Metabolic dysfunction−associated liver disease and diabetes: Matrix remodeling, fibrosis, and therapeutic implications DOI
Weiguo Fan,

Toby M. Bradford,

Natalie J. Török

et al.

Annals of the New York Academy of Sciences, Journal Year: 2024, Volume and Issue: 1538(1), P. 21 - 33

Published: July 12, 2024

Abstract Metabolic dysfunction−associated liver disease (MASLD) and steatohepatitis (MASH) are becoming the most common causes of chronic in United States worldwide due to obesity diabetes epidemics. It is estimated that by 2030 close 100 million people might be affected patients with type 2 especially at high risk. Twenty 30% MASLD can progress MASH, which characterized steatosis, necroinflammation, hepatocyte ballooning, advanced cases, fibrosis progressing cirrhosis. Clinically, it recognized progression diabetic accelerated role various genetic epigenetic factors, as well cell–matrix interactions stromal remodeling, have recently been recognized. While there has great drug development clinical trials for MASLD/MASH, complexity these pathways highlights need improve diagnosis/early detection develop more successful antifibrotic therapies not only prevent but reverse fibrosis.

Language: Английский

EASL–EASD–EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD) DOI Creative Commons
Frank Tacke, Paul Horn, Vincent Wai–Sun Wong

et al.

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 81(3), P. 492 - 542

Published: June 7, 2024

Language: Английский

Citations

332
Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets DOI Creative Commons
Joshua S. Fleishman, Sunil Kumar

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 25, 2024

Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. acid signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, neoplastic conditions, strongly influencing health disease. No curative treatment exists for any bile influenced disease, while most promising well-developed therapeutic was recently rejected by FDA. Here, we provide bottom-up approach on mechanistically explaining their biochemistry, physiology, pharmacology at canonical non-canonical receptors. Using this mechanistic model explain how abnormal physiology drives disease pathogenesis, emphasizing ceramide synthesis may serve unifying pathogenic feature cardiometabolic diseases. We an in-depth summary pre-existing receptor modulators, shortcomings, propose solutions they be remedied. Lastly, rationalize novel targets further translational drug discovery future perspectives. Rather than dismissing therapeutics due to recent setbacks, believe that there is immense clinical potential high likelihood success therapeutics.

Language: Английский

Citations

77
Metabolic reprogramming in liver fibrosis DOI Creative Commons
Paul Horn, Frank Tacke

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(7), P. 1439 - 1455

Published: May 31, 2024

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident non-resident heterogeneous cell populations, ultimately leading to deposition extracellular matrix organ failure. Shifts phenotypes functions involve pronounced transcriptional protein synthesis changes that require adaptations cellular substrate metabolism, including glucose lipid resembling associated the Warburg effect cancer cells. Cell activation are regulated by stress responses, unfolded response, endoplasmic reticulum stress, autophagy, ferroptosis, nuclear receptor signaling. These crucial for inflammatory fibrogenic macrophages, lymphoid cells, hepatic stellate Modulation these pathways, therefore, offers opportunities novel therapeutic approaches halt even reverse fibrosis progression.

Language: Английский

Citations

67
EASL-EASD-EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) DOI Creative Commons
Frank Tacke, Paul Horn, Vincent Wai–Sun Wong

et al.

Obesity Facts, Journal Year: 2024, Volume and Issue: 17(4), P. 374 - 444

Published: Jan. 1, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty (NAFLD), is defined as (SLD) in the presence of one or more cardiometabolic risk factor(s) and absence harmful alcohol intake. The spectrum MASLD includes steatosis, metabolic steatohepatitis (MASH, NASH), fibrosis, cirrhosis MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis treatment for MASLD. Case-finding strategies with using non-invasive tests, should be applied individuals factors, abnormal enzymes, and/or radiological signs hepatic particularly type 2 diabetes (T2D) obesity additional factor(s). A stepwise approach blood-based scores (such FIB-4) and, sequentially, imaging techniques transient elastography) suitable to rule-out/in advanced which predictive liver-related outcomes. In adults MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise discouraging consumption well optimal management comorbidities use incretin-based therapies (e.g. semaglutide, tirzepatide) T2D obesity, if indicated advised. Bariatric surgery also option obesity. If locally approved dependent label, non-cirrhotic MASH significant fibrosis (stage ≥2) considered a MASH-targeted resmetirom, demonstrated histological effectiveness acceptable safety tolerability profile. No pharmacotherapy can currently recommended cirrhotic stage. Management adaptations drugs, nutritional counselling, surveillance portal hypertension HCC, transplantation decompensated cirrhosis.

Language: Английский

Citations

62
FXR agonists in NASH treatment DOI Creative Commons
Luciano Adorini, Michael Trauner

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(5), P. 1317 - 1331

Published: Aug. 9, 2023

The farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear highly expressed in the liver and intestine, regulates expression of genes involved cholesterol homeostasis, hepatic gluconeogenesis, lipogenesis, inflammation fibrosis, addition to controlling intestinal barrier integrity, preventing bacterial translocation maintaining gut microbiota eubiosis. Non-alcoholic steatohepatitis (NASH), an advanced stage non-alcoholic fatty disease, is characterized by steatosis, hepatocyte damage (ballooning) inflammation, leading cirrhosis hepatocellular carcinoma. NASH represents major unmet medical need, but no pharmacological treatments have yet been approved. pleiotropic mechanisms development offer range therapeutic opportunities among them FXR activation has emerged as established target. Various agonists with different physicochemical properties, which can be broadly classified BA derivatives, non-BA-derived steroidal agonists, non-steroidal partial are clinical development. In this review we will summarize key preclinical features most critically evaluate their potential treatment.

Language: Английский

Citations

57
NAFLD and NAFLD Related HCC: Emerging Treatments and Clinical Trials DOI Open Access
Tushar Khare,

Karina Liu,

Lindiwe Oslee Chilambe

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(1), P. 306 - 306

Published: Jan. 1, 2025

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated (MAFLD), is the most prevalent worldwide. It associated with an increased risk of developing hepatocellular carcinoma (HCC) in background cirrhosis or without cirrhosis. The prevalence NAFLD-related HCC increasing all over globe, and surveillance NAFLD cases not that common. In present review, we attempt to summarize promising treatments clinical trials focused on NAFLD, nonalcoholic steatohepatitis (NASH), past five seven years. We categorized based type intervention. Most are still running, only a few completed conclusive results. trial NCT03942822, 25 mg/day milled chia seeds improved condition. Completed NCT03524365 concluded Rouxen-Y gastric bypass (RYGB) sleeve gastrectomy (SG) results histological resolution NASH worsening fibrosis, while NCT04677101 validated sensitivity/accuracy blood biomarkers predicting fibrosis stage. Moreover, empagliflozin (NCT05694923), curcuvail (NCT06256926), obeticholic acid (NCT03439254) were but did provide However, NCT03900429 reported effective improvement by at least one stage, activity score (NAS), as well lipid profile patients 80 100 mg MGL-3196 (resmetirom). Funded Madrigal Pharmaceuticals, Rezdiffra (resmetirom), used NCT03900429, first FDA-approved drug for treatment NAFLD/NASH.

Language: Английский

Citations

4
Metabolic dysfunction-associated steatotic liver disease in adults DOI
Daniel Q. Huang, Vincent Wai–Sun Wong, Mary E. Rinella

et al.

Nature Reviews Disease Primers, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 6, 2025

Language: Английский

Citations

3
Targeting Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Available and Future Pharmaceutical Options DOI Open Access

Emmanouil Koullias,

Maria Papavdi,

John Koskinas

et al.

Cureus, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects an ever-increasing part of the global population, affecting millions individuals worldwide. Despite progress in treatment other diseases, there is a scarcity liver-specific drugs targeting MASLD. In light that, research has focused both on pipeline multiple different receptors implicated pathogenesis disease, as well medications already approved for indications, that might exert beneficial effects The fact MASLD associated with increased prevalence obesity and type 2 diabetes mellitus (T2DM) establishes possible pathway respect to available pharmaceutical interventions this group patients, such glucagon-like peptide-1 receptor agonists (GLP-1RAs) sodium-glucose co-transporter-2 inhibitors (SGLT2-is). Thus, hitherto at hand, along upcoming members these families, provide much-needed options our arsenal. This review attempts explore old novel dimensions continuous effort medical society improve patient outcomes.

Language: Английский

Citations

2
Consensus Guidelines for the Diagnosis and Management of Metabolic Dysfunction-Associated Steatotic Liver Disease in Adult Asian Indians with Type 2 Diabetes DOI
Anoop Misra, Ashish Kumar, Mohammad Shafi Kuchay

et al.

Diabetes & Metabolic Syndrome Clinical Research & Reviews, Journal Year: 2025, Volume and Issue: 19(3), P. 103209 - 103209

Published: March 1, 2025

Language: Английский

Citations

2
NAFLD in the 21st Century: Current Knowledge Regarding Its Pathogenesis, Diagnosis and Therapeutics DOI Creative Commons
Dimitris Kounatidis, Natalia G. Vallianou,

Eleni Geladari

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(4), P. 826 - 826

Published: April 9, 2024

Non-alcoholic fatty liver disease (NAFLD) is a major public health issue worldwide. It the most common in Western countries, andits global prevalence estimated to be up 35%. However, its diagnosis may elusive, because biopsy relatively rarely performed and usually only advanced stages of disease. Therefore, several non-invasive scores applied more easily diagnose monitor NAFLD. In this review, we discuss various biomarkers imaging that could useful diagnosing managing Despite fact general measures, such as abstinence from alcohol modulation other cardiovascular risk factors, should applied, mainstay prevention management weight loss. Bariatric surgery suggested means confront addition, pharmacological treatment with GLP-1 analogues or GIP agonist tirzepatide advisable. focus on utility agonists lowering body weight, their pharmaceutical potential, safety profile, already evidenced inanimal human studies. We also elaborate options, use vitamin E, probiotics, especially next-generation prebiotics context. Finally, explore future perspectives regarding administration analogues, agonists, probiotics/prebiotics prevent combat The newest drugs pegozafermin resmetiron, which seem very promising, arealso discussed.

Language: Английский

Citations

13