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Hepatic processing of Z variant α-1-antitrypsin alters ERAD capacity to regulate cholesterol biosynthesis in a zebrafish model

ABSTRACT: Homozygosity for the Z allele of α1-antitrypsin (ZAAT) predisposes affected individuals to developing liver disease as the serpin misfolds and forms insoluble polymers that accumulate in the endoplasmic reticulum (ER) of hepatocytes, resulting in gain-of-function hepatotoxicity. This prevents secretion of ZAAT leading to serum insufficiency. A zebrafish model expressing human ZAAT in the liver shows no signs of hepatic accumulation despite displaying serum insufficiency, suggesting defect in ZAAT secretion occurs independently of its tendency to accumulate in hepatocytes. In this study, global transcriptomic approach was used to identify pathways activated and operating in the ZAAT-expressing zebrafish liver. The analysis provided strong evidence of suppressed Srebp2-mediated cholesterol biosynthesis. qPCR confirms this observation in the human liver cell line stably expressing ZAAT. We proposed that the engagement of misfolded ZAAT by the ER-associated degradation (ERAD) system inhibits the turnover of Srebp2-repressing elements therefore hindering the activation of Srebp2.

ORGANISM(S): Danio rerio

PROVIDER: GSE215899 | GEO | 2023/02/15

REPOSITORIES: GEO

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Hepatic processing of Z variant α-1-antitrypsin alters ERAD capacity to regulate cholesterol biosynthesis in a zebrafish model

Project description:Homozygosity for the Z allele of α1-antitrypsin (ZAAT) predisposes affected individuals to developing liver disease as the serpin misfolds and forms insoluble polymers that accumulate in the endoplasmic reticulum (ER) of hepatocytes, resulting in gain-of-function hepatotoxicity. This prevents secretion of ZAAT leading to serum insufficiency. A zebrafish model expressing human ZAAT in the liver shows no signs of hepatic accumulation despite displaying serum insufficiency, suggesting defect in ZAAT secretion occurs independently of its tendency to accumulate in hepatocytes. In this study, proteomic and transcriptomic analysis of the ZAAT-expressing zebrafish liver provided strong evidence of suppressed Srebp2-mediated cholesterol biosynthesis. qPCR confirms this observation in the human liver cell line stably expressing ZAAT. We proposed that the engagement of misfolded ZAAT by the ER-associated degradation (ERAD) system inhibits the turnover of Srebp2-repressing elements therefore hindering the activation of Srebp2. Protein quality control factors was manipulated to dissect the intracellular processing of ZAAT further mechanistically. Ablation of erlec1 resulted in a further suppression in the cholesterol biosynthesis pathway, confirming a role of this ER lectin in targeting misfolded ZAAT to ERAD. Deletion of the two ER mannosidase I homologs in zebrafish enhanced ZAAT secretion without inducing hepatic accumulation. Together, the present study provides novel insights into hepatic ZAAT processing and suggest potential therapeutic targets to improve ZAAT secretion and alleviate serum insufficiency in this form of α1-antitrypsin disease.

2023-03-10 | PXD036830 | Pride

Hepatic loss of Lis1 leads to fatty liver and predisposes to tumorigenesis in mice

Project description:We found that genetic deletion of Lis1 (also known as Pafah1b1) in mouse liver led to increased lipid accumulation and inflammation in the liver. Further analysis revealed that loss of Lis1 led to endoplasmic reticulum (ER) stress and reduced triglyceride secretion. Attenuation of ER stress by tauroursodeoxycholic acid (TUDCA) diminished lipid accumulation in the Lis1 defecient hepatocytes. In addition, Golgi was disorganized in Lis1 deficient livers. These mutants exhibited increased hepatocyte ploidy and accelerated development of liver cancer when treated with DEN. Taken together, these findings suggest that Lis1 is involved in the development and progression of liver diseases from steatosis to liver cancer and provide a useful model for delineating the molecular pathways that lead to these diseases.

2018-02-15 | GSE108096 | GEO

Hepatocytes cyclooxygenase-2 deficiency improves liver injury via inhibition of endoplasmic reticulum stress and epithelial-mesenchymal transition

Project description:The mechanism underlying the loss of normal liver tissues in liver cirrhosis, mainly hepatocytes, is not well-characterized. Endoplasmic reticulum (ER) stress-induced cell death has emerged as a potential mechanism for chronic liver diseases. We have previously demonstrated that cyclooxygenase-2 (COX-2) is closely related to the progress of liver cirrhosis. In this study, we aimed to verify whether hepatocytes COX-2 deficiency could protect liver injury via inducing ER stress in liver cirrhosis.

2024-04-28 | GSE183888 | GEO

Hepatic Sel1L-Hrd1 ER-Associated Degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH

Project description:Fibroblast growth factor 21 (Fgf21) is a liver-derived, fasting-induced hormone with broad effects on growth, nutrient metabolism and insulin sensitivity. Here, we report the discovery of a novel mechanism regulating Fgf21 expression under growth and fasting-feeding. The Sel1LHrd1 complex is the most conserved branch of mammalian endoplasmic reticulum (ER)- associated degradation (ERAD) machinery. Mice with liver-specific deletion of Sel1L exhibit growth retardation with markedly elevated circulating Fgf21, reaching levels close to those in Fgf21 transgenic mice or pharmacological models. Mechanistically, we show that the Sel1LHrd1 ERAD complex controls Fgf21 transcription by regulating the ubiquitination and turnover (and thus nuclear abundance) of ER-resident transcription factor Crebh, while having no effect on the other well-known Fgf21 transcription factor Pparα. Our data reveal a physiologically regulated, inverse correlation between Sel1L-Hrd1 ERAD and Crebh-Fgf21 levels under fasting-feeding and growth. This study not only establishes the importance of Sel1L-Hrd1 ERAD in the liver in the regulation of systemic energy metabolism, but also reveals a novel hepatic “ERADCrebh- Fgf21” axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation.

2018-08-17 | GSE118658 | GEO

Raf/MEK signatures in zebrafish liver cells

Project description:An inducible oncogenic cell line ZFL-ΔRaf1-ER was established, in which oncogenic human Raf-1(ΔRaf1) can be activated in zebrafish liver cells by administration of 4-hydroxytamoxifen (4HT). Transcriptional profilling of the ZFL-ΔRaf1-ER cells with and without administration of 4HT and/or the MEK inhibitor U0126 defined the gene signatures transcriptionally regulated by hyperactive Raf/MEK/MAPK signaling in zebrafish liver cells.

2011-07-07 | GSE29308 | GEO

Raf/MEK signatures in zebrafish liver cells

Project description:An inducible oncogenic cell line ZFL-?Raf1-ER was established, in which oncogenic human Raf-1(?Raf1) can be activated in zebrafish liver cells by administration of 4-hydroxytamoxifen (4HT). Transcriptional profilling of the ZFL-?Raf1-ER cells with and without administration of 4HT and/or the MEK inhibitor U0126 defined the gene signatures transcriptionally regulated by hyperactive Raf/MEK/MAPK signaling in zebrafish liver cells. The ZFL-?Raf1-ER cells were cultured in 12-well plates till confluence. Cell were starved for 4h in plain medium and susequently treated with or without 1µM 4HT and/or 30µM U0126 for 12h. Biological triplications were taken for each condition.

2011-07-07 | E-GEOD-29308 | biostudies-arrayexpress

Drug-induced hepatotoxicity screening in primary mouse hepatocytes, an Omics approach.

Project description:Drug-induced hepatotoxicity is a leading cause of attrition of candidate drugs in drug development. Therefore new screening methods are necessary which predict these hazards more accurate and earlier in the drug development process. Of all in vitro hepatotoxicity models, primary human hepatocytes are considered as 'the gold standard'. However, the use of these hepatocytes is hindered by their scarcity and major inter-individual variation. These limitations may be overcome with use of primary mouse hepatocytes. Within this context changes in protein expressions in primary mouse hepatocytes, after exposure to cyclosporin A were studied using differential gel electrophoresis. Thereafter, the mRNA expression levels of these deregulated proteins from cyclosporin A-treated cells were analyzed. Cyclosporin A induced ER stress and altered the ER-Golgi transport, which may alter vesicle mediated transport and protein secretion. Moreover are the differentially expressed proteins observed upon challenge by cyclosporin A, associated with cholestatic mechanisms. For each biological experiment, one hybridization was conducted and one sample per array. In total, 6 arrays were used for 2 different conditions (Csa or control at 48 hours).

2013-04-01 | E-GEOD-33742 | biostudies-arrayexpress

Intracellular labile iron is a key regulator of hepcidin expression and iron metabolism

Project description:Liver iron overload can induce hepatic expression of hepcidin and regulates iron metabolism. However, the mechanism of iron regulating iron metabolism remains known. Intracellular labile iron represents the nonferritin-bound, redox-active iron which is transitory and serves as a crossroad of cell iron metabolism. The role of intracellular labile iron played in iron metabolism has largely been elucidated. Here we show that intracellular labile iron of hepatocytes has dual function in iron metabolism. It can induce hepatocytes expressing hepcidin via ER stress induced transcription factors on the one hand, on the other hand stimulate BMP2 and BMP6 expression of liver sinusoidal endothelial cells (LSECs) though TNFα secreted by hepatocytes to further regulate iron metabolism. Blockade of TNFα could dysregulate the iron metabolism during iron overload. Our findings reveal the important role of intracellular labile iron in iron metabolism and represent a novel way to modulate iron metabolism during iron overload.

2023-05-03 | GSE186655 | GEO

Lack of de novo phosphatidylinositol synthesis leads to endoplasmic reticulum stress and hepatic steatosis in cdipt-deficient zebrafish

Project description:cdipt is an essential gene in the synthesis of phosphatidylinositol (PtdIns) in the zebrafish, Danio rerio. The zebrafish mutant cdipt^hi559Tg (ZL782) carries a retroviral insertion which inactivates cdipt. Homozygous mutants exhibit hepatocellular endoplasmic reticulum (ER) stress and non-alcoholic fatty liver disease (NAFLD) pathologies at 5 days post fertilization (dpf). This study reveals a novel link between PtdIns, ER stress, and steatosis.

2011-05-09 | GSE17711 | GEO

Sel1L is Indispensable for Mammalian ERAD, ER Homeostasis and Survival

Project description:Sel1L is an adaptor protein for the E3 ligase Hrd1 involved in endoplasmic reticulum-associated degradation (ERAD). Its physiological importance in mammalian ERAD, however, remains to be established. Here, using the inducible Sel1L knockout mouse and cell models, we provide the first in vivo evidence that Sel1L is indispensable for Hrd1 stability, ER homeostasis and survival. Acute loss of Sel1L leads to premature death in adult mice within 3 weeks with profound pancreatic atrophy. Contrary to current belief, our data show that mammalian Sel1L is required for Hrd1 stability and ERAD function both in vitro and in vivo. Sel1L deficiency disturbs ER homeostasis, activates ER stress, attenuates translation and promotes cell death. Serendipitously, using biochemical approach coupled with mass spectrometry, we found that Sel1L deficiency causes the aggregation of both small and large ribosomal subunits. Thus, Sel1L is an indispensable component of mammalian ERAD and ER homeostasis, which is essential for protein translation, pancreatic function, cellular and organismal survival.

2013-12-04 | GSE52929 | GEO

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