Pharmacological Therapeutics: Current Trends for Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD).
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ABSTRACT:
SUBMITTER: Prasoppokakorn T
PROVIDER: S-EPMC8666366 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease affecting a quarter of the global population and is often associated with adverse health outcomes. The increasing prevalence of MAFLD occurs in parallel to that of metabolic syndrome (MetS), which in fact plays a major role in driving the perturbations of cardiometabolic homeostasis. However, the mechanisms underpinning the pathogenesis of MAFLD are incompletely understood. Compelling evidence from animal and human studies suggest that heightened activation of the sympathetic nervous system is a key contributor to the development of MAFLD. Indeed, common treatment strategies for metabolic diseases such as diet and exercise to induce weight loss have been shown to exert their beneficial effects at least in part through the associated sympathetic inhibition. Furthermore, pharmacological and device-based approaches to reduce sympathetic activation have been demonstrated to improve the metabolic alterations frequently present in patients with obesity, MetSand diabetes. Currently available evidence, while still limited, suggests that sympathetic activation is of specific relevance in the pathogenesis of MAFLD and consequentially may offer an attractive therapeutic target to attenuate the adverse outcomes associated with MAFLD.
| S-EPMC8073135 | biostudies-literature
Project description:Most currently recommended therapies for metabolic dysfunction-associated fatty liver disease (MAFLD) involve diet control and exercise therapy. We searched PubMed and compiled the most recent research into possible forms of programmed cell death in MAFLD, including apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis. Here, we summarize the state of knowledge on the signaling mechanisms for each type and, based on their characteristics, discuss how they might be relevant in MAFLD-related pathological mechanisms. Although significant challenges exist in the translation of fundamental science into clinical therapy, this review should provide a theoretical basis for innovative MAFLD clinical treatment plans that target programmed cell death.
| S-EPMC8103580 | biostudies-literature
Project description:BackgroundAlthough metabolic associate fatty liver disease (MAFLD) is associated with obesity, it can also occur in lean patients. MAFLD is more aggressive in lean patients compared to obese patients, with a higher risk of mortality. Specific biomarkers to diagnose differentially lean or overweight MAFLD are missing. Histones and nucleosomes are released in the bloodstream upon cell death. Here, we propose a new, fast, imaging and epigenetics based approach to investigate the severity of steatosis in lean MAFLD patients.ResultsA total of 53 non-obese patients with histologically confirmed diagnosis of MAFLD were recruited. Twenty patients displayed steatosis grade 1 (0-33%), 24 patients with steatosis grade 2 (34-66%) and 9 patients with steatosis grade 3 (67-100%). The levels of circulating nucleosomes were assayed using enzyme-linked immunosorbent assay, while individual histones or histone dimers were assayed in serum samples by means of a new advanced flow cytometry ImageStream(X)-adapted method. Circulating nucleosome levels associated poorly with MAFLD in the absence of obesity. We implemented successfully a multi-channel flow methodology on ImageStream(X), to image single histone staining (H2A, H2B, H3, H4, macroH2A1.1 and macroH2A1.2). We report here a significant depletion of the levels of histone variants macroH2A1.1 and macroH2A1.2 in the serum of lean MAFLD patients, either individually or in complex with H2B.ConclusionsIn summary, we identified a new circulating histone signature able to discriminate the severity of steatosis in individuals with lean MAFLD, using a rapid and non-invasive ImageStream(X)-based imaging technology.
| S-EPMC7441674 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) has recently become the most common liver disease with a global prevalence of over 25% and is expected to increase. Recently, experts have reached a consensus that "fatty liver disease associated with metabolic dysfunction or MAFLD" may be a more appropriate and inclusive definition than NAFLD. Like the former name NAFLD, MAFLD, as a manifestation of multiple system metabolic disorders involving the liver, has certain heterogeneity in its pathogenesis, clinical manifestations, pathological changes and natural outcomes. We found that there is a delicate dynamic balance among intestinal microflora, metabolites and host immune system to maintain a healthy intestinal environment and host health. On the contrary, this imbalance is related to diseases such as MAFLD. However, there are no clear studies on how dietary nutrients affect the intestinal environment and participate in the pathogenesis of MAFLD. This review summarizes the interactions among dietary nutrients, intestinal microbiota and MAFLD in an attempt to provide evidence for the use of dietary supplements to regulate liver function in patients with MAFLD. These dietary nutrients influence the development and progression of MAFLD mainly through the hepatic-intestinal axis by altering dietary energy absorption, regulating bile acid metabolism, changing intestinal permeability and producing ethanol. Meanwhile, the nutrients have the ability to combat MAFLD in terms of enriching abundance of intestinal microbiota, reducing Firmicutes/Bacteroidetes ratio and promoting abundance of beneficial gut microbes. Therefore, family therapy with MAFLD using a reasonable diet could be considered.
| S-EPMC9247350 | biostudies-literature
Project description:BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most prevalent metabolic syndromes worldwide. However, no approved pharmacological treatments are available for MAFLD. Chenpi, one kind of dried peel of citrus fruits, has traditionally been utilized as a medicinal herb for liver diseases. Didymin is a newly identified oral bioactive dietary flavonoid glycoside derived from Chenpi. In this study, we investigated the therapeutic potential of Didymin as an anti-MAFLD drug and elucidated its underlying mechanisms.MethodsHigh-fat diet (HFD)-induced MAFLD mice and alpha mouse liver 12 (AML12) cells were utilized to evaluate the effects and mechanisms of Didymin in the treatment of MAFLD. Liver weight, serum biochemical parameters, and liver morphology were examined to demonstrate the therapeutic efficacy of Didymin in MAFLD treatment. RNA-seq analysis was performed to identify potential pathways that could be affected by Didymin. The impact of Didymin on Sirt1 was corroborated through western blot, molecular docking analysis, microscale thermophoresis (MST), and deacetylase activity assay. Then, a Sirt1 inhibitor (EX-527) was utilized to confirm that Didymin alleviates MAFLD via Sirt1. Western blot and additional assays were used to investigate the underlying mechanisms.ResultsOur results suggested that Didymin may possess therapeutic potential against MAFLD in vitro and in vivo. By promoting Sirt1 expression as well as directly binding to and activating Sirt1, Didymin triggers downstream pathways that enhance mitochondrial biogenesis and function while reducing apoptosis and enhancing lipophagy.ConclusionsThese suggest that Didymin could be a promising medication for MAFLD treatment. Furthermore, its therapeutic effects are mediated by Sirt1.
| S-EPMC10731721 | biostudies-literature
Project description:Hepatic steatosis signifies onset of metabolic dysfunction-associated fatty liver disease (MAFLD) caused by disrupted metabolic homeostasis compromising liver function. Regular consumption of common beans reduces the risk of metabolic impairment, but its effective dose, the impact of biological sex, and underlying mechanisms of action are unknown. We fed female and male C57BL6/J mice with obesogenic yet isocaloric diets containing 0%, 17.5%, 35%, and 70% of total dietary protein derived from cooked whole common beans. Liver tissue was collected for histopathology, lipid quantification, and RNA-seq analyses. Beans qualitatively and quantitatively diminished hepatic fat deposition at the 35% dose in female and 70% dose in male mice. Bean-induced differentially expressed genes (DEGs) most significantly mapped to hepatic steatosis and revealed dose-responsive inhibition of de novo lipogenesis markers (Acly, Acaca, Fasn, Elovl6, Scd1, etc.) and triacylglycerol biosynthesis, activation of triacylglycerol degradation, and downregulation of sterol regulatory element-binding transcription factor 1 (SREBF1) signaling. Upregulated fatty acid β-oxidation was more prominent in females, while suppression of Cd36-mediated fatty acid uptake—in males. Sex-dependent bean effects also involved DEGs patterns downstream of peroxisome proliferator-activated receptor α (PPARα) and MLX-interacting protein-like (MLXIPL). Therefore, biological sex determines amount of common bean in the diet required to prevent hepatic lipid accumulation.
| S-EPMC9920904 | biostudies-literature
Project description:BackgroundAs fat and obesity play a vital role in the pathophysiology of metabolic dysfunction-associated fatty liver disease (MAFLD), this study aims to investigate the association between the fat mass and obesity-associated gene (FTO) and MAFLD.MethodsSix SNPs (rs6499640, rs1421085, rs8050136, rs3751812, rs9939609 and rs9930506) within FTO were genotyped for 741 MAFLD patients (median age, 69.98; interquartile range, 66.55-75.93) and 825 healthy people (median age, 69.94; interquartile range, 66.39-75.64). Allele and genotype frequencies, pairwise linkage disequilibrium (LD) and haplotype analysis were calculated.ResultsBMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, triglyceride, alanine transaminase, glutamyl transpeptidase and the prevalence of diabetes were found to be higher in the MAFLD individuals comparing to the control ones (P < 0.05). For rs1421085, the C allele frequency was remarkably higher in MAFLD after Bonferroni correction (OR [95% CI] =1.353 [1.095-1.671]; P corr =0.030), and a significantly different genotype result was observed in log-additive model (OR [95% CI] =1.369 [1.108-1.691]; P corr =0.024). For rs8050136, significantly increased A allele frequency was observed in MAFLD (OR [95% CI] =1.371 [1.109-1.695]; P corr =0.024), and A-allele carriers showed increased MAFLD risk (OR [95% CI] =1.393 [1.103-1.759]; P corr =0.030). For rs3751812, the T allele frequency was remarkably higher in MAFLD (OR [95% CI] =1.369 [1.108-1.691]; P corr =0.024), and T-allele carriers demonstrated high MAFLD risk (OR [95% CI] =1.392 [1.103-1.756]; P corr =0.030). For rs9939609, A allele frequency was also remarkably high in MAFLD (OR [95% CI] =1.369 [1.108-1.691]; P corr =0.024), and A-allele carriers were more susceptible to MAFLD (OR [95% CI] =[1.103-1.756]; P corr =0.030). A strong LD was found among rs1421085, rs8050136, rs3751812 and rs9939609 (r2 >0.8), and individuals with C-A-T-A haplotype had an elevated MAFLD risk (P =0.005).ConclusionThe case-control study indicated that C variant of rs1421085, A variant of rs8050136, T variant of rs3751812 and A variant of rs9939609 are associated with elevated MAFLD risk in the older Chinese Han population.
| S-EPMC7429205 | biostudies-literature
Project description:BackgroundMetabolic-associated fatty liver disease (MAFLD) is a new term of nonalcoholic fatty liver disease (NAFLD), with newly proposed diagnostic criteria. The applicability of common noninvasive testing for screening NAFLD is unclear for the detection of MAFLD and requires reevaluation. We aimed to validate the effectiveness of traditional NAFLD-related steatosis indices for diagnosing MAFLD and to determine the optimal cutoff values as well as compare their accuracy between NAFLD and MAFLD diagnosis.MethodsThis study enrolled 1866 participants from the National Health and Nutrition Examination Survey (NHANES) database (2017-2018). The diagnostic performances of fatty liver index (FLI), Framingham Steatosis Index (FSI), Zhejiang University index (ZJU), lipid accumulation product (LAP), hepatitis steatosis index (HSI) and visceral adiposity index (VAI) were evaluated using the area under the receiver operator characteristic (AUROC) curve and the optimal cutoff points were calculated according to maximum Youden's index.ResultsFLI had the highest AUROC (0.840) for predicting MAFLD in the whole population, with a cutoff value of 56.93. The AUROCs of FLI, FSI, ZJU, LAP, HSI and VAI for predicting MAFLD/NAFLD were 0.840/0.812, 0.833/0.811, 0.826/0.811, 0.826/0.799, 0.814/0.803 and 0.747/0.729, respectively. The AUROC values of all indices decreased in the subgroup of the population with overweight or diabetes.ConclusionThe NAFLD-related scores would be equally useful to screen MAFLD and seemed to be more compatible with MAFLD. The FLI was optimal in both MAFLD and NAFLD diagnoses. However, a new predictive indicator suitable for various characteristics of the population is worth further development in the future.
| S-EPMC9951794 | biostudies-literature
Project description:Consumption of beans protects from the development of obesity. We established that dietary bean exerts dose- and sex-dependent effects on the liver transcriptome in the context of lipid metabolism, which prevents the onset of metabolic-associated fatty liver disease.
2023-03-12 | GSE227120 | GEO
Project description:In 2020, international consensus guidelines recommended the renaming of non-alcoholic fatty liver disease (NAFLD) to metabolic-associated fatty liver disease (MAFLD), supported by diagnostic criteria. MAFLD affects up to 25% of the global population. However, the rates of MAFLD are likely to be underestimated due to the increasing prevalence of type 2 diabetes mellitus (T2DM) and obesity. Within the next decade, MAFLD has been projected to become a major cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide, as well as the most common indication for liver transplantation in the US. This transition in terminology and clinical criteria may increase momentum and clinical evidence at multiple levels, including patient diagnosis, management, and care, and provide the basis for new research areas and clinical development for therapeutics. The diagnostic criteria for MAFLD are practical, simple, and superior to the existing NAFLD criteria for identifying patients at increased risk of developing progressive liver disease. This Editorial aims to present the historical evolution of the terminology for fatty liver disease and the advantages of diagnosis, patient management, and future research on MAFLD.
| S-EPMC8284081 | biostudies-literature