Peroxisome proliferator–activated receptor delta and liver diseases

Hepatology Communications, Год журнала: 2025, Номер 9(2)

Опубликована: Фев. 1, 2025

Peroxisome proliferator-activated receptors (PPARs) are nuclear involved in transcriptional regulation and play an important role many physiological metabolic processes. Unlike PPAR-alpha PPAR-gamma, PPAR-delta is ubiquitously expressed, its activity key to maintaining proper homeostasis within the liver. not only regulates physiologic processes of lipid, glucose, bile acid metabolism but also attenuates pathologic responses alcohol metabolism, inflammation, fibrosis, carcinogenesis, considered therapeutic target liver diseases. Promising results have been reported clinical trials for agonists disease, selective agonist seladelpar was recently conditionally approved United States as a new treatment option primary biliary cholangitis. This review provides overview PPAR-delta’s function biology liver, examines kinetics potential across different diseases, discusses current status involving agonists.

Язык: Английский

---

Therapeutic potential of elafibranor in alcohol-associated liver disease: Insights into macrophage modulation and fibrosis reduction

World Journal of Biological Chemistry, Год журнала: 2025, Номер 16(1)

Опубликована: Март 5, 2025

Alcohol-associated liver disease (ALD) is a major global health concern, contributing to injury, morbidity, and mortality. Elafibranor (EFN), dual peroxisome proliferator-activated receptor α/δ agonist, has shown promise as therapeutic candidate in preclinical studies. EFN reduces fibrosis by inhibiting lipid accumulation, apoptosis, inflammatory pathways (LPS/TLR4/NF-κB), while enhancing autophagy antioxidant responses. It also improves intestinal barrier function modulates gut microbiota, reducing endotoxin-producing bacteria increasing beneficial species. By strengthening the suppressing pro-inflammatory mediators like tumor necrosis factor-alpha interleukin-6, mitigates hepatic stellate cell activation fibrogenic signaling. Macrophages play central role ALD progression, EFN's ability modulate macrophage activity further highlights its anti-inflammatory properties. This review emphasizes dual-targeted approach, addressing both dysfunctions, distinguishing it from conventional treatments. While results are promising, remains under clinical investigation, with ongoing trials evaluating safety efficacy. Future research should focus on elucidating molecular mechanisms advancing application establish potential human populations. represents novel, comprehensive strategy for management, targeting pathologies.

Язык: Английский

---

Elafibranor: A promising treatment for alcoholic liver disease, metabolic-associated fatty liver disease, and cholestatic liver disease

World Journal of Gastroenterology, Год журнала: 2024, Номер 30(40), С. 4393 - 4398

Опубликована: Окт. 16, 2024

Liver diseases pose a significant threat to human health. Although effective therapeutic agents exist for some liver diseases, there remains critical need advancements in research address the gaps treatment options and improve patient outcomes. This article reviews assessment of Elafibranor's effects on fibrosis intestinal barrier function mouse model alcoholic disease (ALD), as reported by Koizumi

Язык: Английский

---

Elafibranor alleviates alcohol-related liver fibrosis by restoring intestinal barrier function

World Journal of Gastroenterology, Год журнала: 2024, Номер 30(43), С. 4660 - 4668

Опубликована: Окт. 31, 2024

We discuss the article by Koizumi et al published in World Journal of Gastroenterology . Our focus is on therapeutic targets for fibrosis associated with alcohol-related liver disease (ALD) and mechanism action elafibranor (EFN), a dual agonist peroxisome proliferator-activated receptor α (PPARα) PPAR δ (PPARδ). EFN currently phase III clinical trials treatment metabolic dysfunction-associated fatty primary biliary cholangitis. ALD progresses from alcoholic to steatohepatitis (ASH), chronic ASH eventually leading fibrosis, cirrhosis, and, some cases, hepatocellular carcinoma. The pathogenesis driven hepatic steatosis, oxidative stress, acetaldehyde toxicity. Alcohol consumption disrupts lipid metabolism inactivating PPARα, exacerbating progression ALD. primarily activates promoting lipolysis β-oxidation ethanol-stimulated HepG2 cells, which significantly reduces apoptosis, an mouse model. Additionally, alcohol gut-liver axis at several interconnected levels, contributing proinflammatory environment liver. helps alleviate intestinal hyperpermeability restoring tight junction protein expression autophagy, inhibiting apoptosis inflammatory responses, enhancing barrier function through PPARδ activation.

Язык: Английский

---

Signaling pathways that activate hepatic stellate cells during liver fibrosis

Frontiers in Medicine, Год журнала: 2024, Номер 11

Опубликована: Сен. 18, 2024

Liver fibrosis is a complex process driven by various factors and key feature of chronic liver diseases. Its essence tissue remodeling caused excessive accumulation collagen other extracellular matrix. Activation hepatic stellate cells (HSCs), which are responsible for production, plays crucial role in promoting the progression fibrosis. Abnormal expression signaling pathways, such as TGF-β/Smads pathway, contributes to HSCs activation. Recent studies have shed light on these providing valuable insights into development Here, we will review six pathways that been studied more recent years.

Язык: Английский

---

Dual peroxisome proliferator-activated receptor α/δ agonists: Hope for the treatment of alcohol-associated liver disease?

World Journal of Gastroenterology, Год журнала: 2024, Номер 30(37), С. 4163 - 4167

Опубликована: Сен. 26, 2024

In this letter, we review the article “Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model alcohol-associated disease”. We focus specifically detrimental effects disease (ALD) human health. Given its insidious onset increasing incidence, awareness ALD can contribute to reducing prevalence diseases. comprises spectrum several different disorders, including steatosis, steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma. The pathogenesis is exceedingly complex. Previous studies have shown that peroxisome proliferator-activated receptors (PPARs) regulate lipid metabolism, glucose homeostasis inflammatory responses within organism. Additionally, their dysfunction major contributor progression ALD. Elafibranor an oral, dual PPARα δ agonist. effectiveness treatment remains unclear. emphasize harm burden it places society. Furthermore, summarize clinical management all stages present new insights into potential therapeutic targets. discuss mechanisms action agonists, significance antifibrotic future research directions.

Язык: Английский

---

Elafibranor: A promising treatment for alcohol-associated liver disease?

World Journal of Gastroenterology, Год журнала: 2024, Номер 30(39), С. 4313 - 4317

Опубликована: Окт. 11, 2024

We comment on an article by Koizumi et al . Elafibranor (EFN) is a dual pero-xisome proliferator-activated receptor α/δ agonist. The experimental results from demonstrated that EFN significantly increases intestinal barrier function and ameliorates liver fibrosis. These positive outcomes suggest could be promising therapeutic option for alcohol-associated disease (ALD). However, this study has limitations necessitate further research to evaluate the efficacy of EFN. Future studies should consider use more appropriate animal models cell types, optimize administration routes dosages drug, conduct in-depth investigation into underlying mechanisms action determine effects in humans. With sustained research, potential emerge as novel agent treatment ALD.

Язык: Английский

---

Peroxisome proliferator-activated receptor agonists: A new hope towards the management of alcoholic liver disease

World Journal of Gastroenterology, Год журнала: 2024, Номер 30(35), С. 3965 - 3971

Опубликована: Сен. 12, 2024

In this editorial, we examine a paper by Koizumi et al , on the role of peroxisome proliferator-activated receptor (PPAR) agonists in alcoholic liver disease (ALD). The study determined whether elafibranor protected intestinal barrier and reduced fibrosis mouse model ALD. also underlines PPARs function lipid homeostasis, which are both affected Effective therapies necessary for ALD because it is critical health issue that affects people worldwide. This editorial analyzes possibility PPAR as treatments As key factors inflammation metabolism, offer multiple methods managing complex etiology We assess abilities PPARα, PPARγ, PPARβ/δ to prevent steatosis, inflammation, due diseases. Recent research carried out preclinical clinical settings has shown can reduce severity disease. discusses data analyzed obstacles, advantages, mechanisms action Further needed understand efficacy, safety, treating

Язык: Английский

---

Novel intervention for alcohol-associated liver disease

World Journal of Gastroenterology, Год журнала: 2024, Номер 30(39), С. 4308 - 4312

Опубликована: Окт. 11, 2024

A recently published article in the World Journal of Gastroenterology clarified that elafibranor, a dual peroxisome proliferator activated receptor α/δ (PPARα/δ) agonist, reduced inflammation and fibrosis alcohol-associated liver disease (ALD). This letter aims to discuss findings presented article. ALD is global health problem, no effective drugs has been approved by Food Drug Administration cure it. Thus, finding targeted therapies great urgency. Herein, we focus on pathogenesis role PPARα/δ its development. Consistent with conclusion interest, think elafibranor may be promising therapeutic option for ALD, due pivotal involvement disease. However, treatment dose, timing, side effects need further investigated future studies.

Язык: Английский

---

Bile acids supplementation improves colonic mucosal barrier via alteration of bile acids metabolism and gut microbiota composition in goats with subacute ruminal acidosis (SARA)

Ecotoxicology and Environmental Safety, Год журнала: 2024, Номер 287, С. 117313 - 117313

Опубликована: Ноя. 1, 2024

Subacute ruminal acidosis (SARA) is a common metabolic disease due to feeding high-concentrate (HC) diets ruminants, especially dairy cows, in intensive farming system. Long term HC commonly induce damages hindgut barrier, leading the translocation of harmful substances such as endotoxins (LPS) from lumen blood, which results low-grade inflammation and stress response. Secondary bile acids (SBAs) play an important role maintaining intestinal homeostasis. However, function SBAs on epithelial barrier SARA remains unclear. In this study, 15 growing goats were randomly divided into 3 groups, control group (30 % concentrate dry matter, CON), (70 SARA), SARA+BAs matte, supplemented with g/d/goat BAs, SARA+BAs). The changes mucosal permeability, gut microbiota (BAs) profile was measured colon. showed that compared CON group, level plasma D-lactate diamine oxidase activity (DAO) (P < 0.05) elevated while BAs supplementation significantly decreased DAO 0.05). thickness colonic mucosa, goblet cells (GCs) number 0.01) abundance MUC2 occludin expression markedly increased GCs improved barrier. effectively reduced content LPS volatile fatty (VFAs) digesta Furthermore, ameliorated SARA-induced reduction total 0.001), primary 0.05), conjugated including taurocholic acid (TCA), taurochenodeoxycholic (TCDCA) taurodeoxycholic (TDCA), well hyodeoxycholic (HDCA) lithocholic (LCA) contents digesta. 16S rRNA gene sequence analysis revealed Prevotella Treponema, but Akkermansia positively correlated abundance. Roseburia, Negativibacillus, Lactobacillus, unclassified_f_prevotellaceae, TCA, TCDCA, TDCA levels. RNA-Seq that, activated PPAR signaling pathway GCs. summary, remodels profiles metabolites, activates pathway, eventually ameliorates damage.

Язык: Английский

---