Molecular and ultrastructure study of endoplasmic reticulum stress in hepatic steatosis: role of hepatocyte nuclear factor 4α and inflammatory mediators

El-Khair, Salwa M Abo; Ghoneim, Fatma M; Shabaan, Dalia A.; Elsamanoudy, Ayman Z.

doi:10.1007/s00418-019-01823-2

Cited by 14 publications

(7 citation statements)

References 62 publications

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“…The effect of inflammatory signaling on HNF4α expression and function is not completely clear, but previous studies show that proinflammatory cytokines may decrease HNF4α activity, which is consistent with this observation. [25,26] Most important, patients who were able to maintain higher HNF4α activity had significantly higher survival. This was also observed in the case of LC, where a subset of patients with higher HNF4α function had better outcomes in all disease endpoints, including decompensation, development of HCC, and survival.…”

Section: Discussionmentioning

confidence: 99%

Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans

et al. 2022

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Background and Aims Hepatocyte nuclear factor 4 alpha (HNF4α) is indispensable for hepatocyte differentiation and critical for maintaining liver health. Here, we demonstrate that loss of HNF4α activity is a crucial step in the pathogenesis of chronic liver diseases (CLDs) that lead to development of HCC. Approach and Results We developed an HNF4α target gene signature, which can accurately determine HNF4α activity, and performed an exhaustive in silico analysis using hierarchical and K‐means clustering, survival, and rank‐order analysis of 30 independent data sets containing over 3500 individual samples. The association of changes in HNF4α activity to CLD progression of various etiologies, including HCV‐ and HBV‐induced liver cirrhosis (LC), NAFLD/NASH, and HCC, was determined. Results revealed a step‐wise reduction in HNF4α activity with each progressive stage of pathogenesis. Cluster analysis of LC gene expression data sets using the HNF4α signature showed that loss of HNF4α activity was associated with progression of Child‐Pugh class, faster decompensation, incidence of HCC, and lower survival with and without HCC. A moderate decrease in HNF4α activity was observed in NAFLD from normal liver, but a further significant decline was observed in patients from NAFLD to NASH. In HCC, loss of HNF4α activity was associated with advanced disease, increased inflammatory changes, portal vein thrombosis, and substantially lower survival. Conclusions In conclusion, these data indicate that loss of HNF4α function is a common event in the pathogenesis of CLDs leading to HCC and is important from both diagnostic and therapeutic standpoints.

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Section: Discussionmentioning

confidence: 99%

Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans

et al. 2022

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“…It was also revealed that this bromodomain inhibitor might induce ER stress, which then leads to apoptosis [55]. Electron microscopic observations showed thicker and fused ER in fibroblasts [56], dilated ER in rat in diaphragm muscle [57], and hepatocytes [58] also as a result of ER stress, similarly as in Chara. In internodal cells of C. vulgaris thallus, the action of heavy metals (mercury) also caused the appearance of dilated ER cisternae [59].…”

Section: Discussionmentioning

confidence: 88%

Blocking the Bromodomains Function Contributes to Disturbances in Alga Chara vulgaris Spermatids Differentiation

Wojtczak

2020

Cells

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Bromodomain containing (BRD) proteins play an essential role in many cellular processes. The aim of this study was to estimate activity of bromodomains during alga Chara vulgaris spermatids differentiation. The effect of a bromodomain inhibitor, JQ1 (100 μM), on the distribution of individual stages of spermatids and their ultrastructure was studied. The material was Feulgen stained and analysed in an electron microscope. JQ1 caused shortening of the early stages of spermiogenesis and a reverse reaction at the later stages. Additionally, in the same antheridium, spermatids at distant developmental stages were present. On the ultrastructural level, chromatin fibril system disorders and significantly distended endoplasmic reticulum (ER) cisternae already at the early stages were observed. Many autolytic vacuoles were also visible. The ultrastructural disturbances intensified after prolonged treatment with JQ1. The obtained data show that JQ1 treatment led to changes in the spermatid number and disturbances in chromatin condensation and to cytoplasm reduction. The current studies show some similarities between C. vulgaris and mammals spermiogenesis. Taken together, these results suggest that JQ1 interferes with the spermatid differentiation on many interdependent levels and seems to induce ER stress, which leads to spermatid degeneration. Studies on the role of bromodomains in algae spermiogenesis have not been conducted so far.

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“…Reaction mixtures were incubated for 10 min at 95°C, followed by 40 cycles of 15 s at 95°C and 30 s at 60°C. The primer sequences for rat GFAP (sense, 5′-CCTTGAGTCCTTGCGCGGCA-3′, antisense, 5′- TTGGCCCTCCTCCTCCAGCC-3′) ( Liu C. et al, 2012 ), rat TNF-α: forward, 5′- AAT GGC CTC CCT CAT CAG TT-3′; reverse, 5′- CCA CTT GGT TTG CTA CGA -3′ ( Abo El-khair et al, 2020 ), rat AQP4: forward, 5′-TGAATCCAGCTCGATCCTTTG-3′; reverse, 5′-TATCCAGTGGTTTTCCCAGTTTC-3′ ( Shi et al, 2017 ), Kir4.1/Kcnj10 (forward: 5′-GTGACAGGCAAACTGCTTCA-3′; reverse: 5′-GGGCTATCAGAGGCTGTGTC-3′) ( Liu Y. Z. et al, 2012 ).…”

Section: Methodsmentioning

confidence: 99%

Astrocytes profiling in acute hepatic encephalopathy: Possible enrolling of glial fibrillary acidic protein, tumor necrosis factor-alpha, inwardly rectifying potassium channel (Kir 4.1) and aquaporin-4 in rat cerebral cortex

Elsherbini

Ghoneim²,

El-Mancy³

et al. 2022

Front. Cell. Neurosci.

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Hepatic encephalopathy (HE) is a neurological disarray manifested as a sequel to chronic and acute liver failure (ALF). A potentially fatal consequence of ALF is brain edema with concomitant astrocyte enlargement. This study aims to outline the role of astrocytes in acute HE and shed light on the most critical mechanisms driving this role. Rats were allocated into two groups. Group 1, the control group, received the vehicle. Group 2, the TAA group, received TAA (300 mg/kg) for 3 days. Serum AST, ALT, and ammonia were determined. Liver and cerebral cortical sections were processed for hematoxylin and eosin staining. Additionally, mRNA expression and immunohistochemical staining of cortical GFAP, TNFα, Kir4.1, and AQP4 were performed. Cortical sections from the TAA group demonstrated neuropil vacuolation and astrocytes enlargement with focal gliosis. GFAP, TNFα, and AQP4 revealed increased mRNA expression, positive immunoreactivity, and a positive correlation to brain water content. In contrast, Kir 4.1 showed decreased mRNA expression and immunoreactivity and a negative correlation to brain water content. In conclusion, our findings revealed altered levels of TNFα, Kir 4.1, GFAP, and AQP4 in HE-associated brain edema. A more significant dysregulation of Kir 4.1 and TNFα was observed compared to AQP4 and GFAP.

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Molecular and ultrastructure study of endoplasmic reticulum stress in hepatic steatosis: role of hepatocyte nuclear factor 4α and inflammatory mediators

Cited by 14 publications

References 62 publications

Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans

Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans

Blocking the Bromodomains Function Contributes to Disturbances in Alga Chara vulgaris Spermatids Differentiation

Astrocytes profiling in acute hepatic encephalopathy: Possible enrolling of glial fibrillary acidic protein, tumor necrosis factor-alpha, inwardly rectifying potassium channel (Kir 4.1) and aquaporin-4 in rat cerebral cortex

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