Specific metabolic impairments indicate loss of sustained liver improvements in metabolic dysfunction-associated steatotic liver disease treatment
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ABSTRACT:
SUBMITTER: Luo L
PROVIDER: S-EPMC11336549 | biostudies-literature | 2024 Apr
REPOSITORIES: biostudies-literature
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Project description:Global hepatic DNA methylation change has been linked to human patients with metabolic dysfunction-associated steatotic liver disease (MASLD). DNA demethylation is regulated by the TET family proteins, whose enzymatic activities require 2-oxoglutarate (2-OG) and iron that both are elevated in MASLD human patients. We aimed to investigate liver TET1 in MASLD progression. Depleting TET1 using two different strategies substantially alleviated MASLD progression. Knockout of TET1 slightly improved diet induced obesity and glucose homeostasis. Intriguingly, hepatic cholesterols, triglycerides, and CD36 were significantly decreased upon TET1 depletion. Consistently, liver specific TET1 KO led to improvement of MASLD progression. Mechanistically, TET1 promoted CD36 expression through transcriptional upregulation via DNA demethylation control. Overexpression of CD36 reversed the impacts of TET1 downregulation on fatty acid uptake in hepatocytes. More importantly, targeting TET1 with a small molecule inhibitor significantly suppressed MASLD progression. Liver TET1 plays a deleterious role in MASLD, suggesting the potential of targeting TET1 in hepatocytes to suppress MASLD.
| S-SCDT-10_1038-S44321-025-00224-4 | biostudies-other
Project description:BackgruoundGiven the association between nonalcoholic fatty liver disease and metabolic risks, a new term, metabolic dysfunction- associated steatotic liver disease (MASLD) has been proposed. We aimed to explore the association between MASLD and all-cause, cause-specific mortalities.MethodsWe included individuals with steatotic liver disease (SLD) from the Korean National Health Insurance Service. Moreover, SLD was defined as a fatty liver index ≥30. Furthermore, MASLD, metabolic alcohol-associated liver disease (MetALD), and alcoholic liver disease (ALD) with metabolic dysfunction (MD) were categorized based on alcohol consumption and MD. We also analyzed all-cause, liver-, cancer-, hepatocellular carcinoma (HCC)- and cardiovascular (CV)-related mortalities.ResultsThis retrospective nationwide cohort study included 1,298,993 individuals aged 40 to 79 years for a mean follow-up duration of 9.04 years. The prevalence of MASLD, MetALD, and ALD with MD was 33.11%, 3.93%, and 1.00%, respectively. Relative to the "no SLD" group, multivariable analysis identified that MASLD (adjusted hazard ratio [aHR], 1.28; 95% confidence interval [CI], 1.26 to 1.31), MetALD (aHR, 1.38; 95% CI, 1.32 to 1.44), and ALD with MD group (aHR, 1.80; 95% CI, 1.68 to 1.93) have a significantly higher risk of all-cause mortality. Furthermore, MASLD, MetALD, ALD with MD groups showed higher liver-, cancer-, and HCC-related mortality than "no SLD" group. While all-cause specific mortalities increase from MASLD to MetALD to ALD with MD, the MetALD group shows a lower risk of CV-related mortality compared to MASLD. However, ALD with MD group still have a higher risk of CV-related mortality compared to MASLD.ConclusionSLD is associated with an increased risk of all-cause, liver-, cancer-, HCC-, and CV-related mortalities.
| S-EPMC11788553 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), both of them accounting for fatty liver disease (FLD), are among the most common chronic liver diseases globally, contributing to substantial public health burden. Both NAFLD and ALD share a similar picture of clinical presentation yet may have differences in prognosis and treatment, which renders early and accurate diagnosis difficult but necessary. While NAFLD is the fastest increasing chronic liver disease, the prevalence of ALD has seemingly remained stable in recent years. Lately, the term steatotic liver disease (SLD) has been introduced, replacing FLD to reduce stigma. SLD represents an overarching term to primarily comprise metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), as well as alcohol-related liver disease (ALD), and MetALD, defined as a continuum across which the contribution of MASLD and ALD varies. The present review discusses current knowledge on common denominators of NAFLD/MASLD and ALD in order to highlight clinical and research needs to improve our understanding of SLD.
| S-EPMC10452742 | biostudies-literature
Project description:Background/aimsEvidence suggests that the gastrointestinal microbiome plays a significant role in the biology of metabolic dysfunction-associated steatotic liver disease (MASLD). However, it remains unclear whether disparities in the gut microbiome across intestinal tissular compartments between the sexes lead to MASLD pathogenesis.MethodsSex-specific analyses of microbiome composition in two anatomically distinct regions of the gut, the small intestine and colon, were performed using an experimental model of MASLD. The study involved male and female spontaneously hypertensive rats and the Wistar-Kyoto control rat strain, which were fed either a standard chow diet or a high-fat diet for 12 weeks to induce MASLD (12 rats per group). High-throughput 16S sequencing was used for microbiome analysis.ResultsThere were significant differences in the overall microbiome composition of male and female rats with MASLD, including variations in topographical gut regions. The beta diversity of the jejunal and colon microbiomes was higher in female rats than in male rats (PERMANOVA p-value=0.001). Sex-specific analysis and discriminant features using LEfSe showed considerable variation in bacterial abundance, along with distinct functional properties, in the jejunum and colon of animals with MASLD. Significantly elevated levels of lipopolysaccharide and protein expression of Toll-like receptor 4 were observed in the livers of male rats with MASLD compared with their female counterparts.ConclusionThis study uncovered sexual dimorphism in the gut microbiome of MASLD and identified microbial heterogeneity within intestinal compartments. Insights into sex-specific variations in gut microbiome composition could facilitate customised treatment strategies.
| S-EPMC11791572 | biostudies-literature
Project description:The incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) have been steadily increasing worldwide, with a huge societal and economic burden. Recently, NAFLD and non-alcoholic steatohepatitis have been renamed and redefined as metabolic dysfunction associated steatotic liver disease (MASLD) and steatohepatitis (Metabolic Dysfunction Associated Steatohepatitis (MASH)), which result from an imbalance between metabolic and inflammatory stress (mainly as a consequence of adipose tissue dysfunction and insulin resistance) and the defence and repair mechanisms of the steatotic liver. Once MASLD progresses to end-stage of liver disease, treatment efficacy becomes limited and may require liver transplantation. Early detection and intervention are crucial. Lifestyle modification is consequently the cornerstone of its management. Timely consideration of bariatric surgeries should be given to patients meeting specific criteria. A multidisciplinary approach is warranted, starting from the concept that MASLD/MASH is at the centre of the cardiovascular-liver-metabolic syndrome. In some cases, pharmacological treatment can complement lifestyle modification. Several drugs used to treat the cardiometabolic co-morbidities have some potential efficacy in slowing Down disease progression, and some have demonstrated efficacy on histological endpoints that are likely to translate into long-term clinical benefits. Optimising the use of these drugs within their licenced indications is thus paramount for patients with MASLD. Several MASH-specific drugs are on the horizon and are likely to enrich our therapeutic armamentarium in the near future, particularly in non-cirrhotic stages of the disease. Much work still needs to be done to understand the specific features of MASH cirrhosis and develop efficacious treatments for this disease stage.
| S-EPMC10954426 | biostudies-literature
Project description:ImportanceIn the US, hepatocellular carcinoma (HCC) has been the most rapidly increasing cancer since 1980, and metabolic dysfunction-associated steatotic liver disease (MASLD) is expected to soon become the leading cause of HCC.ObjectiveTo develop a prediction model for HCC incidence in a cohort of patients with MASLD.Design, setting, and participantsThis prognostic study was conducted among patients aged at least 18 years with MASLD, identified using diagnosis of MASLD using International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes; natural language processing of radiology imaging report text, which identified patients who had imaging evidence of MASLD but had not been formally diagnosed; or the Dallas Steatosis Index, a risk equation that identifies individuals likely to have MASLD with good precision. Patients were enrolled from Kaiser Permanente Northern California, an integrated health delivery system with more than 4.6 million members, with study entry between January 2009 and December 2018, and follow-up until HCC development, death, or study termination on September 30, 2021. Statistical analysis was performed during February 2023 and January 2024.ExposureData were extracted from the electronic health record and included 18 routinely measured factors associated with MASLD.Main outcome and measuresThe cohort was split (70:30) into derivation and internal validation sets; extreme gradient boosting was used to model HCC incidence. HCC risk was divided into 3 categories, with the cumulative estimated probability of HCC 0.05% or less classified as low risk; 0.05% to 0.09%, medium risk; and 0.1% or greater, high risk.ResultsA total of 1 811 461 patients (median age [IQR] at baseline, 52 [41-63] years; 982 300 [54.2%] female) participated in the study. During a median (range) follow-up of 9.3 (5.8-12.4) years, 946 patients developed HCC, for an incidence rate of 0.065 per 1000 person-years. The model achieved an area under the curve of 0.899 (95% CI, 0.882-0.916) in the validation set. At the medium-risk threshold, the model had a sensitivity of 87.5%, specificity of 81.4%, and a number needed to screen of 406. At the high-risk threshold, the model had a sensitivity of 78.4%, a specificity of 90.1%, and a number needed to screen of 241.Conclusions and relevanceThis prognostic study of more than 1.8 million patients with MASLD used electronic health record data to develop a prediction model to discriminate between individuals with and without incident HCC with good precision. This model could serve as a starting point to identify patients with MASLD who may need intervention and/or HCC surveillance.
| S-EPMC11240192 | biostudies-literature
Project description:BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) affects roughly 1 in 3 adults and is a leading cause of liver transplants and liver related mortality. A deeper understanding of disease pathogenesis is essential to assist in developing blood-based biomarkers.MethodsHere, we use data-independent acquisition mass spectrometry to assess disease-state associated protein profiles in human liver, blood plasma, and white adipose tissue (WAT).ResultsIn liver, we find that MASLD is associated with an increased abundance of proteins involved in immune response and extracellular matrix (ECM) and a decrease in proteins involved in metabolism. Cell type deconvolution of the proteome indicates liver endothelial and hepatic stellate cells are the main source of ECM rearrangements, and hepatocytes are the major contributor to the changes in liver metabolism. In the blood, profiles of several MASLD-associated proteins correlate with expression in WAT rather than liver and so could serve as suitable liver disease predictors in a multi-protein panel marker. Moreover, our proteomics-based logistic regression models perform better than existing methods for predicting MASLD and liver fibrosis from human blood samples.ConclusionsOur comprehensive proteomic analysis deepens the understanding of liver function and MASLD pathology by elucidating key cellular mechanisms and multi-organ interactions, and demonstrates the robustness of a proteomics-based biomarker panel to enhance diagnosis of MASLD and significant fibrosis.
| S-EPMC11876662 | biostudies-literature
Project description: Not available
| S-EPMC11704021 | biostudies-literature
Project description:DNA demethylation is regulated by the TET family proteins, whose enzymatic activity requires 2-oxoglutarate (2-OG) and iron that both are elevated in MASLD. We aimed to investigate liver TET1 in MASLD progression. Depleting TET1 substantially alleviated MASLD progression. Whole body Knockout of TET1 (TKO) slightly improved diet induced obesity and glucose homeostasis. Intriguingly, hepatic cholesterols, triglycerides, were significantly decreased upon TET1 depletion. Moreover, targeting TET1 with a small molecule inhibitor significantly suppressed MASLD progression. Liver TET1 plays a deleterious role in MASLD, suggesting the potential of targeting TET1 in hepatocytes to suppress MASLD.
2025-03-04 | GSE286394 | GEO
Project description:A proteomic and peptidomics analysis of serum from patients suffering from metabolic dysfunction-associated steatotic liver disease. Proteomics was performed initially on a set of patients with varying degrees of liver disease. Following close analysis of the results, a peptidomics based analysis was performed and identified significant numbers of degraded and oxidised peptides from apolipoproteins. A more targeted peptidomics analysis was performed on a larger cohort and the oxidation status of small apolipoproteins demonstrated a high accuracy of precision for liver disease diagnosis.
2025-01-21 | PXD052061 | Pride