifies significant advancement in the treatment of metabolic dysfunction-associated steatohepatitis (MASH); nonetheless, the heterogeneity of MASLD renders it challenging for a single medication to address the requirements of all patients. Consequently, it is essential to formulate varied therapeutic approaches for distinct pathogenic causes and phases of disease. Fibroblast growth factor 21 (FGF21), a member of the fibroblast growth factor family, plays a positive and protective role in MASLD. It attenuates hepatic steatosis and lipotoxicity, ameliorates insulin resistance (IR), reduces oxidative stress, endoplasmic reticulum (ER) stress, and inflammation, as well as possesses anti-fibrotic effects. As a result, FGF21 has the potential to treat MASLD. In this review, we will address the possible mechanisms of FGF21 therapy for MASLD to facilitate the development of clinical therapies targeting FGF21 for MASLD.

G protein-coupled receptors (GPCRs) are important potential drug targets for the treatment of metabolic disorders. The D2 dopamine receptor (DRD2), a GPCR receptor, is a member of the dopamine receptor family. However, the role of DRD2 in regulating lipid metabolism, especially in hepatic steatosis, is unclear.

Eight-week male mice were fed HFHC/MCD to induce the MASH model. AAV2/8 containing the TBG promoter was used to knock down and overexpress DRD2 in mouse liver. Co-immunoprecipitation, Western lotting, immunofluorescence, and immunohistochemistry were used to investigate the mechanisms and screen DRD2 antagonists.

The study found that activation of PKC leads to the elevation and internalisation of DRD2 in a high-fat environment. Knockdown of DRD2 in mouse liver can effectively interfere with the progression of MASH, while overexpression of DRD2 significantly aggravates the process of MASH. The study on the mechanism of DRD2 regulating lipid metabolism found that the internalisation of DRD2 could lead to dephosphorylation of pAKT (T308) by binding to β-arrestin2 and pAKT, thereby inducing ubiquitin-dependent degradation of AMPK and exacerbating steatosis. L-741626, a DRD2 antagonist, was found to interfere with the internalisation of DRD2 in a high-fat environment. It has been shown that L-741626 can treat MASH by regulating the AKT-AMPK signalling axis in vitro and in vivo.

In conclusion, this study demonstrated that internalisation of DRD2 in a high-fat environment aggravated MASH progression through the AKT-AMPK signalling axis. Furthermore, L-741626, as a DRD2 antagonist, has the potential to treat MASH.

In the current era, metabolic dysfunction-associated steatotic liver disease (MASLD) has gradually developed into a major type of chronic liver disease that is widespread globally. Numerous studies have shown that the gut microbiota plays a crucial and indispensable role in the progression of MASLD. Currently, the gut microbiota has become one of the important entry points for the research of this disease. Therefore, the aim of this review is to elaborate on the further associations between the gut microbiota and MASLD, including the changes and differences in the microbiota between the healthy liver and the diseased liver. Meanwhile, considering that metabolic dysfunction-associated fatty liver and metabolic dysfunction-associated steatohepatitis are abnormal pathological states in the development of the disease and that the liver exhibits different degrees of fibrosis (such as mild fibrosis and severe fibrosis) during the disease progression, we also conduct a comparison of the microbiota in these states and use them as markers of disease progression. It reveals the changes in the production and action mechanisms of short-chain fatty acids and bile acids brought about by changes in the gut microbiota, and the impact of lipopolysaccharide from Gram-negative bacteria on the disease. In addition, the regulation of the gut microbiota in disease and the production and inhibition of related disease factors by the use of probiotics (including new-generation probiotics) will be explored, which will help to monitor the disease progression of patients with different gut microbiota compositions in the future and carry out personalized targeted therapies for the gut microbiota. This will achieve important progress in preventing and combating this disease.

Non-alcoholic fatty liver disease (NAFLD) is a global cause of liver dysfunction. This spectrum of hepatic disorders can progress to severe conditions, such as non-alcoholic steatohepatitis (NASH) and cirrhosis, due to oxidative stress and sustained cellular injury. With limited pharmacological options, glutathione (GSH), a key antioxidant, has shown promising potential in reducing oxidative stress, maintaining redox balance, and improving liver function. This literature review examines studies from 2014-2024 exploring GSH therapy in NAFLD patients. Eligible studies assessed GSH as the primary intervention for NAFLD in human subjects, reporting outcomes such as liver function or oxidative stress markers. Randomized clinical trials (RCTs) were eligible, while combination therapy studies were included if GSH's effect could be isolated. Exclusions applied to non-NAFLD studies, animal/in vitro models, and non-GSH antioxidant interventions. Analysis of three studies (totaling 109 participants) demonstrated consistent improvements in alanine transaminase (ALT) levels and reductions in oxidative stress markers like 8-hydroxy-2-deoxyguanosine (8-OHdG). However, small sample sizes and inconsistent protocols limit generalizability. Further large-scale RCTs are required to confirm GSH's efficacy, determine optimal dosing, and assess long-term effects. This literature review highlights GSH's potential as a novel NAFLD therapeutic strategy while emphasizing the need for further studies to refine its clinical application.

N6-methyladenosine (m6A) is involved in the development of non-alcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the effect of m6A methyltransferase METTL3 on liver damage in high-fat diet (HFD)-induced mouse model and hepatocyte damage treated with free fatty acid (FFA). Plasma lipid, lipogenesis, viability, and apoptosis were measured to assess injury. m6A methylation was evaluated using m6A dot blot, methylated RNA immunoprecipitation, dual-luciferase reporter assay, and RNA decay assay. The results indicated that METTL3 was highly expressed in the liver of HFD mice, which knockdown improved plasma lipid and reduced liver lipids. Additionally, silencing of METTL3 promoted cell viability, inhibited apoptosis, reduced lipid concentrations, and downregulated lipogenesis-related marker levels. Moreover, METTL3 promoted the m6A methylation of FAS and enhanced its stability. In conclusion, silencing of METTL3 attenuates the progression of NAFLD by FAS m6A methylation, suggesting that METTL3 may be a promising target for treating NAFLD.

Metabolic dysfunction-associated steatotic liver disease, a prevalent chronic liver condition, can cause severe complications like hepatitis, cirrhosis, and hepatocellular carcinoma. In recent years, glucagon-like peptide-1 receptor agonists (GLP - 1RA) have shown unique therapeutic advantages and may become a preferred treatment for it. This meta-analysis aims to systematically examine GLP-1RA associated adverse events, providing a basis for guiding patient clinical management.

We conducted a search for randomized controlled trials (RCTs) investigating the therapeutic effects of GLP-1RA in the treatment of metabolic dysfunction-associated steatotic liver disease across four databases: PubMed, Embase, Web of Science, and Cochrane Library. The search period extended from the inception of each database until December 2023. Information pertaining to various adverse events was collected as outcome measures. Statistical analysis of the results and assessment of bias risk were conducted utilizing Review Manager (version 5.4.1) software.

An analysis of 10 studies encompassing 960 participants revealed a significantly higher overall incidence of adverse events in the GLP-1RA group compared to the control group (OR: 2.40 [1.10, 5.26], P = 0.03). Subgroup analysis based on treatment duration demonstrated a higher rate of adverse events in the GLP-1RA group during follow-ups of less than 30 weeks (P = 0.0005, OR: 3.58 [1.75, 7.32]), but no statistical difference was observed between the two groups in follow-ups exceeding 30 weeks. There was no statistically significant difference between the two groups in adverse events leading to discontinuation (P = 0.29, OR: 1.47 [0.72, 2.98]). However, a notable difference was observed in gastrointestinal adverse events (P < 0.00001, OR: 4.83 [3.36, 6.95]).

GLP-1RA exhibits an overall higher incidence of adverse events in the treatment of metabolic dysfunction-associated steatotic liver disease, particularly in the gastrointestinal domain. Short-term use of GLP-1RA may be associated with a greater occurrence of adverse events, underscoring the importance of educating patients on preventive measures and establishing tolerance. However, there was no statistically significant difference between the two groups in severe adverse events and adverse events leading to discontinuation, confirming the safety profile of GLP-1RA application.

Background: Short sleep duration significantly increases the risk of liver disease. This study aims to investigate the relationship between weekend catch-up sleep (WCS) duration and hepatic steatosis in adults with varying weekday sleep durations in the United States. Methods: A cross-sectional analysis was conducted using adult participants from NHANES 2017 to March 2020. Anthropometry measurements, clinical features, biochemical parameters, and sleep duration (weekdays and weekends) were recorded. The controlled attenuation parameter (CAP) was utilized to evaluate the degree of liver steatosis. Student's t-test and Mann-Whitney U test were used for unpaired samples. Adjusted multi-variable logistic regression analysis was employed to evaluate the relationship between weekend catch-up sleep and hepatic steatosis. Results: Weekend sleep habits varied based on age, obesity, race, education level, and marital status. Individuals with insufficient weekday sleep (<6 hours) and inadequate WCS (<1 hour) exhibited a significant increase in liver CAP values and a markedly higher probability of hepatic steatosis. In contrast WCS >1 hour effectively reduced the probability of hepatic steatosis. Individuals who adequately compensated for sleep on weekends had lower ratios of AST/ALT, total bilirubin and creatinine levels. Among different BMI populations, WCS was significantly associated with liver health in those with insufficient weekday sleep (<6 hours), whereas in individuals with adequate or sufficient weekday sleep (≥6 hours), WCS only reduced the progression of steatosis in individuals with normal BMI (<25). Conclusion: Adequate weekend catch-up sleep was associated with a lower the incidence of hepatic steatosis in individuals with insufficient weekday sleep duration.

Metabolic diseases like obesity and diabetes are on the rise, and therapies with biomacromolecules (such as proteins, peptides, antibodies, and oligonucleotides) play a crucial role in their treatment. However, these drugs are traditionally injected. For patients with chronic diseases (e.g., metabolic diseases), long-term injections are accompanied by inconvenience and low compliance. Oral administration is preferred, but the delivery of biomacromolecules is challenging due to gastrointestinal barriers. In this article, we introduce the available biomacromolecule drugs for the treatment of metabolic diseases. The gastrointestinal barriers to oral drug delivery and strategies to overcome these barriers are also explored. We then discuss strategies for alleviating metabolic defects, including glucose metabolism, lipid metabolism, and energy metabolism, with oral biomacromolecules such as insulin, glucagon-like peptide-1 receptor agonists, proprotein convertase subtilisin/kexin type 9 inhibitors, fibroblast growth factor 21 analogues, and peptide YY analogues.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disease, mainly associated with excessive accumulation of fat in the liver. It has become a global health concern. The diagnosis of NAFLD is often done through liver biopsy; however, noninvasive methods have their own advantages. Dietary intervention, especially increased dietary protein alongside managing overall body weight, have been shown to be a promising strategy to lessen the impact of NAFLD. Dietary protein has been shown to reduce fat accumulation in the liver by increasing liver metabolism, eliciting satiety, improving insulin sensitivity, and enhancing muscle mass retention, collectively aiding in weight management. Both animal and plant proteins have benefits; however, plant proteins have demonstrated more metabolic advantages, while animal proteins have more downsides. Bridging the protein gap is critical, particularly in areas with limited availability to high-quality protein or in populations where dietary protein intake is inadequate. This commentary highlights the importance of obtaining sufficient protein from readily available and sustainable food sources. Furthermore, diets high in protein, like the Mediterranean diet, have proven to delay the advancement and likelihood of NAFLD. In conclusion, adequate dietary protein plays a crucial part in diminishing the risk of NAFLD, and efforts in public health should concentrate on addressing protein deficiency to decrease the growing burden of liver disease.

Non-alcoholic fatty liver disease (NAFLD), the most prevalent chronic liver illness, is characterized by hepatic steatosis. Exercise and probiotics can regulate the gut microbiota to treat NAFLD; however, their combined effects and the mechanisms of gut-liver communication remain unclear. Inconsistent results on probiotic efficacy further warrant investigation. In this study, zebrafish fed a high-fat diet (HFD) for six weeks were subjected to swimming exercise (HFDE), probiotic intervention (HFDP), or a combination of both (HFDEP) for 10 weeks to explore their effects on NAFLD and the corresponding mechanism. The results showed that NAFLD alleviation followed the order HFDEP > HFDE > HFDP. HFDEP and HFDE treatments effectively reduced Body Mass Index (BMI), relative liver weight, liver vacuolation density, lipid droplets in liver sections, triglyceride, free fatty acid, glucose, and pyruvic acid. In contrast, a single probiotic treatment had limited impact, suggesting a complementary role in NAFLD treatment. Glucose and fatty acid metabolism were central to the "gut-liver" axis. The reduced conversion of glucose to pyruvic acid, decreased fatty acid synthesis and esterification, and accelerated fatty acid transformation to CO2 contributed to NAFLD improvement under HFDE and HFDEP treatments. This study provides promising theoretical groundwork for potential prevention and treatment strategies for NAFLD.

Non-alcoholic fatty liver disease (NAFLD), also known as metabolic dysfunction- associated with fatty liver disease (MAFLD), is one of the most prevalent chronic liver diseases globally. NAFLD is characterized by the accumulation of liver fat unrelated to excessive alcohol consumption. Non-alcoholic steatohepatitis (NASH) is the disease progression of NAFLD and could develop into cirrhosis and hepatocellular carcinoma. In previous studies, the preclinical efficacy of alisol B and alisol B 23-acetate against NASH and metabolic syndrome was identified. However, there is a paucity of literature pertaining to the specialized structural optimization of alisol B for the treatment of NASH. In this study, a series of alisol B derivatives (1-21) were designed, synthesized and evaluated in order to improve the activity of alisol B and to obtain candidate compounds for treating NASH. The effects of the synthesized compounds on de novo lipogenesis and α-SMA gene expression were tested to explore the preliminary structure-activity relationship (SAR). Compounds 14 and 21 were selected for further in vivo investigation. The high-fat diet plus carbon tetrachloride (HFD + CCl4)-induced NASH mice model was employed for biological evaluation in vivo. Compounds 14 and 21 effectively improved hepatic steatosis, ballooning, inflammatory infiltration, and hepatic fibrosis in the livers of HFD + CCl4 mice. Thus, 14 and 21 are promising lead compounds for the treatment of NASH.

Resistance training, as a modality of physical exercise, has been recognized as a fundamental pillar in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Current reviews, however, have not given due priority to the specific effects of this type of training on hepatic and clinical markers in individuals with MASLD. This study aimed to compile the available evidence on the impact of resistance training on hepatic and clinical parameters in individuals diagnosed with MASLD. To this end, a systematic search was conducted in the PubMed, Lilacs, Embase, Cochrane, SciELO, and Pedro databases, as well as a manual search, covering the period from January 2011 to December 2023. Randomized clinical trials that evaluated liver fat, insulin resistance, and liver enzymes in individuals with MASLD who were exclusively subjected to resistance training interventions were selected. This study is registered with International Prospective Register of Systematic Reviews (PROSPERO) (CRD4202236638) and the risk of bias in the eligible studies was assessed using ROB 2. Six studies were included, totaling 232 adult participants. Resistance training resulted in a significant reduction in liver fat ( P  < 0.001), liver enzymes ( P  < 0.05), and insulin resistance ( P  < 0.05) in individuals in the strength training group. Furthermore, greater adherence to resistance training (>90%) was observed compared to aerobic training. It is concluded that resistance training can be an easily accepted and consistent option for adults with MASLD, playing an important role in improving the clinical and hepatic markers of these individuals.

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as NAFLD) is a common liver disease worldwide and carries the risk of progressing to severe liver conditions, such as fibrosis and liver cancer. In the context of MASLD, evaluating fat accumulation in the liver and the subsequent production of oxidative stress is essential to understand the disease propagation. However, clinical studies using human patients to investigate the fat accumulation and the onset of oxidative stress in MASLD face ethical and technical challenges, highlighting the importance of alternative methods. To understand the relationship between fatty acid metabolism, lipid accumulation, oxidative stress generation, and antioxidant mechanisms in hepatocytes, we proposed a new mathematical model. The importance of this model lies in its ability to track the time-dependent changes in oxidative stress and glutathione concentration in response to the input of fatty acids. Furthermore, the model allows for the evaluation of the effects of altering the activity of the key enzymes involved in those mechanisms. Our model is anticipated to provide new insights into MASLD therapy strategies by identifying key pathways and predicting the effects of drug-induced changes in enzyme activity.

Lipid metabolism plays a crucial role in maintaining homeostasis and overall health, as lipids are essential molecules involved in bioenergetic processes. An increasing body of research indicates that disorders of lipid metabolism can contribute to the development and progression of various diseases, including hyperlipidemia, obesity, non-alcoholic fatty liver disease (NAFLD), diabetes mellitus, atherosclerosis, and cancer, potentially leading to poor prognoses. The activation of the oxidative stress pathway disrupts lipid metabolism and induces cellular stress, significantly contributing to metabolic disorders. A well-documented crosstalk and interconnection between these metabolic disorders exists. Consequently, researchers have sought to identify antioxidant-rich substances in readily accessible everyday foods for potential use as complementary therapies. Curcumin, known for its anti-inflammatory and antioxidant properties, has been shown to enhance cellular antioxidant activity, mitigate oxidative stress, and alleviate lipid metabolism disorders by reducing reactive oxygen species (ROS) accumulation. These effects include decreasing fat deposition, increasing fatty acid uptake, and improving insulin sensitivity. A review of the existing literature reveals numerous studies emphasizing the role of curcumin in the prevention and management of metabolic diseases. Curcumin influences metabolic disorders through multiple mechanisms of action, with the oxidative stress pathway playing a central role in various lipid metabolism disorders. Thus, we aimed to elucidate the role of curcumin in various metabolic disorders through a unified mechanism of action, offering new insights into the prevention and treatment of metabolic diseases. Firstly, this article provides a brief overview of the basic pathophysiological processes of oxidative stress and lipid metabolism, as well as the role of oxidative stress in the pathogenesis of lipid metabolism disorders. Notably, the article reviews the role of curcumin in mitigating oxidative stress and in preventing and treating diseases associated with lipid metabolism disorders, including hyperlipidemia, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, obesity, and diabetes, thereby highlighting the therapeutic potential of curcumin in lipid metabolism-related diseases.

The gut microbiota has emerged as a critical player in metabolic and liver health, with its influence extending to the pathogenesis and progression of steatotic liver diseases. This review delves into the gut-liver axis, a dynamic communication network linking the gut microbiome and liver through metabolic, immunological, and inflammatory pathways. Dysbiosis, characterized by altered microbial composition, contributes significantly to the development of hepatic steatosis, inflammation, and fibrosis via mechanisms such as gut barrier dysfunction, microbial metabolite production, and systemic inflammation. Dietary patterns, including the Mediterranean diet, are highlighted for their role in modulating the gut microbiota, improving gut-liver axis integrity, and attenuating liver injury. Additionally, emerging microbiota-based interventions, such as fecal microbiota transplantation and bacteriophage therapy, show promise as therapeutic strategies for steatotic liver disease. However, challenges such as population heterogeneity, methodological variability, and knowledge gaps hinder the translational application of current findings. Addressing these barriers through standardized approaches and integrative research will pave the way for microbiota-targeted therapies to mitigate the global burden of steatotic liver disease.

Context: Previous studies have reported that pregnant women with non-alcoholic fatty liver disease (NAFLD) face an increased risk of gestational hypertension (GH) and preeclampsia (PE). However, no study has assessed the relationship between the Hepatic Steatosis Index (HSI), a biomarker for NAFLD, in early pregnancy and the subsequent risk of GH and PE. Objective: We aimed to investigate the relationship between HSI in early pregnancy and the risks of GH and PE in Chinese women. Methods: Based on the China Birth Cohort Study conducted from February 2018 to December 2022, this prospective cohort study collected liver enzyme and body mass index data from pregnant participants during 6-13+6 gestational weeks. The incidences of GH and PE were monitored until delivery. Results: This study included 39,114 pregnant women, and GH and PE incidences were 4.2% and 4.1%, respectively. After multivariable adjustment, the risks of GH (Q2: OR = 1.35, 95% CI = 1.13-1.62; Q3: OR = 1.86, 95% CI = 1.57-2.20; Q4: OR = 3.81, 95% CI = 3.25-4.46) and PE (Q2: OR = 1.22, 95% CI = 1.01-1.47; Q3: OR = 1.96, 95% CI = 1.65-2.32; Q4: OR = 3.60, 95% CI = 3.07-4.22) significantly increased with higher HSI quartiles. Further analysis indicated that compared to women aged 35 years or older, HSI in pregnant women under 35 years had relatively stronger predictive value for GH (OR ≥ 35 = 4.527, 95% CI = 3.762-5.446 vs. OR < 35 = 2.325, 95% CI = 1.729-3.128) and PE (OR ≥ 35 = 4.13, 95% CI = 3.433-4.983 vs. OR < 35 = 2.348, 95% CI = 1.736-3.176). Conclusion: Elevated HSI may be associated with an increased risk of GH and PE.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is increasingly prevalent, and systemic inflammation markers may play a role in its pathogenesis. This study aimed to investigate the relationship between neutrophil-albumin ratio (NAR) and MAFLD.

This population-based study was performed using data from NHANES 2017-2018 and included 4526 individuals with a median age of 44 years old, and the males account for 46.13% (n = 2088). Ultrasound-defined MAFLD was diagnosed using a controlled attenuation parameter (CAP) threshold of ≥ 285 dB/m. Differences in baseline characteristics between patients with CAP ≥ 285 dB/m and < 285 dB/m were analyzed. A generalized additive model (GAM) and restricted cubic splines (RCS) were applied to explore the nonlinear relationship between NAR and CAP, followed by generalized linear models (GLMs). Threshold effect analysis was performed to identify the inflection point in the nonlinear relationship. CAP-related variables were ranked using XG Boost and random forest algorithms, and predictive models were developed and evaluated.

The study population included 1,503 patients with CAP ≥ 285 dB/m. NAR was significantly elevated in subjects with CAP ≥ 285 dB/m (P < 0.001), and nonlinear relationships between NAR and CAP were observed. NAR was positively associated with CAP in three GLMs, and this relationship remained after adjusting for confounding factors or dividing NAR into tertiles. Additionally, when NAR < 1.436, a one-unit rise in NAR was linked to a 3.304-fold increase in the risk of NAFLD (OR = 3.304, 95% CI: 2.649-4.122). The NAR-based random forest model showed the best predictive performance with AUC values of 0.978 (training) and 0.813 (validation).

NAR is positively associated with CAP, and the NAR-based random forest model is optimal for predicting MAFLD risk, highlighting the importance of NAR in predicting MAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver-related morbidity and mortality, with hepatic steatosis being the hallmark symptom. Salvia miltiorrhiza Bunge (Smil, Dan-Shen) and Ligusticum striatum DC (Lstr, Chuan-Xiong) are commonly used to treat cardiovascular diseases and have the potential to regulate lipid metabolism. However, whether Smil/Lstr combo can be used to treat NAFLD and the mechanisms underlying its lipid-regulating properties remain unclear.

To assess the feasibility and reliability of a short-term high-fat diet (HFD) induced zebrafish model for evaluating hepatic steatosis phenotype and to investigate the liver lipid-lowering effects of Smil/Lstr, as well as its active components.

The phenotypic alterations of liver and multiple other organ systems were examined in the HFD zebrafish model using fluorescence imaging and histochemistry. The liver-specific lipid-lowering effects of Smil/Lstr combo were evaluated endogenously. The active molecules and functional mechanisms were further explored in zebrafish, human hepatocytes, and hamster models.

In 5-day HFD zebrafish, significant lipid accumulation was detected in the blood vessels and the liver, as evidenced by increased staining with Oil Red O and fluorescent lipid probes. Hepatic hypertrophy was observed in the model, along with macrovesicular steatosis. Smil/Lstr combo administration effectively restored the lipid profile and alleviated hepatic hypertrophy in the HFD zebrafish. In oleic-acid stimulated hepatocytes, Smil/Lstr combo markedly reduced lipid accumulation and cell damage. Subsequently, based on zebrafish phenotypic screening, the natural phthalide senkyunolide I (SEI) was identified as a major molecule mediating the lipid-lowering activities of Smil/Lstr combo in the liver. Moreover, SEI upregulated the expression of the lipid metabolism regulator PPARα and downregulated fatty acid translocase CD36, while a PPARα antagonist sufficiently blocked the regulatory effect of SEI on hepatic steatosis. Finally, the roles of SEI on hepatic lipid accumulation and PPARα signaling were further verified in the hamster model.

We proposed a zebrafish-based screening strategy for modulators of hepatic steatosis and discovered the regulatory roles of Smil/Lstr combo and its component SEI on liver lipid accumulation and PPARα signaling, suggesting their potential value as novel candidates for NAFLD treatment.

This study investigates the protective effects of lactic acid, a metabolite of Bifidobacterium, on non-alcoholic fatty liver disease (NAFLD) induced by a high-sugar, high-fat diet (HFD) in mice, in the context of the gut-liver axis.

A NAFLD mouse model was established using a HFD, and different intervention groups were set up to study the protective effects of Bifidobacterium and its metabolite lactic acid. The groups included a control group, NAFLD group, Bifidobacterium treatment group, Glyceraldehyde-3-P (G-3P) co-treatment group, and NOD-like receptor family pyrin domain containing 3 (NLRP3) overexpression group. The evaluation of liver function and lipid metabolism was conducted using the liver-to-body weight ratio, histological staining, and biochemical assays. Enzyme-linked immunosorbent assay (ELISA) was performed to measure inflammatory cytokines, and western blotting was used to analyze the expression of NLRP3 inflammasome and autophagy-related molecules. In vitro, an NAFLD cell model was established using oleic acid, with cells treated with lactic acid and NLRP3 overexpression to assess lipid droplet accumulation and inflammation.

In vivo findings indicated that, in comparison to CBX group (Control group without antibiotic treatment), NAFLD/CBX group (NAFLD group without antibiotic administration) and NAFLD/ABX group (NAFLD group with antibiotic administration) exhibited increased liver-to-body weight ratio, higher lipid droplet accumulation, aggravated liver histopathological damage, and elevated levels of AST (Aspartate Aminotransferase), ALT (Alanine Aminotransferase), TC (Total Cholesterol), TG (Triglycerides), LDL-C (Low-Density Lipoprotein Cholesterol), IL-6 (Interleukin-6), TNF-α (Tumor Necrosis Factor-alpha), IL-1β (Interleukin-1 beta), and NLRP3-related molecules, while HDL-C (High-Density Lipoprotein Cholesterol) levels significantly decreased. Intervention with Bifidobacterium significantly reversed these adverse changes. Further addition of G-3P led to more pronounced improvement in NAFLD symptoms, while overexpression of NLRP3 weakened the protective effects of Bifidobacterium. In vitro results indicated that Ole group exhibited heightened lipid droplet accumulation and expression of NLRP3 inflammasome-related molecules relative to the control group. Treatment with lactic acid effectively reversed these changes; however, the protective effect of lactic acid was significantly weakened with NLRP3 overexpression.

Lactic acid can alleviate lipid metabolism disorders in NAFLD induced by diet through the inhibition of inflammation mediated by the NLRP3 inflammasome and the regulation of the autophagy process.

Excessive hepatic lipid accumulation and inflammatory injury are significant pathological manifestations of nonalcoholic fatty liver disease (NAFLD). Our previous research discovered that diosgenin, a natural steroidal saponin derived from Chinese herbs, can reduce hepatic lipid accumulation and steatosis; however, the exact mechanism remains unclear. This study aimed to investigate the protective mechanisms of diosgenin against NAFLD. We utilized network pharmacology and molecular docking approaches to identify the pathways through which diosgenin improves NAFLD. In high-fat diet (HFD)-fed rats, we measured biochemical markers in the serum and liver. Liver histopathology was assessed using HE and oil-red O staining. In free fatty acids (FFAs)-induced HepG2 cells, we employed the cell transfection overexpression method to verify the regulatory relationship of the identified pathways. The mechanisms in vitro and in vivo were examined using quantitative polymerase chain reaction and Western blot analyses. Bioinformatics analysis indicated that the mTOR-FASN/HIF-1α/RELA/VEGFA pathway may be the target pathway for diosgenin in alleviating NAFLD. Diosgenin inhibited hepatic lipid accumulation and pro-inflammatory cytokines in HFD-fed rats, and reduced intracellular lipid accumulation as well as TG, TC, IL-1β, and TNF-α levels in FFAs-induced HepG2 cells. Mechanistically, diosgenin downregulated the expression of p-mTOR, FASN, HIF-1α, RELA, and VEGFA, which are associated with lipid synthesis and inflammation. Overexpression of mTOR abolished the beneficial effects of diosgenin on lipid reduction and inflammation, as well as its inhibitory effects on the expression of FASN, HIF-1α, RELA, and VEGFA. In conclusion, diosgenin alleviates NAFLD through mTOR-mediated inhibition of lipid accumulation and inflammation.

Nonalcoholic fatty liver disease (NAFLD) is considered one of the most common metabolic disorders worldwide. Although the pathoetiology of NAFLD is not fully elucidated, recent evidence suggests the involvement of stress, inflammation, and programmed death in the onset and progression of the disease. This investigation aimed to evaluate the effects of ellagic acid (EA), a known herbal antioxidant, on a high-fat diet (HFD)-induced animal model of NAFLD by evaluating the status of lipid profile, necroptosis (RIPK1, RIPK3, and MLKL), autophagy (LC3, ATG5, and BECN1), inflammation (TNF-α, IL-6, IL-4, and IL-10), and stress (SOD, CAT, GR, GPx, and MDA). In this regard, rats were randomly divided into 6 groups as follows: normal diet controls, HFD (supplemented with high caloric diet model), EA low dose (HFD and 10 mg/kg/day EA), EA middle dose (HFD and 25 mg/kg/day EA), EA high dose (HFD and 50 mg/kg/day EA), and Rosiglitazone (HFD and 10 mg/kg/day Rosi). After the treatment, the levels of markers related to necroptosis and autophagy in the liver tissue as well as the lipid profiles, inflammation, and oxidative stress status were analyzed. It was shown that the dose of EA was able to improve the weight gain and lipid profile when compared to NAFLD animals (p-value < 0.001). Moreover, EA increased the level of LC3 and ATG5 while decreasing BECN 1, RIPK1, RIPK3, and MLKL compared to the HFD-induced NAFLD rats (p-value < 0.05). TNF-α and IL-6 were decreased after EA administration, whereas IL-4 and IL-10 levels were increased (p-value < 0.001). Furthermore, the increase in the activity of SOD, CAT, GR, and GPx along with the decrease in MDA levels indicated the suppression of oxidative stress by EA treatment compared to the NAFLD rats (p-value < 0.0001). The current findings may suggest that EA improves NAFLD via modulation of necroptosis, autophagy, inflammation, and stress.

Flaxseed and olive oil effectively treat numerous diseases and health conditions, particularly metabolic disorders. Traditional medicine has used both oils for managing cardiovascular disease, diabetes, gastrointestinal dysfunctions, metabolic-dysfunction-associated fatty liver disease (MAFLD), obesity, and more. This review explores the bioactive and polyphenolic compounds in flaxseed and olive oils that provide anti-inflammatory, antioxidant, anti-microbial, hepatoprotective, cardioprotective, antidiabetic, and gastroprotective benefits. Flaxseed oil contains beneficial compounds like alpha-linolenic acid (ALA), lignans, ferulic acid, p-coumaric acid, and phytosterols. It contributes to its therapeutic effects on fatty liver disease and other conditions. Olive oil contains phenolic compounds, including oleic acid, hydroxytyrosol, and tocopherols, which are similarly linked to metabolic health benefits, especially in managing MAFLD. The purpose of this review is to elucidate the mechanisms of action of these bioactive compounds, highlighting their potential in managing various metabolic diseases.

Metabolic syndrome (MS) represents a complex cluster of metabolic disorders primarily characterized by obesity, insulin resistance, hyperglycemia, dyslipidemia, hypertension, and hyperuricemia. Diet and functional ingredients play a pivotal role in seeking non-pharmacological strategies to prevent and ameliorate MS. Astaxanthin (AST), a carotenoid found in various marine organisms, exhibits exceptional antioxidant properties and holds great promise as a natural compound that improves MS. This article introduces the basic properties of AST, including its absorptance and metabolic pathways, along with various isomers. Most importantly, we comprehensively review the effects and mechanisms of AST on improving the primary components of MS. These mechanisms primarily involve regulating signal transduction, transport, or metabolic pathways within the body, as well as influencing intestinal microbiota and metabolites, thereby exerting positive effects on metabolism and inhibiting the occurrence of MS. This review emphasizes the potential efficacy of AST in managing MS. However, more studies are needed to confirm the clinical effect of AST on MS and reveal potential molecular mechanisms.

Chronic liver disease has a substantial global prevalence and mortality rate. Macrophages, pivotal cells in innate immunity, exhibit remarkable heterogeneity and plasticity and play a considerable role in maintaining organ homeostasis, modulating inflammatory responses, and influencing disease progression in the liver. Exosomes, which can serve as conduits for intercellular communication, biomarkers, and therapeutic targets for a spectrum of diseases, have recently garnered increasing attention recently. Given that the liver is the organ with the highest macrophage content, a thorough understanding of the influence of macrophage-derived exosomes (MDEs) on noncancer liver disease pathogenesis and their potential therapeutic applications is paramount. Interactions among MDEs, hepatocytes, hepatic stellate cells (HSCs), and other nonparenchymal cells constitute a complex network regulates liver immune homeostasis. In this review, we summarize the latest progress in the current understanding of MDE heterogeneity and cellular crosstalk in noncancer liver diseases, as well as their potential clinical applications. Additionally, challenges and future directions are underscored.

This study investigates the novel therapeutic potential of quercetin and kaempferol, two bioactive compounds derived from Carthamus tinctorius L., in treating nonalcoholic fatty liver disease (NAFLD) by modulating the bile acid receptor NR1H4 (Nuclear Receptor Subfamily 1 Group H Member 4) and its associated metabolic pathways. A rat model of NAFLD was established, and RNA sequencing and proteomics were carefully employed to identify differential gene expressions associated with the disease. The active components of Carthamus tinctorius L. were screened, followed by the construction of a comprehensive network that maps the interactions between these components, NR1H4 and NAFLD-related pathways. Both in vitro (using HepG2 cells) and in vivo experiments were conducted to evaluate the effects on NR1H4 expression levels through Western blot and RT-qPCR analyses. Our findings identify NR1H4 as a pivotal target in NAFLD. Network pharmacology analysis indicates that quercetin and kaempferol play crucial roles in combating NAFLD, with in vitro and in vivo experiments confirming their ability to mitigate hepatocyte steatosis by enhancing NR1H4 expression. Notably, the protective effects of these compounds were inhibited by the NR1H4 antagonist guggulsterone, highlighting the importance of NR1H4 upregulation. This study demonstrates the novel therapeutic efficacy of quercetin and kaempferol from Carthamus tinctorius L. in treating NAFLD through NR1H4 upregulation. This mechanism contributes to the regulation of lipid metabolism, improvement of liver function, reduction of inflammation, and alleviation of oxidative stress, offering a promising direction for future NAFLD treatment strategies.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a typical hepatic steatosis with metabolic dysfunction. The composite dietary antioxidant index (CDAI) measures individual antioxidant capacity, and the relationship with MAFLD has received little attention. Our goal is to explore the association of CDAI with MAFLD.

Participants were selected from the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2020. CDAI was calculated basing on six dietary antioxidants, including zinc, selenium, carotenoids, and vitamins A, C, and E. Univariate regression and multivariable logistic regression analysis were conducted to evaluate the correlation between CDAI and MAFLD. We performed subgroup analysis to study the correlation in various populations.

A total of 18,163 participants, including 13,969 MAFLD and 4,194 non-MAFLD, were included. CDAI was significantly negatively correlated with MAFLD. After adjusting for all confounders (including age, gender, race, marital status, poverty ratio, education level, drinking status, smoking status, and physical activity), individuals in the highest quartile of CDAI exhibited a 27% lower likelihood of developing MAFLD than those in the lowest quartile (OR = 0.73; 95% CI [0.66, 0.81], p < 0.001). Physical activity subgroup analysis showed that this negative association was significant in the moderate-intensity physical exercise population (Model 3 in Q4, OR = 0.72; 95% CI [0.58-0.89], p < 0.001). Additionally, the changes in vitamins C were independently associated with MAFLD (Model 3, OR = 0.90; 95% CI [0.86-0.93], p < 0.001).

We found a negative relationship between higher CDAI scores and MAFLD. This study provided a new reference for exploring dietary interventions that affect MAFLD to reduce its incidence.

Metabolic-associated fatty liver disease (MAFLD) is a major public health problem worldwide. This study aimed to determine the prevalence of MAFLD and evaluate the diagnostic accuracy of the Fatty Liver Index (FLI) compared to ultrasonography for detecting fatty liver in adults attending a tertiary care hospital in Gujarat, India.

This cross-sectional study included 500 adults visiting the outpatient department between January 2023 and December 2023. MAFLD was diagnosed on ultrasound. FLI was calculated using body mass index, waist circumference, triglycerides, and gamma-glutamyl transpeptidase levels. FLI ≥ 60 indicated fatty liver. Logistic regression analysis identified factors associated with fatty liver.

MAFLD prevalence was 32.2% on ultrasound. High FLI (≥ 60) was present in 26.2%. Male sex, higher BMI, waist circumference, night shift work, diabetes, and triglycerides were independent predictors of fatty liver. FLI showed excellent diagnostic accuracy with a sensitivity of 96%, specificity of 92.5%, and AUC of 0.92 for detecting fatty liver on ultrasound.

MAFLD prevalence among adults was high in this hospital-based sample. FLI can serve as an accurate non-invasive tool for identifying individuals with a high probability of MAFLD. These findings emphasize the need for larger population-based studies and the implementation of regular MAFLD screening programs in high-risk groups.

The incidence of Non-alcoholic fatty liver disease (NAFLD) in China and USA is extremely high and rising. TikTok has become a popular channel for medical information dissemination and we aimed to evaluate the quality and reliability of NAFLD related videos on TikTok, in both its USA and Chinese versions.

We analyzed the top 100 NAFLD videos on both the USA version and Chinese version of TikTok, a total of 200 videos, from which keywords were extracted and scored using the Global Quality Scale (GQS), modified DISCERN (mDISCERN), and Medical Quality Video Evaluation Tool (MQ-VET). Exploring the relationship between video quality and audience related factors, as well as ranking, through Spearman correlation analysis.

The mDISCERN scores of videos on the USA version of TikTok is higher than that on the Chinese version (P < 0.01), but there is no significant difference in the GQS and MQ-VET scores. The GQS, mDISCERN and MQ-VET scores of videos published by medical practitioners were significantly higher than those of non-medical practitioners (P < 0.001). However, there was no significant correlation between video quality and popularity indicators.

The quality of NAFLD related short videos on TikTok is acceptable, but the reliability is mediocre, and there is still room for improvement. The videos published by USA medical practitioners are more reliable than those of Chinese medical practitioners. The most concerned topic of both countries is diet. The TikTok recommendation algorithm may limit access to high-quality health videos, and further research on other platforms and languages is necessary.