Impaired protein tyrosine phosphatase delta is a driver of hepatic metabolic syndrome
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA633851 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11811983.fastq.gz | Fastqsanger.gz | |||
| SRR11811984.fastq.gz | Fastqsanger.gz | |||
| SRR11811985.fastq.gz | Fastqsanger.gz | |||
| SRR11811986.fastq.gz | Fastqsanger.gz | |||
| SRR11811987.fastq.gz | Fastqsanger.gz |
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Project description:Background & Aims: The protein tyrosine phosphatase delta (PTPRD) is suppressed in several diseases including cancers and hepatitis C virus (HCV) infection. To identify hepatic pathways responsive to PTPRD function and their role in liver disease, we analyzed liver transcriptomic and clinical data from patients and established a Ptprd-deficient liver disease mouse model. Methods: Based on liver transcriptomic data, healthy patients were classified according to PTPRD expression and gene set enrichment analysis (GSEA) was performed to identify signaling pathways associated with low PTPRD expression. We established a liver disease mouse model combining impaired PTPRD expression (Ptprd+/-) and high-fat diet to assess its impact on liver transcriptomics and hepatic metabolism. Identified pathways were validated by perturbation studies in primary human hepatocytes. The clinical relevance was validated in a cohort of patients with fatty liver disease by ranking of individuals according to hepatic PTPRD expression prior analyzing the association with metabolic disease markers. Results: In healthy individuals and Ptprd+/- mice fed with normal diet, low PTPRD levels associated with a gene expression pattern involved in glucose/lipid metabolism in the liver. During diet-induced liver disease, low hepatic PTPRD led to increased blood glucose and hepatic lipid levels in the Ptprd+/- animals. Moreover, Ptprd+/- animals exhibited a pronounced unfolded protein response, which has a potential impact on hepatic insulin signaling. Indeed, silencing of PTPRD in PHH blunted the insulin-induced AKT phosphorylation. Accordingly, obese patients with low hepatic PTPRD expression exhibit increased levels of clinical markers associated with metabolic disease. Conclusion: Our data suggests an important regulatory role of hepatic PTPRD in maintaining glucose/lipid homeostasis and how its impaired expression is associated with clinical manifestations of metabolic disease.
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Project description:Background & Aims: Protein tyrosine phosphatase delta (PTPRD) is suppressed in several diseases including HCV infection. To identify hepatic pathways responsive to PTPRD function and their role in non-viral liver disease, we analyzed liver transcriptomic and clinical data from patients and established a Ptprd-deficient liver disease mouse model. Methods: Healthy patients were classified according to hepatic PTPRD expression and transcriptomic analysis was performed to identify signaling pathways associated with low PTPRD levels. We combined an animal model for metabolic dysfunction-associated steatohepatitis (MASH) with genetically impaired PTPRD expression (Ptprd+/-) to assess its impact on the liver transcriptome and metabolic function. Identified pathways were validated by perturbation studies in primary human hepatocytes and differentiated HepaRG cells. Substrate specificity was validated by pull-down assay. The clinical relevance was explored in a cohort of patients with fatty liver disease by ranking individuals according to hepatic PTPRD expression and analyzing its association with metabolic disease markers. Results: In healthy individuals and Ptprd+/- mice, PTPRD levels associated with hepatic glucose/lipid metabolism and peroxisomal function. Hepatic PTPRD expression is impaired in metabolic liver disease. Moreover, we revealed PTPRD as a STAT3 phosphatase in the liver, which is a regulator of peroxisomal function. Silencing of STAT3 in HepaRG cells treated with free-fatty acids was able to rescue the expression of genes implicated in lipid metabolism. During MASH, low hepatic PTPRD led to increased liver steatosis in the Ptprd+/- animals and pronounced unfolded protein response, which impacts insulin signaling. Silencing of PTPRD in PHH blunted insulin-induced AKT phosphorylation. In line with this, obese patients with low hepatic PTPRD expression exhibit increased levels of clinical markers associated with metabolic disease. Conclusion: Our data suggest an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis and how its impaired expression is associated with clinical manifestations of metabolic liver disease.
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Project description:Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease (HepaRG cells).
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