Hepatic inflammatory responses in liver fibrosis

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(10), P. 633 - 646

Published: July 3, 2023

Language: Английский

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An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(2), P. 552 - 566

Published: April 14, 2023

Language: Английский

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PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 245, P. 108391 - 108391

Published: March 22, 2023

Language: Английский

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Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies

Molecular Aspects of Medicine, Journal Year: 2023, Volume and Issue: 95, P. 101231 - 101231

Published: Dec. 5, 2023

Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury well persistent activation inflammatory response and fibrogenesis. fibrosis is a major determinant for disease (CLD) progression in the last two decades our understanding on molecular cellular mechanisms underlying fibrogenic CLD has dramatically improved, boosting pre-clinical studies clinical trials designed to find novel therapeutic approaches. From these several critical concepts have emerged, starting reveal complexity pro-fibrotic microenvironment which involves very complex, dynamic interrelated interactions between different hepatic extrahepatic cell populations. This review will offer first recapitulation established pathophysiological basic principles by intentionally focus attention NAFLD/NASH, metabolic-related form with high impact general population emerging leading cause worldwide. NAFLD/NASH-related pro-inflammatory profibrogenic be analysed information cells, mediators signalling pathways taken advantage methodological approaches techniques (single genomics, imaging mass cytometry, vitro two- three-dimensional models, etc.). We next overview recent advancement diagnostic prognostic tools, including serum biomarkers polygenic scores, support analysis biopsies. Finally, this provide current therapies treatment NAFLD/NASH patients.

Language: Английский

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Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(5), P. 1110 - 1120

Published: July 28, 2023

Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed validate original 18-month biopsy analysis from phase III REGENERATE trial OCA NASH with consensus panel analysis, provide additional histology data larger population, evaluate safety >8,000 total patient-years' exposure nearly 1,000 participants receiving study drug >4 years.Digitized whole-slide images were evaluated independently by panels three pathologists using Clinical Research Network scoring system. Primary endpoints (1) ≥1 stage improvement no worsening or (2) resolution fibrosis. Safety was assessed laboratory values adverse events.Prespecified efficacy analyses included 931 participants. The proportion achieving 22.4% 25 mg vs. 9.6% placebo (p <0.0001). More achieved (6.5% 3.5%, respectively; p = 0.093). Histology population 1,607 supported these results. 2,477 incidence treatment-emergent events (TEAEs), serious TEAEs, deaths not substantively different across groups. Pruritus most common TEAE. Rates adjudicated hepatic, renal, cardiovascular low similar groups.These results confirm effect mg. generally well tolerated over long-term dosing. These support positive benefit:risk profile patients NASH.Patients (NASH) often have scarring (fibrosis), which causes an increased risk liver-related illness death. Preventing progression cirrhosis reversing are main goals NASH. In this clinical obeticholic (REGENERATE), we reaffirmed our previous demonstrating that superior improving more rigorous biopsies taken at month 18. also showed resulted dose-dependent reductions serum biochemistries stiffness measurements compared placebo, even whom histologic did change 18 months, providing evidence benefit extends beyond what captured ordinal CRN favorable supporting benefit:

Language: Английский

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FXR agonists in NASH treatment

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

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Antifibrotic therapy in nonalcoholic steatohepatitis: time for a human-centric approach

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

Published: June 2, 2023

Language: Английский

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Evaluation of PXL065 – deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1)

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 78(5), P. 914 - 925

Published: Feb. 18, 2023

Language: Английский

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Treating NASH by targeting peroxisome proliferator-activated receptors

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(5), P. 1302 - 1316

Published: July 17, 2023

Language: Английский

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A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(6), P. 1371 - 1393.e7

Published: May 7, 2024

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well ameliorates established fibrosis without affecting total calorie intake. Furthermore, the blunted NASH-HCC when applied therapeutically. timing, length, number cycles type diet were critical parameters determining benefits fasting. Combined proteome, transcriptome, metabolome analyses peroxisome-proliferator-activated receptor alpha (PPARα) glucocorticoid-signaling-induced PCK1 act co-operatively hepatic executors response. In line with this, PPARα targets reduced human NASH. Notably, only initiated during active phase mice robustly induced glucocorticoid signaling free-fatty-acid-induced signaling. However, hepatocyte-specific deletion partially abrogated contrast, combined knockdown Ppara Pck1 vivo abolished beneficial outcomes against inflammation fibrosis. Moreover, overexpression alone or together lowered triglycerides steatosis. Our data support notion is a promising intervention subsequent liver cancer.

Language: Английский

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