Metabolic-Dysfunction-Associated Steatotic Liver Disease—Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Treatments

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(20), P. 15473 - 15473

Published: Oct. 23, 2023

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a chronic that affects more than quarter of the global population and whose prevalence increasing worldwide due to pandemic obesity. Obesity, impaired glucose metabolism, high blood pressure atherogenic dyslipidemia are risk factors for MASLD. Therefore, insulin resistance may be closely associated with development progression Hepatic entry increased fatty acids released from adipose tissue, increase in acid synthesis reduced oxidation hepatic overproduction triglyceride-rich lipoproteins induce Since also induces atherosclerosis, leading cause death MASLD patients cardiovascular disease. Considering diseases determines prognosis patients, therapeutic interventions should reduce body weight improve coronary factors, addition an improving function. Lifestyle modifications, such as improved diet exercise, surgical interventions, bariatric surgery intragastric balloons, have shown by reducing weight. Sodium cotransporter 2 inhibitors (SGLT2i) glucagon-like peptide-1 receptor agonists (GLP-1RAs) been suppress occurrence diseases. Both SGLT2i GLP-1 reported enzymes, steatosis fibrosis. We recently selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator pemafibrate PPARα multiple anti-atherogenic properties. Here, we consider pathophysiology mechanisms action drugs whether combination therapy could treatments

Language: Английский

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Current Therapeutic Landscape for Metabolic Dysfunction-Associated Steatohepatitis

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1778 - 1778

Published: Feb. 19, 2025

In recent years, “metabolic dysfunction-associated steatotic liver disease” (MASLD) has been proposed to better connect disease metabolic dysfunction, which is the most common chronic worldwide. MASLD affects more than 30% of individuals globally, and it diagnosed by combination hepatic steatosis obesity, type 2 diabetes, or two risk factors. begins with buildup extra fat, often greater 5%, within liver, causing hepatocytes become stressed. This can proceed a severe form, steatohepatitis (MASH), in 20–30% people, where inflammation causes tissue fibrosis, limits blood flow over time. As fibrosis worsens, MASH may lead cirrhosis, failure, even cancer. While pathophysiology not fully known, current “multiple-hits” concept proposes that dietary lifestyle factors, genetic epigenetic factors contribute elevated oxidative stress inflammation, fibrosis. review article provides an overview pathogenesis evaluates existing therapies as well pharmacological drugs are currently being studied clinical trials for MASH.

Language: Английский

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Pentadecanoic Acid (C15:0), an Essential Fatty Acid, Shares Clinically Relevant Cell-Based Activities with Leading Longevity-Enhancing Compounds

Nutrients, Journal Year: 2023, Volume and Issue: 15(21), P. 4607 - 4607

Published: Oct. 30, 2023

Pentadecanoic acid (C15:0) is an essential odd-chain saturated fatty with broad activities relevant to protecting cardiometabolic, immune, and liver health. C15:0 activates AMPK inhibits mTOR, both of which are core components the human longevity pathway. To assess potential for enhance processes associated healthspan, we used cell-based molecular phenotyping assays compare three longevity-enhancing candidates: acarbose, metformin, rapamycin. (n = 36 in 10 12 cell systems) rapamycin 32 had most clinically relevant, dose-dependent activities. At their optimal doses, (17 µM) (9 shared 24 across systems, including anti-inflammatory (e.g., lowered MCP-1, TNFα, IL-10, IL-17A/F), antifibrotic, anticancer activities, further supported by previously published vitro vivo studies. Paired prior demonstrated abilities target pathways, hallmarks aging, aging rate biomarkers, type 2 diabetes, heart disease, cancer, nonalcoholic our results support as nutrient equivalent to, or surpassing, leading candidate compounds.

Language: Английский

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Review of current and new drugs for the treatment of metabolic-associated fatty liver disease

Hepatology International, Journal Year: 2024, Volume and Issue: unknown

Published: June 8, 2024

Language: Английский

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Different Coactivator Recruitment to Human PPARα/δ/γ Ligand-Binding Domains by Eight PPAR Agonists to Treat Nonalcoholic Fatty Liver Disease

Biomedicines, Journal Year: 2024, Volume and Issue: 12(3), P. 624 - 624

Published: March 11, 2024

Three peroxisome proliferator-activated receptor subtypes, PPARα, PPAR(ß/)δ, and PPARγ, exert ligand-dependent transcriptional control in concert with retinoid X receptors (RXRs) on various gene sets harboring PPAR response elements (PPREs) their promoter regions. Ligand-bound PPAR/RXR complexes do not directly regulate transcription; instead, they recruit multiprotein coactivator to specific genomic regulatory loci cooperatively activate transcription. Several coactivators are expressed a single cell; however, ligand-bound can be associated only one through consensus LXXLL motif. Therefore, altered transcription induced by subtypes/agonists may attributed the recruitment of species. Using time-resolved fluorescence resonance energy transfer assay, we analyzed four peptides (PGC1α, CBP, SRC1, TRAP220) human PPARα/δ/γ-ligand-binding domains (LBDs) using eight dual/pan agonists (bezafibrate, fenofibric acid, pemafibrate, pioglitazone, elafibranor, lanifibranor, saroglitazar, seladelpar) that are/were anticipated treat nonalcoholic fatty liver disease. These all recruited PPARα/γ-LBD varying potencies efficacy. Only five PPARδ-LBD, concentration-dependent responses differed from those PPARα/γ-LBD. results indicate expression PPREs different caused, part, coactivators, which responsible for unique pharmacological properties these agonists.

Language: Английский

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Peroxisome proliferator-activated receptor agonists and antagonists: an updated patent review (2020-2023)

Expert Opinion on Therapeutic Patents, Journal Year: 2024, Volume and Issue: 34(1-2), P. 83 - 98

Published: Feb. 1, 2024

The search for novel compounds targeting Peroxisome Proliferator-Activated Receptors (PPARs) is currently ongoing, starting from the previous successfully identification of selective, dual or pan agonists. In last years, researchers' efforts are mainly paid to discovery PPARγ and δ modulators, both agonists antagonists, selective with a dual-multitarget profile. Some these under clinical trials treatment primary biliary cirrhosis, nonalcoholic fatty liver disease, hepatic, renal diseases.

Language: Английский

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MAFLD Pandemic: Updates in Pharmacotherapeutic Approach Development

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(7), P. 6300 - 6314

Published: June 21, 2024

With around one billion of the world's population affected, era metabolic-associated fatty liver disease (MAFLD) pandemic has entered global stage. MAFLD is a chronic progressive with accompanying metabolic disorders such as type 2 diabetes mellitus and obesity which can progress asymptomatically to cirrhosis subsequently hepatocellular carcinoma (HCC), for date there are almost no approved pharmacologic options. Because very complex etiology it also affects extrahepatic organs, multidisciplinary approach required when comes finding an effective safe active substance treatment. The optimal drug should diminish steatosis, fibrosis inflammation in liver, winner authorisation seems be that significantly improves histology. Saroglitazar (Lipaglyn

Language: Английский

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Hepatic fructose metabolism is antagonized by growth hormone/insulin-like growth factor signaling via regulation of ketohexokinase expression

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract Overconsumption of added sugars such as fructose has been associated with a remarkable decline in metabolic health. Fructose is primarily metabolized by the small intestines and liver, via phosphorylation mediated ketohexokinase (KHK). KHK activity traditionally viewed lacking negative feedback mechanisms, those present to limit glucose metabolism, leading excessive fat accumulation characteristic dysfunction-associated liver disease (MASLD). In this study, we observe downregulation hepatocytes diet-induced genetic models MASLD. Reduced coincides decreased flux fructose-derived carbons into glycolytic amino acid pathways, suggesting presence mechanisms that KHK-mediated fructolysis liver. We subsequently focused on growth hormone (GH)/insulin-like factor (IGF) signaling pathway potential mechanism antagonizing expression. transgenic mice enhanced GH signaling, levels are reduced, whereas reduced leads increased Additionally, administration IGF-1 cell cultures induces time-dependent degradation KHK, facilitated direct interactions between receptor (IGF-1R). Single-nuclei RNA sequencing revealed elevated IGF-1R expression from MASLD mice, supported human patient samples, which also show Taken together, these findings describe novel GH/IGF-1 regulates offering new insights how adapts stress fructose-driven dysfunction.

Language: Английский

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Proteomics Profiling Reveals Pharmaceutical Excipient PEG400 Induces Nuclear-Receptor-Activation-Affected Lipid Metabolism and Metabolic Enzyme Expression

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1732 - 1732

Published: Feb. 18, 2025

PEG400 is widely used as a pharmaceutical excipient in the biomedical field. Increasing evidence suggests that not an inert drug carrier; it can influence activity of various drug-metabolizing enzymes and transporters, thereby affecting vivo process drugs. It also alleviate obesity adipose tissue inflammation induced by high-fat diet. In this study, we employed proteomics to investigate impact on hepatic protein expression rats. We found over 40 metabolic were altered, with UDP-glucuronosyltransferase 1a9 (Ugt1a9) showing most significant upregulation. This observation consistent our previous findings. KEGG pathway enrichment analysis revealed influences retinol metabolism, steroid hormone biosynthesis, bile secretion, fatty acid degradation, peroxisome proliferator-activated receptor (PPAR) signaling pathway, pentose glucuronate interconversions. Western blot molecular docking quantitatively analyze related proteins. The results demonstrated promotes metabolism produce retinoic acid; enhances secretion upregulating synthesis transporter proteins; activates PPARα regulate fat metabolism-related proteins, reducing lipid accumulation. Furthermore, natural ligands for nuclear receptors, acids may activate receptors initiate regulation target gene expression. upregulation PPARα, retinoid X alpha (RXRα), pregnane (PXR). RXRα form dimer or PXR genes, which explain changes numerous enzymes. study provides comprehensive understanding effects liver rats, reveals its potential biological functions, offers new insights into application development PEG400.

Language: Английский

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Competitive Ligand-Induced Recruitment of Coactivators to Specific PPARα/δ/γ Ligand-Binding Domains Revealed by Dual-Emission FRET and X-Ray Diffraction of Cocrystals

Antioxidants, Journal Year: 2025, Volume and Issue: 14(4), P. 494 - 494

Published: April 20, 2025

Peroxisome proliferator-activated receptors (PPARs), composed of the α/δ/γ subtypes, are ligand-activated nuclear receptors/transcription factors that sense endogenous fatty acids or therapeutic drugs to regulate lipid/glucose metabolism and oxidative stress. PPAR forms a multiprotein complex with retinoid X receptor corepressor in an unliganded/inactive state, ligand binding induces replacement coactivator initiate transcription various genes, including metabolic antioxidant ones. We investigated processes by which is replaced two coactivators compete for PPARα/δ/γ-ligand-binding domains (LBDs) using single- dual-emission fluorescence resonance energy transfer (FRET) assays. Single-FRET revealed respective PPARα/δ/γ-selective agonists (pemafibrate, seladelpar, pioglitazone) induced dissociation peptides, NCoR1 NCoR2, from PPARα/δ/γ-LBDs recruitment CBP TRAP220. Meanwhile, dual-FRET demonstrated these simultaneous four CBP, TRAP220, PGC1α, SRC1, were competitively recruited different preferences upon activation. Furthermore, five newly obtained cocrystal structures X-ray diffraction, PPARα-LBDs–NCoR2/CBP/TRAP220/PGC1α PPARγ-LBD–NCoR2, co-analyzed those our previous studies. This illustrates bound same PPARα-LBD loci via their consensus LXXLL motifs liganded state; NCoR1/NCoR2 corepressors IXXXL sequences within LXXXIXXXL unliganded activation AF-2 helix 12 formation interfered created space coactivator. These PPARα/γ-related biochemical physicochemical findings highlight coregulator dynamics on limited loci.

Language: Английский

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