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

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Seladelpar: First Approval

Drugs, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 22, 2024

Язык: Английский

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Pruritus in Chronic Cholestatic Liver Diseases, Especially in Primary Biliary Cholangitis: A Narrative Review

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(5), С. 1883 - 1883

Опубликована: Фев. 22, 2025

Patients with chronic cholestatic liver diseases often experience itch and struggle this symptom. We discuss the mechanism of in patients diseases, such as primary biliary cholangitis (PBC) others, their therapies, including ileal bile acid transporter (IBAT) inhibitors. In PBC, there are high serum/plasma concentrations multiple factors, salts, bilirubin, endogenous opioids, lysophosphatidic (LPA), autotaxin, histamine. Bile LPA, autotaxin affect mediators skin sensory nerves, while opioid balance affects spinal cord. Itch is sensitized by both peripheral central nervous systems. Both mechanisms involved disease. Although IBAT inhibitors have been approved for use pediatric conditions, progressive familial intrahepatic cholestasis Alagille syndrome, inhibition seems to be a promising treatment refractory PBC. A traditional non-systematic review results narrative review. Multidisciplinary cooperation, involving hepatologists, dermatologists, pharmacists, could provide better PBC suffering from itch. conclusion, we summarized existing knowledge on caused especially focus therapies. This provides therapeutic options diseases.

Язык: Английский

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Potential Role of Bile Acids in the Pathogenesis and Treatment of PBC

Journal of Contemporary Medical Practice, Год журнала: 2025, Номер 7(2), С. 99 - 102

Опубликована: Фев. 28, 2025

Primary biliary cholangitis (PBC) is a chronic cholestatic disease whose pathogenesis involves complex interplay of genetic predisposition, environmental triggers, and aberrant activation the immune system. It characterized by immune-mediated bile duct injury intrahepatic cholestasis, which ultimately leads to cirrhosis even liver failure. Cholestasis an important pathogenetic feature pathophysiological alteration PBC, in toxicity accumulation, inflammatory activation, fibrosis drive, immunomodulatory abnormalities combine drive progression. In addition, targeted acid (bile acid) therapy has shown therapeutic efficacy improving biochemistry survival majority patients, current first-line for PBC therapy, with acids thought play role progression treatment. This review focuses on potential impact process its treatment, discusses state research view informing further studies PBC.

Язык: Английский

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PPAR-Mediated Bile Acid Glucuronidation: Therapeutic Targets for the Treatment of Cholestatic Liver Diseases

Cells, Год журнала: 2024, Номер 13(15), С. 1296 - 1296

Опубликована: Авг. 1, 2024

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and sclerosing (PSC), result from an impairment of bile flow that leads to the hepatic retention acids, causing injury. Until recently, only approved treatments for PBC were ursodeoxycholic acid (UDCA) obeticholic (OCA). While these therapies slow progression in early stage disease, approximately 40% patients respond incompletely UDCA, advanced cases do not respond. UDCA does improve survival with PSC, often have dose-limiting pruritus reactions OCA. Left untreated, diseases can progress fibrosis cirrhosis, resulting failure need transplantation. These shortcomings emphasize urgent alternative treatment strategies. Recently, nuclear hormone receptors been explored as pharmacological targets adjunct therapy because they regulate enzymes involved metabolism detoxification. In particular, peroxisome proliferator-activated receptor (PPAR) has emerged a therapeutic target or PSC who experience incomplete response UDCA. PPARα is predominantly expressed liver, it plays essential role regulation cytochrome P450 (CYP) uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes, both which are critical enzyme families glucuronidation, respectively. Importantly, agonists, e.g., fenofibrate, shown benefits reducing elevated markers cholestasis elafibranor, first PPAR (dual α, β/δ) agonist, FDA-approved second-line PBC. Additionally, newer agonists various isoforms (β/δ, γ) under development although their impact on glucuronidation pathways less characterized. This review will focus PPAR-mediated pathway outcomes PSC.

Язык: Английский

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Second‐Line Treatment for Patients With Primary Biliary Cholangitis: A Systematic Review With Network Meta‐Analysis

Liver International, Год журнала: 2024, Номер 45(1)

Опубликована: Дек. 25, 2024

Approximately 40% of patients with Primary Biliary Cholangitis (PBC) show incomplete response to ursodeoxycholic acid, thus needing second-line treatment prevent disease progression. As no head-to-head comparison study is available, we used a network meta-analysis (NMA) compare efficacy and safety available therapies.

Язык: Английский

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High C-reactive protein-to-albumin ratio levels are associated with osteoporosis in patients with primary biliary cholangitis

Frontiers in Endocrinology, Год журнала: 2024, Номер 15

Опубликована: Май 30, 2024

Inflammation contributes to the development of metabolic bone diseases. The C-reactive protein-to-albumin ratio (CAR) is an inflammation-based marker with a prognostic value for several This study investigated relationship between CAR and osteoporosis (OP) in patients primary biliary cholangitis (PBC).

Язык: Английский

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The treatment of primary biliary cholangitis: from shadow to light

Therapeutic Advances in Gastroenterology, Год журнала: 2024, Номер 17

Опубликована: Янв. 1, 2024

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease characterized by the destruction of small intrahepatic bile ducts, which can progress to liver cirrhosis. The gold standard in treatment PBC ursodeoxycholic acid (UDCA), indicated all patients with because it improves not only biochemical parameters but also patients’ survival. An important milestone identification at risk assessment response UDCA. Patients who respond have lower incidence hepatic events and better prognosis than do not. Several scoring systems be used assess identify non-responders will benefit from second-line treatment. Obeticholic (OCA) currently approved for PBC, effective UDCA therapy or patients, tolerated therapy. However, OCA contraindicated advanced cirrhosis portal hypertension. Moreover, pruritus may limiting factor administration OCA. Fibrates shown promising data supporting their use they improve elastographic findings possible antipruritic effects. Therefore, idea triple seems interesting. Clinical research focusing on several other groups drugs: peroxisome proliferator-activated receptor (PPAR) δ- α/δ agonists, non-steroidal farnesoid X fibroblast growth 19 modulators, inhibitors nicotinamide adenine dinucleotide phosphate oxidase 1 4.

Язык: Английский

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Evaluating the safety and efficacy of seladelpar for adults with primary biliary cholangitis

Expert Opinion on Pharmacotherapy, Год журнала: 2024, Номер 25(11), С. 1517 - 1523

Опубликована: Июль 23, 2024

Seladelpar (MBX-8025) is a once-daily administered highly specific PPAR-δ agonist in Phase 3 and extension trials for use patients with primary biliary cholangitis (PBC).

Язык: Английский

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PPARα, PPARδ, or both—that is the question!

Hepatology, Год журнала: 2024, Номер 80(1), С. 8 - 10

Опубликована: Фев. 16, 2024

Cholestatic pruritus may affect 2 out of 3 individuals with, for example, primary biliary cholangitis (PBC) and sclerosing (PSC), the most common chronic cholestatic liver diseases.1 shows a diurnal variation with peak intensity early at night be localized particularly limbs but can also generalized. It mild, severe, dramatically impairing quality life.1 Potential pruritogens in cholestasis are thought to activate receptors on unmyelinated C fibers (itch neurons) skin, thereby triggering complex neural network leading sensation itch desire scratch. Proposed candidate include certain lysophospholipids,2 sulfated progesterone metabolites, endogenous opioids, among others.1 A number observations raised doubts role bile acids as potential cholestasis. For effective reduction serum by treatment potent acid sequestrant colesevelam did not reduce perception subjects PBC PSC moderate severe when compared placebo randomized placebo-controlled trial3 rare genetic disorder, Na+-taurocholate cotransporting polypeptide deficiency, who live millimolar range (more than 100-fold higher upper limit normal) were reported suffer from all.1 Thus, total appear unlikely dominant disorders. Medical therapy has clearly advanced recent years introduction peroxisome proliferator-activated receptor (PPAR) agonist bezafibrate an antipruritic strategy Europe Asia. In addition case series, academic randomized, trials showed beneficial effects versus pruritus: BEZURSO trial,4 (n = 100) treated bezafibrate+ursodeoxycholic (UDCA) or placebo+UDCA years. During this period, mostly mild secondary study end point improved together markers placebo.4 FITCH trial,5 so far largest trial 74) suffering (5–10/10, visual analog scale), weeks added UDCA (in cases) markedly majority included comparison (ambitious scale improvement ≥ 50% 45% vs. 11%, p 0.003). Secondary points, including morning evening intensity, validated 5D-Itch questionnaire, domain Liver Disease Symptom Index 2.0 confirmed results point. The pan-PPAR meanwhile been recommended first-line EASL clinical practice guidelines cholangitis. An equivalent update is awaited. Bezafibrate stimulates PPARα, PPARδ(=β), PPARγ. questioned whether selective PPARα PPARδ agonists could equally agonists. While like fenofibrate (or ciprofibrate) show activity PBC, effect weaker that bezafibrate.6 Recently, seladelpar (formerly MBX-8025; 10 mg daily) was more regard cholestasis, after months industry-driven ENHANCE trial, phase 265 patients under appropriate.7 Although mean difference Seladelpar daily (but 5 alleviating (as determined rating (NRS)) best (mean Δ −1.59, 0.02) only restricted subgroup 56 (21%, those NRS 4 baseline) (restriction missed mention abstract Hepatology publication7), data interest. Still, 5D-itch PBC-40 tended be, documented significantly analysis 4,7 making relevance these findings less convincing conditions tested achieved previously Japan Europe.4–6 We read great interest post hoc analyses above-introduced published present issue Hepatology.8 This paper, authored Kremer et al further elaborated well-tolerated dose daily. Screening samples (i) potentially itch-inducing cytokines such IL-4, IL-17, IL-31, IL-33 ultrasensitive immunoassays single molecule array technology, (ii) autotaxin levels ELISA, (iii) 15 species liquid chromatography-tandem mass spectrometry performed. determinations correlated each other causal not. IL-31 turned elevated cytokine screened, which reacted (Supplemental Figure 1). Therefore, focus presented work directed cytokine. leads through activation IL-31-Oncostatin-M-specific receptor-subunit β heterodimer TRPA1-positive TRPV1-positive neurons. Serum diverse inflammatory conditions, diseases, metabolic dysfunction–associated steatohepatitis, PSC,9 dermatological disorders, atopic dermatitis, psoriasis, urticaria, all accompanied itch, diseases without accompanying allergic airway axial spondyloarthritis. question recently arose cause consequence itch: mouse model dermatitis displays scratching behavior nail clipping reduced levels, possibly due impaired ability damage skin barrier, implicating increased rather scratch activity.10 article, authors > 30-fold 161 completed 3-month period 50 age-, sex- weight-matched healthy controls, confirming others.9 They observed 3-fold cohort volunteers expected), mainly high normal range. correlation between shown (Figure interpretation, it would have desirable correlate plasma alkaline phosphatase activities established marker prognostic (noncirrhotic) had associated trial.5 then analyzed (5 impressive decrease -52% group months, different remarkable finding 2). Notably, farnesoid X discussed alternative second-line PPAR cholangiopathies—and obeticholic approved authorities (U.S. Food & Drug Administration, European Medicines Agency)—have stimulate formation parallel induction itch.9 third step, tried link baseline whole (n=161), although they otherwise focused their pruritus-related responsive (NRS 4).7,8 3A strong accumulation points lower left, considerable numbers intense very low scattering left area where localized. interesting see relied discussing seladelpar.7,8 validation 2B) even correlation. graphs raise some relevant 4) subgroup. Consequently, 3C "clinically relevant" 2) 11 55 (20.0%) placebo-treated 13 53 (24.5%) group, (18.9%) different. drug appears based presented. Supplemental paper there level conjugated unconjugated acids. increase during part explain difference. paper. Finally, confirms autotaxin, forms one pruritogen pruritus, lysophosphatidic acid,2 involved agonist-induced amelioration conclusion, presents clear evidence inhibitory pruritogenic while quite minor (21%) (NRC cohort. On basis results, remains unclear what extent pathophysiologically linked limited responded. From perspective, bezafibrate4–6 least first treatment, head-to-head comparisons lacking. If therapeutic studies, might conclude combined agonism pruritus.

Язык: Английский

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