Combinatorial therapy with BAR502 and UDCA resets FXR and GPBAR1 signaling and reverses liver histopathology in a model of NASH DOI Creative Commons
Silvia Marchianò, Michele Biagioli, Elva Morretta

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Jan. 28, 2023

Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids signaling molecules acting on main receptors the Farnesoid-x-receptor (FXR) G protein coupled receptor GPB AR1. Clinical trials have shown that FXR agonism might result in side effects along with lack of efficacy restoring liver histopathology. For these reasons a multi-targets combined agonists agent targeting additional molecular mechanisms improved over selective agonists. In present study we compared BAR502, dual FXR/GPBAR1 ligand) alone or combination ursodeoxycholic acid (UDCA) model NAFLD/NASH induced by feeding mice Western diet 10 weeks. The results demonstrated while BAR502 UDCA partially protected against damage caused diet, two, reversed pro-atherogenic lipid profile completely histopathology damage, attenuating steatosis, ballooning, inflammation fibrosis. Additionally, both agents increased insulin sensitivity bile signaling, modulated up top 85 genes comparison feed strongly reducing expression inflammatory markers such as chemokines cytokines. redirected metabolism toward species GPBAR1 agonist reduced content fecal excretion. Together, data, highlight potential role combinatorial based treating NAFLD.

Language: Английский

Fibrosis: from mechanisms to medicines DOI
Neil C. Henderson, Florian Rieder, Thomas A. Wynn

et al.

Nature, Journal Year: 2020, Volume and Issue: 587(7835), P. 555 - 566

Published: Nov. 25, 2020

Language: Английский

Citations

1229
MAFLD identifies patients with significant hepatic fibrosis better than NAFLD DOI Creative Commons
Sakura Yamamura, Mohammed Eslam, Takumi Kawaguchi

et al.

Liver International, Journal Year: 2020, Volume and Issue: 40(12), P. 3018 - 3030

Published: Sept. 30, 2020

Abstract Background & Aims Diagnostic criteria for metabolic associated fatty liver disease (MAFLD) have been proposed, but not validated. We aimed to compare the diagnostic accuracy of MAFLD definition vs existing NAFLD identify patients with significant fibrosis and characterize impact mild alcohol intake. Methods enrolled 765 Japanese (median age 54 years). were diagnosed in 79.6% 70.7% respectively. Significant was defined by FIB‐4 index ≥1.3 stiffness ≥6.6 kPa using shear wave elastography. Mild intake as <20 g/day. Factors analysed logistic regression decision‐tree analyses. Results Liver higher compared (7.7 6.8 kPa, P = .0010). In regression, (OR 4.401; 95% CI 2.144‐10.629; < .0001), 1.761; 1.081‐2.853; .0234), 1.721; 95%CI 1.009‐2.951; .0463) independently fibrosis. By analysis, MAFLD, or consumption initial classifier The sensitivity detecting than (93.9% 73.0%). even an increase prevalence (25.0% 15.5%; .0181). Conclusions better identifies a group evaluated non‐invasive tests. Moreover, is worsening hepatic measures.

Language: Английский

Citations

366
Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment DOI Creative Commons
Leen Heyens, Dana Busschots,

Ger H. Koek

et al.

Frontiers in Medicine, Journal Year: 2021, Volume and Issue: 8

Published: April 14, 2021

An increasing percentage of people have or are at risk to develop non-alcoholic fatty liver disease (NAFLD) worldwide. NAFLD comprises different stadia going from isolated steatosis steatohepatitis (NASH). NASH is a chronic state inflammation that leads the transformation hepatic stellate cells myofibroblasts. These produce extra-cellular matrix results in fibrosis. In normal situation, fibrogenesis wound healing process preserves tissue integrity. However, sustained and progressive fibrosis can become pathogenic. This takes many years often asymptomatic. Therefore, patients usually present themselves with end-stage e.g., cirrhosis, decompensated even hepatocellular carcinoma. Fibrosis has also been identified as most important predictor prognosis NAFLD. Currently, only minority be hence referred for treatment. not because largely asymptomatic, but due fact currently biopsy still golden standard accurate detection performing harbors some risks requires resources expertise, applicable every clinical setting unsuitable screening. Consequently, non-invasive diagnostic tools, mainly based on analysis blood other specimens imaging developed development. this review, we will first give an overview pathogenic mechanisms evolution serves basis subsequent discussion current future biomarkers anti-fibrotic drugs.

Language: Английский

Citations

163
Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside DOI Open Access
Don C. Rockey, Scott L. Friedman

Gastroenterology, Journal Year: 2021, Volume and Issue: 160(5), P. 1502 - 1520.e1

Published: Jan. 30, 2021

Language: Английский

Citations

105
Breakthroughs in therapies for NASH and remaining challenges DOI Creative Commons
Vlad Ratziu, Sven Francque, Arun J. Sanyal

et al.

Journal of Hepatology, Journal Year: 2022, Volume and Issue: 76(6), P. 1263 - 1278

Published: May 16, 2022

Language: Английский

Citations

105
Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial DOI
Stephen A. Harrison, Manal F. Abdelmalek,

Guy Neff

et al.

˜The œLancet. Gastroenterology & hepatology, Journal Year: 2022, Volume and Issue: 7(7), P. 603 - 616

Published: March 21, 2022

Language: Английский

Citations

97
Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) DOI
Shuang Wang, Scott L. Friedman

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(716)

Published: Oct. 4, 2023

Metabolic dysfunction–associated steatohepatitis (MASH) is a severe form of liver disease that poses global health threat because its potential to progress advanced fibrosis, leading cirrhosis and cancer. Recent advances in single-cell methodologies, refined models, genetic epigenetic insights have provided nuanced understanding MASH fibrogenesis, with substantial cellular heterogeneity livers providing potentially targetable cell-cell interactions behavior. Unlike mechanisms underlying fibrosis regression are still inadequately understood, although antifibrotic targets been recently identified. A treatment framework could lead noninvasive assessment targeted therapies preserve hepatocellular function restore the liver’s architectural integrity.

Language: Английский

Citations

56
Antifibrotic therapy in nonalcoholic steatohepatitis: time for a human-centric approach DOI Open Access
Paul Brennan, Ahmed M. Elsharkawy, Timothy J. Kendall

et al.

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(10), P. 679 - 688

Published: June 2, 2023

Language: Английский

Citations

50
Mediators of necroptosis: from cell death to metabolic regulation DOI Creative Commons

Xiaoqin Wu,

Laura E. Nagy, Jérémie Gautheron

et al.

EMBO Molecular Medicine, Journal Year: 2024, Volume and Issue: 16(2), P. 219 - 237

Published: Jan. 9, 2024

Abstract Necroptosis, a programmed cell death mechanism distinct from apoptosis, has garnered attention for its role in various pathological conditions. While initially recognized involvement death, recent research revealed that key necroptotic mediators, including receptor-interacting protein kinases (RIPKs) and mixed lineage kinase domain-like (MLKL), possess additional functions go beyond inducing demise. These encompass influencing critical aspects of metabolic regulation, such as energy metabolism, glucose homeostasis, lipid metabolism. Dysregulated necroptosis been implicated diseases, obesity, diabetes, dysfunction-associated steatotic liver disease (MASLD) alcohol-associated (ALD), contributing to chronic inflammation tissue damage. This review provides insight into the multifaceted necroptosis, encompassing both these extra-necroptotic functions, context diseases. Understanding this intricate interplay is crucial developing targeted therapeutic strategies diseases currently lack effective treatments.

Language: Английский

Citations

21
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