Transcriptomic profiling of a multiethnic pediatric NAFLD cohort reveals genes and pathways associated with disease

Yao, Kai; Tarabra, Elena; Sia, Daniela; Morotti, Raffaella; Fawaz, Rima; Valentino, Pamela L.; Santoro, Nicola; Caprio, Sonia; Liu, Silvia; Yimlamai, Dean

doi:10.1002/hep4.1940

Cited by 9 publications

(5 citation statements)

References 51 publications

(87 reference statements)

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“…In the context of liver fibrosis in MASLD, IGFBP7 contributes to fibrogenesis by playing a role in the activation and transdifferentiation of hepatic stellate cells 33 . Hepatic IGFBP7 expression was found to be consistently increased in advanced liver fibrosis, as observed in both pediatric and adult comparative cohorts 34 . Knockdown of IGFBP7 in a mouse model of MASLD resulted in a reduction of insulin resistance and hepatic steatosis 35 .…”

Section: Discussionmentioning

confidence: 73%

Development of a novel non-invasive biomarker panel for hepatic fibrosis in MASLD

Verschuren,

Mak,

van Koppen

et al. 2024

Nat Commun

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Accurate non-invasive biomarkers to diagnose metabolic dysfunction-associated steatotic liver disease (MASLD)-related fibrosis are urgently needed. This study applies a translational approach to develop a blood-based biomarker panel for fibrosis detection in MASLD. A molecular gene expression signature identified from a diet-induced MASLD mouse model (LDLr−/−.Leiden) is translated into human blood-based biomarkers based on liver biopsy transcriptomic profiles and protein levels in MASLD patient serum samples. The resulting biomarker panel consists of IGFBP7, SSc5D and Sema4D. LightGBM modeling using this panel demonstrates high accuracy in predicting MASLD fibrosis stage (F0/F1: AUC = 0.82; F2: AUC = 0.89; F3/F4: AUC = 0.87), which is replicated in an independent validation cohort. The overall accuracy of the model outperforms predictions by the existing markers Fib-4, APRI and FibroScan. In conclusion, here we show a disease mechanism-related blood-based biomarker panel with three biomarkers which is able to identify MASLD patients with mild or advanced hepatic fibrosis with high accuracy.

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Section: Discussionmentioning

confidence: 73%

Development of a novel non-invasive biomarker panel for hepatic fibrosis in MASLD

Verschuren,

Mak,

van Koppen

et al. 2024

Nat Commun

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“…179,180 IGFBP-7 has been shown to induce steatosis and fibrosis in rodents, with elevated levels being linked to advanced fibrosis in humans with NAFLD. [181][182][183][184] We systematically analyzed 266 biomarkers across two separate cohorts in Paper IV. Employing several statistical analyses, our primary focus was to identify the most robust biomarker candidates capable of discriminating between different fibrosis stages.…”

Section: Discussionmentioning

confidence: 99%

Non-Alcoholic Fatty Liver Disease : Insights into Alcohol Consumption, Genetics, and Proteomics

Blomdahl

2023

Linköping University Medical Dissertations

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NAFLD (Non-Alcoholic Fatty Liver Disease) affects approximately a quarter of the global population and is closely linked to type 2 diabetes mellitus and obesity. The disease spectrum ranges from steatosis and steatohepatitis to fibrosis, cirrhosis, and hepatocellular cancer. However, accurately predicting which patients will experience a progressive disease course remains a significant challenge. The variant gene of PNPLA3 is known to be associated with NAFLD and a more progressive disease, although its precise function remains unclear.Patients with NAFLD typically consume small to moderate amounts of alcohol, with recommended thresholds set at a maximum of 210 gram per week for males and 140 grams per week in females. However, the impact of alcohol consumption on liver disease in NAFLD remains disputed, with conflicting research findings.Liver biopsy is considered the gold standard for diagnosing NAFLD. However, due to its impracticality for such a large population with the condition, various non-invasive methods have been explored for diagnosing and evaluating NAFLD.This thesis aimed to investigate the potential effects of moderate alcohol consumption on NAFLD histology, explore the potential role of variant PNPLA3 in NAFLD, and assess the use of proteomics in classifying fibrosis.In Papers I and II, moderate alcohol consumption was assessed through questionnaires, clinical interviews, and measurement of the direct alcohol biomarker phosphatidylethanol (PEth). Paper I, a cross-sectional study including 86 participants, showed an association between moderate consumption and advanced fibrosis. Moderate consumption was defined as consuming more than 66 grams of ethanol per week or a PEth-value over 50 ng/mL. Notably, individuals with both moderate alcohol consumption and a diagnosis of type 2 diabetes exhibited significantly more advanced fibrosis. Paper II was a cohort study where 82 participants were followed over 17.2 years. Similarly, participants with moderate alcohol consumption displayed significant fibrosis progression. The strongest association was observed in participants with PEth-value of 48 ng/mL or higher, or those with binge drinking.In Paper III, the potential role of variant PNPLA3 was explored, exhibiting impaired autophagic flux and reduced lipophagy in variant PNPLA3 cells. Liver biopsies of NAFLD individuals with variant PNPLA3 displayed an accumulation of lipid droplets positive for both PNPLA3 and

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“…We obtained the RNA sequencing datasets of chicken and human liver samples from the sequence read archive database (https://www.ncbi.nlm.nih.gov/sra) ( Table-1 ) (Accession numbers GSE185051 [ 17 ] and GSE111909 [ 9 ] for humans and chickens, respectively). In detail, the chicken datasets were derived from biopsies of the first generation of Jingxing–Huang chickens (three birds with a fatty liver condition and three control birds) [ 9 ].…”

Section: Methodsmentioning

confidence: 99%

“…In detail, the chicken datasets were derived from biopsies of the first generation of Jingxing–Huang chickens (three birds with a fatty liver condition and three control birds) [ 9 ]. For human datasets, clinically indicated ultrasound-guided liver biopsies were collected from NAFLD patients (n = 15) and healthy candidates (n = 5) [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

Cross-species analysis of differential transcript usage in humans and chickens with fatty liver disease

Chokeshaiusaha,

Sananmuang,

Puthier

et al. 2023

Vet World

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Background and Aim: Fatty liver disease is a common condition, characterized by excess fat accumulation in the liver. It can contribute to more severe liver-related health issues, making it a critical concern in avian and human medicine. Apart from modifying the gene expression of liver cells, the disease also alters the expression of specific transcript isoforms, which might serve as new biological markers for both species. This study aimed to identify cross-species genes displaying differential expressions in their transcript isoforms in humans and chickens with fatty liver disease. Materials and Methods: We performed differential gene expression and differential transcript usage (DTU) analyses on messenger RNA datasets from the livers of both chickens and humans with fatty liver disease. Using appropriate cross-species gene identification methods, we reviewed the acquired candidate genes and their transcript isoforms to determine their potential role in fatty liver disease’s pathogenesis. Results: We identified seven genes - ALG5, BRD7, DIABLO, RSU1, SFXN5, STIMATE, TJP3, and VDAC2 - and their corresponding transcript isoforms as potential candidates (false discovery rate ≤0.05). Our findings showed that these genes most likely contribute to fatty disease development and progression. Conclusion: This study successfully identified novel human-chicken DTU genes in fatty liver disease. Further research is encouraged to verify the functions and regulations of these transcript isoforms as potential diagnostic markers for fatty liver disease in humans and chickens. Keywords: cross-species biomarkers, differential gene expression, differential transcript usage, fat metabolism, fatty liver disease, lipidosis, transcript isoforms.

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Transcriptomic profiling of a multiethnic pediatric NAFLD cohort reveals genes and pathways associated with disease

Cited by 9 publications

References 51 publications

Development of a novel non-invasive biomarker panel for hepatic fibrosis in MASLD

Development of a novel non-invasive biomarker panel for hepatic fibrosis in MASLD

Non-Alcoholic Fatty Liver Disease : Insights into Alcohol Consumption, Genetics, and Proteomics

Cross-species analysis of differential transcript usage in humans and chickens with fatty liver disease

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