Hepatocyte mARC1 Promotes Fatty Liver Disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA936801 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23539353_1.fastq.gz | Fastqsanger.gz | |||
| SRR23539353_2.fastq.gz | Fastqsanger.gz | |||
| SRR23539354_1.fastq.gz | Fastqsanger.gz | |||
| SRR23539354_2.fastq.gz | Fastqsanger.gz | |||
| SRR23539355_1.fastq.gz | Fastqsanger.gz |
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Project description:Hepatocyte mARC1 Promotes Fatty Liver Disease
| PRJNA927038 | ENA
Project description:Background and Aims Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ~25% worldwide, with significant public health consequences yet has few effective treatments. Human genetics can help elucidate novel biology and identify targets of new therapeutics. Genetic variants in mitochondrial amidoxime reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality, however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with in vitro and in vivo studies of mARC1 knockdown. Methods Analyses including multi-trait colocalization and Mendelian randomization were used to assess the genetic associations of MTARC1. In addition, we established an in vitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra GAN diet NASH mouse model treated with hepatocyte specific GalNAc-siRNA to understand the in vivo impacts of MTARC1. Results We show that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids and body composition and these associations are due to the same causal variant (p.A165T, rs2642438 G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian Randomization, implying therapeutic inhibition of mARC1 could be beneficial. In vitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion and in vivo GalNAc-siRNA mediated knockdown of mARC1 lowered hepatic, but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown in vitro and in vivo. Conclusions Collectively, our findings from human genetics, and in vitro and in vivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD.
2023-04-01 | GSE223652 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ~25% worldwide, with significant public health consequences, yet few effective treatments. Human genetics can help elucidate novel biology and identify targets of new therapeutics. Genetic variants in mitochondrial amidoxime reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality, however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with in vitro and in vivo studies of mARC1 knockdown. Methods: Analyses including multi-trait colocalization and mendelian randomization were used to assess the genetic associations of MTARC1. In addition, we established an in vitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra GAN-diet NASH mouse model treated with hepatocyte specific GalNAc-siRNA to understand the in vivo impacts of MTARC1. Results: We show that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids and body composition and these associations are due to the same causal variant (p.A165T, rs2642438 G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian Randomization, implying therapeutic inhibition of mARC1 could be beneficial. In vitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion and in vivo GalNAc-siRNA mediated knockdown of mARC1 lowered hepatic, but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown in vitro and in vivo. Conclusions: Collectively, our findings from human genetics, and in vitro and in vivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD.
2023-02-20 | GSE225616 | GEO
Project description: Not available
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Project description:Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease
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Project description:Macrophage-derived thrombospondin1 promotes obesity-associated non-alcoholic fatty liver disease
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Project description:Human genome-wide association studies (GWAS) of metabolic-associated steatohepatitis (MASH), the most common liver disease worldwide, have examined either liver injury biomarkers or liver fat content, with lipid metabolism enzymes ranked highly in both analyses. Here, to define pathophysiological pathways independent of lipid metabolism, we focused on a gene of unknown function found in liver biomarker but not liver fat GWAS, EF-Hand Domain Family Member D1 (EFHD1). We now identify EFHD1 as the factor transducing endoplasmic reticulum calcium (Ca2+) release into a mitochondrial fission signal. Mechanistically, EFHD1 ablation prevented Ca2+-dependent actin rearrangements that support fission. Moreover, EFHD1 was critical for increased hepatocyte mitochondrial fission noted during MASH, and promoted cytoplasmic release of mitochondrial double-stranded RNA, a damage-associated molecular pattern driving an integrated stress response and injury via the protein kinase PKR. Finally, acutely inhibiting EFHD1 in mice developing MASH did not substantially alter steatosis but blunted hepatocyte injury, inflammation, and fibrosis.
2026-07-30 | PXD069152 | Pride
Project description:Growth hormone signaling in hepatocytes is fundamentally important. Disruptions in this pathway have led to fatty liver and other metabolic abnormalities. Growth hormone signals through the JAK2/STAT5 pathway. Mice with hepatocyte specific deletion of STAT5 were previously shown to develop fatty liver. Our aim in this study was to determine the effect of deleting JAK2 in hepatocytes on liver gene expression. To do so, we generated animals with hepatocyte specific deletion of JAK2. Hepatocyte-specific JAK2-deficient mice (JAK2L) were generated by mating floxed JAK2 mice (in a mixed (C57Bl/6:129Sv) background) to mice carrying an Alb promoter-regulated Cre transgene on a 100% C57Bl/6 background purchased from the Jackson Labs. Livers were harvested from 8 week old animals for RNA extraction and hybridization.
2011-04-30 | E-GEOD-26188 | biostudies-arrayexpress
Project description:Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD+-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. Here we demonstrate that hepatic SIRT1 regulates fatty acid metabolism by positively regulating PPAR-alpha. Hepatocyte-specific deletion of SIRT1 impairs PPAR-alpha signaling and decreased fatty acid beta-oxidation in the liver. When challenged with a high-fat diet, liver-specific SIRT1 knockout mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress. Taken together, our data indicate that SIRT1 plays a vital role in the regulation of hepatic lipid homeostasis.
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