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, Journal Year: 2024, Volume and Issue: 8(4), P. 355 - 77

Published: Dec. 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.

Language: Английский

Sexual dimorphism of metabolic dysfunction-associated steatotic liver disease DOI
Alessandro Cherubini,

Sara Della Torre,

Serena Pelusi

et al.

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Language: Английский

Citations

20
Validation of microphysiological systems for interpreting patient heterogeneity requires robust reproducibility analytics and experimental metadata DOI Creative Commons
Mark T. Miedel, Mahboubeh Varmazyad, Mengying Xia

et al.

Cell Reports Methods, Journal Year: 2025, Volume and Issue: unknown, P. 101028 - 101028

Published: April 1, 2025

Multi-cell-type, 3D microphysiological systems (MPS) that recapitulate normal organ/organ system functions and the progression of diseases are being applied in drug discovery development programs to enable precision medicine. A critical step for this application is demonstrate reproducibility MPS its ability identify biologic/clinical heterogeneity from experimental variability, which requires capturing detailed metadata associated with studies as well a strong analytical approach assessing reproducibility. Detailed ensure identical study parameters compared when evaluating We have developed Pittsburgh protocol (PReP), uses set common statistical metrics, coefficient variation (CV), ANOVA, intraclass correlation (ICC), pipeline standard evaluate intra- interstudy performance. The PReP can be employed biological/clinical relevant

Language: Английский

Citations

0
A metabolic dysfunction-associated steatotic liver acinus biomimetic induces pancreatic islet dysfunction in a coupled microphysiology system DOI Creative Commons
Julio Aleman,

K. Ravikumar,

Connor Wiegand

et al.

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Oct. 14, 2024

Preclinical and clinical studies suggest that lipid-induced hepatic insulin resistance is a primary defect predisposes to dysfunction in islets, implicating perturbed liver-pancreas axis underlying the comorbidity of T2DM MASLD. To investigate this hypothesis, we developed human biomimetic microphysiological system (MPS) coupling our vascularized liver acinus MPS (vLAMPS) with pancreatic islet (PANIS) enabling MASLD progression be assessed. The modular design (vLAMPS-PANIS) allows intra-organ inter-organ dysregulation deconvoluted. When compared normal fasting (NF) conditions, under early metabolic syndrome (EMS) standalone vLAMPS exhibited characteristics stage MASLD, while no significant differences were observed PANIS. In contrast, EMS, coupled vLAMPS-PANIS islet-specific secretome significantly dysregulated glucose stimulated secretion response direct signaling from islets. Correlations between several pairs vLAMPS-derived PANIS-derived factors altered as NF mechanistically connecting associated hepatic-factors islet-derived GLP-1 synthesis regulation. Since compatible patient-specific iPSCs, platform represents an important step towards addressing patient heterogeneity, identifying disease mechanisms, advancing precision medicine. A liver-islet was used T2DM. This study demonstrated secreted disrupt function potential mechanisms along axis.

Language: Английский

Citations

1
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, Journal Year: 2024, Volume and Issue: 8(4), P. 355 - 77

Published: Dec. 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.

Language: Английский

Citations

0