Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk

New England Journal of Medicine, Journal Year: 2022, Volume and Issue: 387(21), P. 1923 - 1934

Published: Nov. 5, 2022

High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these would lower the incidence of events is uncertain. Pemafibrate, a selective peroxisome proliferator–activated receptor α modulator, reduces and improves other lipid levels.

Language: Английский

---

Targeting fibrosis: mechanisms and clinical trials

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 30, 2022

Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response. Multiple organs can develop fibrosis, including liver, kidney, heart, lung. such as liver cirrhosis, idiopathic pulmonary cystic fibrosis caused substantial disease burden. Persistent abnormal activation of myofibroblasts mediated various signals, transforming growth factor, platelet-derived fibroblast growh has been recongized a major event in occurrence progression fibrosis. Although mechanisms driving organ-specific have not fully elucidated, drugs targeting these identified aberrant signals achieved potent anti-fibrotic efficacy clinical trials. In this review, we briefly introduce aetiology epidemiology several diseases, kidney cardiac Then, summarise cells (epithelial cells, endothelial immune fibroblasts) their interactions addition, also focus on signaling pathways therapeutic targets that regulate myofibroblast activation, cross-linking, metabolism, inflammation Finally, discuss based This review provides reference for further research mechanism, drug development,

Language: Английский

---

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 13, 2022

Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form NAFL, can be progressive and more susceptible to developing cirrhosis hepatocellular carcinoma. Currently, lifestyle interventions are most essential effective strategies for preventing controlling NAFL without development fibrosis. While there still limited appropriate drugs specifically treat NAFL/NASH, growing progress is being seen in elucidating pathogenesis identifying therapeutic targets. In this review, we discussed recent developments etiology prospective targets, as well pharmacological candidates pre/clinical trials patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, Importantly, evidence elucidates that disruption gut-liver axis microbe-derived metabolites drive NAFL/NASH. Extracellular vesicles (EVs) act signaling mediator, resulting accumulation, macrophage stellate cell activation, further promoting inflammation fibrosis progression during Targeting gut microbiota or EVs may serve new treatment Finally, other mechanisms, such therapy genetic approaches, also have enormous potential. Incorporating different mechanisms personalized medicine improve efficacy better benefit patients

Language: Английский

---

Advancements in the treatment of non-alcoholic fatty liver disease (NAFLD)

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 16, 2023

Non-alcoholic fatty liver disease (NAFLD) is a series of diseases, involving excessive lipid deposition in the and often accompanied by obesity, diabetes, dyslipidemia, abnormal blood pressure, other metabolic disorders. In order to more accurately reflect its pathogenesis, an international consensus renamed NAFLD 2020 as (dysfunction) associated with (MAFLD). The changes diet lifestyle are recognized non-drug treatment strategies; however, due complex pathogenesis NAFLD, current drug therapies mainly focused on pathogenic factors, key links related disorders targets. There still lack specific drugs. clinical studies, common treatments include regulation glucose metabolism protect anti-inflammation. based enterohepatic axis, targeting gut microbiota, gradually emerging, various new metabolism-regulating drugs also under development. Therefore, this review article has comprehensively discussed research advancements recent years.

Language: Английский

---

Randomised clinical trial: Pemafibrate, a novel selective peroxisome proliferator‐activated receptor α modulator (SPPARMα), versus placebo in patients with non‐alcoholic fatty liver disease

Alimentary Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 54(10), P. 1263 - 1277

Published: Sept. 16, 2021

Summary Background Pemafibrate is a novel, selective peroxisome proliferator‐activated receptor α modulator (SPPARMα). In mice, improved the histological features of non‐alcoholic steatohepatitis (NASH). patients with dyslipidaemia, it serum alanine aminotransferase (ALT). Aims To evaluate efficacy and safety in high‐risk, fatty liver disease (NAFLD). Methods This double‐blind, placebo‐controlled, randomised multicentre, phase 2 trial 118 (1:1) to either 0.2 mg or placebo, orally, twice daily for 72 weeks. The key inclusion criteria included fat content ≥10% by magnetic resonance imaging‐estimated proton density fraction (MRI‐PDFF); stiffness ≥2.5 kPa, elastography (MRE); elevated ALT levels. primary endpoint was percentage change MRI‐PDFF from baseline week 24. secondary endpoints MRE‐based stiffness, ALT, fibrosis markers lipid parameters. Results There no significant difference between groups (−5.3% vs −4.2%; treatment −1.0%, P = 0.85). However, significantly decreased compared placebo at 48 (treatment −5.7%, 0.036), maintained −6.2%, 0.024), reduction LDL‐C. Adverse events were comparable therapy well tolerated. Conclusions did not decrease but had stiffness. may be promising therapeutic agent NAFLD/NASH, also candidate combination agents that reduce content. ClinicalTrials.gov, number: NCT03350165.

Language: Английский

---

Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis

Clinical and Molecular Hepatology, Journal Year: 2022, Volume and Issue: 29(1), P. 77 - 98

Published: Oct. 13, 2022

The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. dysfunction lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance causes accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress would further contribute to hepatocyte injury death, leading inflammation immune in the liver. During healing process, accumulation an excessive amount fibrosis might occur while healing. development NASH liver fibrosis, gut-liver axis, adipose-liver renin-angiotensin system (RAS) may be dysregulated impaired. Translocation bacteria or its end-products entering could activate hepatocytes, Kupffer cells, stellate exacerbating steatosis, inflammation, fibrosis. Bile acids regulate glucose through Farnesoid X receptors intestine. Increased adipose tissue-derived non-esterified fatty aggravate leptin also plays a role fibrogenesis, decreased adiponectin resistance. Moreover, dysregulation peroxisome proliferator-activated liver, adipose, muscle tissues impair metabolism. In addition, RAS acid metabolism, treatment includes lifestyle modification, pharmacological therapy, non-pharmacological therapy. Currently, weight reduction modification surgery most effective However, vitamin E, pioglitazone, obeticholic have been suggested. this review, we will introduce some new clinical trials experimental therapies for related

Language: Английский

---

PPAR Alpha as a Metabolic Modulator of the Liver: Role in the Pathogenesis of Nonalcoholic Steatohepatitis (NASH)

Biology, Journal Year: 2022, Volume and Issue: 11(5), P. 792 - 792

Published: May 23, 2022

The strong relationship between metabolic alterations and non-alcoholic steatohepatitis (NASH) suggests a pathogenic interplay. However, many aspects have not yet been fully clarified. Nowadays, NASH is becoming the main cause of liver-associated morbidity mortality. Therefore, an effort to understand mechanisms underlying pathogenesis critical. Among nuclear receptor transcription factors, peroxisome-proliferator-activated alpha (PPARα) highly expressed in liver, where it works as pivotal transcriptional regulator intermediary metabolism. In this context, PPARα's function regulating lipid metabolism essential for proper liver functioning. Here, we review genes under control PPARα discuss how aspect can impact inflammatory condition NASH.

Language: Английский

---

Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment

Journal of Physiology and Biochemistry, Journal Year: 2023, Volume and Issue: 79(4), P. 869 - 879

Published: March 28, 2023

Abstract Metabolic dysfunction–associated fatty liver disease (MAFLD) is nowadays considered the manifestation of metabolic syndrome. Its prevalence increasing worldwide in parallel to epidemic diabetes and obesity. MAFLD includes a wide spectrum injury including simple steatosis non-alcoholic steatohepatitis (NASH) that may lead serious complications such as cirrhosis cancer. The complexity its pathophysiology intricate mechanisms underlying progression explains huge variety molecules targeting diverse biological have been tested preclinical clinical settings last two decades. Thanks large number trials few years, most them still ongoing, pharmacotherapy scenario rapidly evolving. three major components MAFLD, steatosis, inflammation, fibrosis seem be safely targeted with different agents at least proportion patients. Likely, next years more than one drug will approved for treatment stages. aim this review synthesize characteristics results advanced NASH evaluate recent advances disease.

Language: Английский

---

NAFLD and NASH: etiology, targets and emerging therapies

Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(3), P. 103910 - 103910

Published: Feb. 1, 2024

Language: Английский

---

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

---