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Roles of PKLR in NAFLD using loss- and gain-of-function mouse models

ABSTRACT: Roles of PKLR in NAFLD using loss- and gain-of-function mouse models

PROVIDER: PRJNA635078 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11849318_1.fastq.gz	Fastqsanger.gz
	SRR11849318_2.fastq.gz	Fastqsanger.gz
	SRR11849319_1.fastq.gz	Fastqsanger.gz
	SRR11849319_2.fastq.gz	Fastqsanger.gz
	SRR11849320_1.fastq.gz	Fastqsanger.gz

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Sex-specific roles of PKLR in NAFLD using gain-of-function mouse models

Project description:Sex-specific roles of PKLR in NAFLD using gain-of-function mouse models

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Roles of PKLR in NAFLD

Project description:Roles of PKLR in NAFLD

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Roles of PKLR in NAFLD using loss- and gain-of-function mouse models

Project description:The etiology of non-alcoholic fatty liver disease (NAFLD) is poorly understood, with males and Mexican population exhibiting markedly increased susceptibility. Using a systems genetics approach, involving multi-omic analysis of ~100 inbred strains, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these candidates, liver pyruvate kinase (L-PK or Pklr) in NAFLD using patient samples and mouse models. We examined L-PK expression in mice of both sexes and in a cohort of bariatric surgery patients. We used liver-specific loss- and gain-of-function strategies in independent animal models of diet-induced steatosis and fibrosis, involving both sexes. Following treatment, we measured several metabolic phenotypes associated with obesity, insulin resistance, dyslipidemia, liver steatosis and fibrosis. Furthermore, liver tissues were used for gene expression and western blots, and liver mitochondria for bioenergetics. Our results demonstrate that L-PK acts in a male-specific manner in the development of liver steatosis and fibrosis. Given that NAFLD/NASH exhibit sexual dimorphism, our results have important implications for the development of personalized therapeutics.

2021-01-19 | GSE151182 | GEO

Sex-specific roles of PKLR in NAFLD using gain-of-function mouse models

Project description:The etiology of non-alcoholic fatty liver disease (NAFLD) is poorly understood, with males and Mexican population exhibiting markedly increased susceptibility. Using a systems genetics approach, involving multi-omic analysis of ~100 inbred strains, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these candidates, liver pyruvate kinase (L-PK or Pklr) in NAFLD using patient samples and mouse models. We examined L-PK expression in mice of both sexes and in a cohort of bariatric surgery patients. We used liver-specific loss- and gain-of-function strategies in independent animal models of diet-induced steatosis and fibrosis, involving both sexes. Following treatment, we measured several metabolic phenotypes associated with obesity, insulin resistance, dyslipidemia, liver steatosis and fibrosis. Furthermore, liver tissues were used for gene expression and Western blots, and liver mitochondria for bioenergetics. Our results demonstrate that L-PK acts in a male-specific manner in the development of liver steatosis and fibrosis. Given that NAFLD/NASH exhibit sexual dimorphism, our results have important implications for the development of personalized therapeutics.

2021-01-19 | GSE157201 | GEO

Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning

Project description:Background & Aims Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver pathologies. However, not medical treatment has been approved for the disease so far. In our previous study, we found PKLR could be a potential target for treatment of NALFD. Here the aim is to investigate the effect of PKLR in in vivo model and reposition a drug which could be used for treatment of NAFLD. Results The Pklr KO reversed the increased hepatic triglyceride level in mice fed with high sucrose diet and partly recovered the transcriptomic changes in liver as well as other three tissues. Both liver and white adipose tissues exhibited dysregulated circadian transcriptomic profiles, and these dysregulations were reversed by hepatic knockout of Pklr. In addition, 10 small molecule drugs were identified as potential inhibitor of PKLR by the drug repositioning pipeline, and two of them significantly inhibited both the PKLR expression and triglyceride level in in vitro model. Finally, the two selected small molecule drugs were evaluated in in vivo rat models and it was demonstrated that these drugs attenuated hepatic steatosis without side effect on other tissues. Conclusion: In conclusion, our study provided biological insights about the critical role of PKLR in NAFLD progression and proposed a treatment strategy for NAFLD patients, which could be validated in further clinical trials.

2022-07-22 | GSE193627 | GEO

Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning

Project description:Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning

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Roles of PKLR in NAFLD

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-01-19 | GSE157203 | GEO

Gene expression profile of NAFLD murine models (Part2 - Microarrays)

Project description:In this project, the gene expression profiles of commonly used murine models of NAFLD were compared to two publically available human datasets to assess proximity to human pathophysiology, focusing on differential expression and pathway enrichment. CCL4 was used as a positive control for fibrosis.

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Gene expression profile of NAFLD murine models (Part1 - NGS)

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Gene expression profile of NAFLD murine models (Part1 - NGS)

Project description:Gene expression profile of NAFLD murine models (Part1 - NGS)

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