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Hepatocyte-specific Angiotensinogen Deficiency Inhibits Western Diet-induced Liver Steatosis With Suppression of Cell Division in Mice

ABSTRACT: Hepatocyte-specific Angiotensinogen Deficiency Inhibits Western Diet-induced Liver Steatosis With Suppression of Cell Division in Mice

PROVIDER: PRJNA1231527 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32569745_1.fastq.gz	Fastqsanger.gz
	SRR32569745_2.fastq.gz	Fastqsanger.gz
	SRR32569746_1.fastq.gz	Fastqsanger.gz
	SRR32569746_2.fastq.gz	Fastqsanger.gz
	SRR32569747_1.fastq.gz	Fastqsanger.gz

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Hepatocyte-specific Angiotensinogen Deficiency Inhibits Western Diet-induced Liver Steatosis With Suppression of Cell Division in Mice

Project description:Liver steatosis is a common cause of chronic liver disease. To investigate the molecular basis of hepatic steatosis, low-density lipoprotein receptor-deficient (LDLR -/-) mice were fed Western diet (WD, 42% of calories from fat) for 5, 14, or 42 days and evaluated against mice fed a normal laboratory diet. Histological analyses revealed that steatosis was detected as early as 14 days of WD feeding. Bulk RNA sequencing demonstrated that WD feeding altered liver transcriptomes related to inflammation and cell adhesion consistent with the progression of liver steatosis. Previous studies determined that hepatocyte-specific deficiency of angiotensinogen (AGT), the unique substrate of the renin-angiotensin system (RAS), alleviates WD-induced hepatic steatosis in mice. However, the effects of hepatic AGT deficiency were not mimicked by pharmacological inhibition of the RAS, and the molecular mechanisms by which AGT deficiency protects against WD-induced steatosis is unknown. Therefore, liver transcriptomes were compared between hepatocyte-specific AGT deficient mice (hepAGT -/-) and their wild-type littermates (hepAGT +/+) after 14 days of WD feeding. Gene ontology analyses showed that upregulated genes in hepAGT -/- mice were enriched for metabolic processes and downregulated genes were enriched for cell division pathways. The integration analysis of the two RNA sequencing data identified 5 key genes, Smpd3, Dtl, Cdc6, Mki67, and Top2a, which were primarily associated with cell division processes in hepAGT +/+ mice and were suppressed in hepAGT -/- mice. In conclusion, hepatic AGT deficiency downregulated genes related to cell division during the progression of liver steatosis.

2025-05-29 | GSE291082 | GEO

Alterations in the hepatocyte epigenetic landscape in steatosis

Project description:Alterations in the hepatocyte epigenetic landscape in steatosis

| PRJNA967364 | ENA

Angiotensinogen in hepatocytes contributes to Western diet-induced liver steatosis.

Project description:Nonalcoholic fatty liver disease (NAFLD) is considered as a liver manifestation of metabolic disorders. Previous studies indicate that the renin-angiotensin system (RAS) plays a complex role in NAFLD. As the only precursor of the RAS, decreased angiotensinogen (AGT) profoundly impacts RAS bioactivity. Here, we investigated the role of hepatocyte-derived AGT in liver steatosis. AGT floxed mice (hepAGT+/+) and hepatocyte-specific AGT-deficient mice (hepAGT-/-) were fed a Western diet and a normal laboratory diet for 12 weeks, respectively. Compared with hepAGT+/+ mice, Western diet-fed hepAGT-/- mice gained less body weight with improved insulin sensitivity. The attenuated severity of liver steatosis in hepAGT-/- mice was evidenced by histologic changes and reduced intrahepatic triglycerides. The abundance of SREBP1 and its downstream molecules, acetyl-CoA carboxylase and FASN, was suppressed in hepAGT-/- mice. Furthermore, serum derived from hepAGT+/+ mice stimulated hepatocyte SREBP1 expression, which could be diminished by protein kinase B (Akt)/mammalian target of rapamycin (mTOR) inhibition in vitro. Administration of losartan did not affect diet-induced body weight gain, liver steatosis severity, and hepatic p-Akt, p-mTOR, and SREBP1 protein abundance in hepAGT+/+ mice. These data suggest that attenuation of Western diet-induced liver steatosis in hepAGT-/- mice is associated with the alternation of the Akt/mTOR/SREBP-1c pathway.

| S-EPMC6889717 | biostudies-literature

Hepatocyte Deletion of Triglyceride-Synthesis Enzyme DGAT2 Reduces Steatosis without Increasing Inflammation or Fibrosis

Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation in hepatocytes and reprepresents a huge public health problem owing to its propensity to progress to non-alcoholic steatohepatitis (NASH), fibrosis, and liver failure. The lipids stored in hepatic steatosis are primarily triglycerides (TGs) synthesized by two acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes. Either DGAT1 or DGAT2 catalyzes this reaction, and these enzymes have been suggested to differentially utilize exogenous or endogenously synthesized fatty acids, with DGAT2 being linked to storage of fatty acids from de novo lipogenesis, a process that is increased in NAFLD. However, whether DGAT2 is more responsible for lipid accumulation in NAFLD and the progression to fibrosis is currently unknown. Also, it is unresolved whether DGAT2 can be safely inhibited as a therapy for NAFLD. Here we induced NAFLD-like disease in mice by feeding a diet rich in fructose, saturated fat, and cholesterol and found that hepatocyte-specfici Dgat2 deficiency reduced expression of de novo lipogenesis genes and lowered liver TGs by ~70%. Importantly, the reduction of steatosis was not accompanied by increased inflammation or fibrosis, and insulin and glucose metabolism were unchanged. Conclusion: This study suggests that hepatic DGAT2 deficiency successfully reduced diet-induced hepatic steatosis and supports the development of DGAT2 inhibitors as a therapeutic strategy for treating NAFLD and preventing downstream consequences.

2020-05-26 | PXD013423 | Pride

Wnt Signaling Regulates Hepatocyte Cell Division by a Transcriptional Repressor Cascade

Project description:Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition, allowing cells to divide. In several tissues including the liver, cell proliferation is inhibited at mitosis by the transcriptional repressors E2F7 and E2F8, leading to formation of polyploid cells. Whether growth factors promote mitosis and cell cycle progression by relieving the E2F7/E2F8-mediated inhibition is unknown. We report here on a new mechanism of cell division control in the postnatal liver, in which Wnt/βcatenin signaling maintains active hepatocyte cell division through Tbx3, a Wnt target gene. Tbx3 directly represses transcription of E2F7 and E2F8, thereby promoting mitosis. This cascade of sequential transcriptional repressors, initiated by Wnt signals, provides a new paradigm for exploring how commonly active developmental signals impact cell cycle completion.

2022-07-02 | GSE205339 | GEO

Loss of hepatocyte cell division leads to liver inflammation and fibrosis

Project description:Loss of hepatocyte cell division leads to liver inflammation and fibrosis

| PRJNA669058 | ENA

Wnt Signaling Regulates Hepatocyte Cell Division by a Transcriptional Repressor Cascade

Project description:Wnt Signaling Regulates Hepatocyte Cell Division by a Transcriptional Repressor Cascade

| PRJNA844408 | ENA

Adult-onset loss of hepatocyte growth hormone receptor (GHR) signaling increases steatosis, associated with enhanced glucokinase activity, de novo lipogenesis (DNL) and pathway selective hepatic insulin resistance

Project description:RNA-seq analysis of livers from control mice, mice with adult onset, hepatocyte-specific GH receptor (GHR) deficiency, and GHR-deficient mice combined with IGF1 expression or expression of constitutively active ('CA') STAT5b. This dataset is part of a large study showing that adult-onset loss of hepatocyte GHR signaling increases steatosis, associated with enhanced glucokinase activity, de novo lipogenesis (DNL) and pathway selective hepatic insulin resistance.

2023-08-21 | GSE222513 | GEO

Mouse purified hepatocyte secretome iTRAQ LC/MS

Project description:This study tests whether hepatic steatosis, independent of inflammation, alters the hepatocyte protein secretory profile, and examines whether changes in the secretory products contribute to the development of metabolic dysfunction in other cell types. Mouse hepatocytes were isolated by flow cytometry and cultured in serum-free conditions. Conditioned media was used for LC/MS analysis to compare hepatocytes from chow fed animals to high-fat diet animals with liver steatosis.

2018-03-14 | PXD002858 | Pride

Genome-wide analysis of gene expression in white adipose tissue in angiotensinogen overexpression transgenic and wild type male B6 mice

Project description:Investigation of differential gene regulation with overexpression of angiotensinogen in white adipose tissue. We hypothesized that angiotensinogen overexpression will disrupt metabolic homeostasis of adipocytes leading to obesity and related chronic diseases. Results indicate that angiotensinogen overexpression differentially regulate genes related metabolic functions in adipose tissue.

2020-07-15 | GSE149231 | GEO

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