PNPLA3 as a driver of steatotic liver disease: navigating from pathobiology to the clinics via epidemiology DOI Open Access
Ralf Weiskirchen, Amedeo Lonardo

Journal of Translational Genetics and Genomics, Год журнала: 2024, Номер 8(4), С. 355 - 77

Опубликована: Дек. 7, 2024

Steatotic liver disease (SLD), particularly metabolic dysfunction-associated SLD, represents a significant public health concern worldwide. Among the various factors implicated in development and progression of this condition, patatin-like phospholipase domain-containing protein 3 (PNPLA3 ) gene has emerged as critical player. Variants PNPLA3 are associated with altered lipid metabolism, leading to increased hepatic fat accumulation subsequent inflammation fibrosis. Understanding role not only enhances our comprehension pathomechanisms driving SLD but also informs potential therapeutic strategies. The molecular mechanisms through which variants contribute dysregulation hepatocyte injury critically discussed present review article. We extensively analyze clinical cohorts population-based studies underpinning association between polymorphisms risk developing its liver-related protean extrahepatic outcomes, concert other modifiers, notably including age, sex, ethnicity adults children. discuss increasingly recognized played by transplantation, autoimmune hepatitis, acquired immunodeficiency syndrome. Finally, we examine implications diagnostics regarding stratification targeted therapies for patients affected context precision medicine approaches.

Язык: Английский

Impact of PNPLA3 I148M on Clinical Outcomes in Patients With MASLD DOI Creative Commons
Salvatore Petta, Angelo Armandi, Elisabetta Bugianesi

и другие.

Liver International, Год журнала: 2024, Номер unknown

Опубликована: Окт. 16, 2024

ABSTRACT Background and Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a heterogenous clinical histopathological entity, where multiple metabolic co‐factors are intertwined with high interindividual variability. The impact severity of each factor (including obesity type 2 diabetes) define systemic dysmetabolism that can lead to either advanced its complication hepatocellular carcinoma events related portal hypertension) or extrahepatic events: incident cardiovascular disease, chronic kidney cancers. balance between environmental factors genetic susceptibility has unique implications in MASLD: the intermittent injury co‐factors, their fluctuation over time specific management, counterbalanced by presence gene variants significantly at levels. I148M variant PNPLA3 most investigated induces more severe steatohepatitis, enhanced fibrogenesis shape incidence long‐term regardless of, worsened by, other risk factors. Methods Results In this review, we will summarise updated evidence on natural history MASLD accounting for classical factors, role sub‐phenotyping (e.g., ‘lean MASLD’), fibrosis progression, as well prognostication, alone combination non‐invasive tools into polygenic scores.

Язык: Английский

Процитировано

9
Human genetics of metabolic dysfunction–associated steatotic liver disease: from variants to cause to precision treatment DOI Creative Commons
Vincent Chen, Annapurna Kuppa, Antonino Oliveri

и другие.

Journal of Clinical Investigation, Год журнала: 2025, Номер 135(7)

Опубликована: Март 31, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic and a leading cause of advanced disease. We review here the genetic basis MASLD. The variants most consistently associated implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, mitochondrial/ER biology. distinct mechanisms which these promote result effects on that may be best suited to precision medicine. Recent work gene-environment interactions has shown risk not fixed exacerbated attenuated modifiable (diet, exercise, alcohol intake) nonmodifiable environmental factors. Some steatosis-associated variants, notably those patatin-like phospholipase domain-containing 3 (PNPLA3) transmembrane 6 superfamily member 2 (TM6SF2), are developing adverse liver-related outcomes provide information beyond clinical stratification tools, especially individuals at intermediate high for Future better characterize heterogeneity combining genetics factors holistically predict develop therapies based required.

Язык: Английский

Процитировано

1
High inherited risk predicts age-associated increases in fibrosis in patients with MASLD DOI
Luis Antonio Díaz, William Alazawi, Saaket Agrawal

и другие.

Journal of Hepatology, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

1
Integrating PNPLA3 into clinical risk prediction DOI Creative Commons
Vincent Chen, Umberto Vespasiani‐Gentilucci

Liver International, Год журнала: 2024, Номер unknown

Опубликована: Сен. 16, 2024

Abstract The PNPLA3 ‐rs738409‐G variant was the first common associated with hepatic fat accumulation and progression of metabolic dysfunction‐associated steatotic liver disease (MASLD). Nevertheless, to date, clinical translation this discovery has been minimal because it not yet clearly demonstrated where genetic information may play an independent additional role in risk prediction. In mini‐review, we will discuss most relevant evidence regarding potential integration into scores algorithms for diagnostics stratification, specifically focusing on MASLD but also extending diseases other etiologies. adds little diagnosing current state disease, whether terms presence/absence steatohepatitis or stage fibrosis. While can important prediction, allowing early definition profiles that enable tailored monitoring interventions over time, is valuable when applied populations relatively high pre‐test probability having significant fibrosis based either non‐invasive tests (e.g. Fibrosis‐4) demographics diabetes). Indeed, context, integrating FIB4 genotype refine though there still no stiffness determined by elastography. Similarly, patients known cirrhosis, knowing a predicting hepatocellular carcinoma, while more doubts remain about decompensation.

Язык: Английский

Процитировано

3
Updated recommendations for the management of metabolic dysfunction–associated steatotic liver disease (MASLD) by the Latin American working group. DOI Creative Commons
Luis Antonio Díaz,

Juan Pablo Arab,

Francisco Idalsoaga

и другие.

Annals of Hepatology, Год журнала: 2025, Номер unknown, С. 101903 - 101903

Опубликована: Март 1, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading causes chronic globally. Based on 2023 definition, MASLD characterized by presence metabolic dysfunction and limited alcohol consumption (<140 grams/week for women, <210 men). Given significant burden in Latin America, this guidance was developed American Association Study Liver (ALEH) Working Group to address key aspects its clinical assessment therapeutic strategies. In ultrasonography recommended as initial screening tool hepatic steatosis due accessibility, while Fibrosis-4 (FIB-4) preferred fibrosis risk stratification, with further evaluation using more specific techniques (i.e., vibration-controlled transient elastography or Enhanced Fibrosis [ELF] test). A Mediterranean diet advised all patients, a target 7-10% weight loss those excess weight. Complete abstinence patients fibrosis, smoking cessation encouraged regardless stage. Pharmacological options should be tailored based steatohepatitis, weight, diabetes, including resmetirom, incretin-based therapies, pioglitazone, sodium-glucose cotransporter-2 inhibitors. Bariatric surgery may considered obesity unresponsive lifestyle medical interventions. Hepatocellular carcinoma cirrhotic consideration given advanced individual risk. Finally, routine cardiovascular proper diabetes prevention management remain crucial MASLD.

Язык: Английский

Процитировано

0
Advancing precision medicine in metabolic dysfunction-associated steatotic liver disease DOI
Bryan Adrián Priego-Parra, Rocío Gallego‐Durán, Berenice M Román-Calleja

и другие.

Trends in Endocrinology and Metabolism, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0
Polygenic Risk Score for Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis: A Narrative Review DOI Open Access
Tatsuo Kanda, Reina Sasaki, Hiroyuki Abé

и другие.

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(11), С. 5164 - 5164

Опубликована: Май 28, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic steatohepatitis (MASH) are spreading worldwide as the most critical causes of cirrhosis hepatocellular carcinoma (HCC). Thus, improving screening managing strategies for patients with MASLD or MASH is necessary. A traditional non-systemic review provided this narrative. Genetic variations associated development MASH, such PNPLA3, TM6SF2, GCKR, MBOAT7, MERTK, HSD17B13, were initially reviewed. PNPLA3 genetic variants appeared to be strongly increased pathogenesis MASLD, cirrhosis, HCC. We also reviewed useful polygenic risk score (PRS) their related occurrence PRSs better predictors HCC in than any single-nucleotide polymorphisms. RNA interference antisense nucleotides against HSD17B13 being developed. Multidisciplinary collaboration cooperation involving hepatologists, geneticists, pharmacologists, pathologists should resolve complicated problems MASH. This narrative highlights importance susceptibility PRS predictive markers personalized medicine future.

Язык: Английский

Процитировано

0
Targeting PNPLA3 to Treat MASH and MASH Related Fibrosis and Cirrhosis DOI Creative Commons
Daniel Lindén, Gregory J. Tesz, Rohit Loomba

и другие.

Liver International, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 28, 2024

ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) is caused by metabolic triggers and genetic predisposition. Among the MASLD risk variants identified today, common PNPLA3 148M variant exerts largest effect size of heritability. The protein causatively linked to development steatosis, inflammation fibrosis in experimental studies therefore an appealing target for therapeutic approaches treat this disease. Several targeted are currently being evaluated clinical trials treatment steatohepatitis (MASH), most severe form promising proof principle data with reduced fat content homozygous allele carriers has been reported from phase 1 following hepatic silencing . Thus, targeting PNPLA3, strongest determinant MASH may hold promise as first precision medicine A histological endpoint‐based 2b study initiated several more expected be evaluate effects on participants variant. scope mini‐review briefly describe genetics, function preclinical evidence well summarise based therapies development.

Язык: Английский

Процитировано

2
Editorial: Genetics for non‐invasive risk stratification—Finding the needle in the haystack? DOI
Vincent Chen

Alimentary Pharmacology & Therapeutics, Год журнала: 2024, Номер 60(3), С. 407 - 408

Опубликована: Июнь 25, 2024

LINKED CONTENT This article is linked to Bridi et al papers. To view these articles, visit https://doi.org/10.1111/apt.18099 and https://doi.org/10.1111/apt.18129

Язык: Английский

Процитировано

1
Editorial: Genetics for noninvasive risk stratification—Finding the needle in the haystack: Authors' reply DOI Open Access

Lana Bridi,

Veeral Ajmera

Alimentary Pharmacology & Therapeutics, Год журнала: 2024, Номер 60(3), С. 409 - 410

Опубликована: Июнь 25, 2024

LINKED CONTENT This article is linked to Bridi et al papers. To view these articles, visit https://doi.org/10.1111/apt.18099 and https://doi.org/10.1111/apt.18123

Язык: Английский

Процитировано

0