NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression

Latif, M. Jawad; Schmídt, G.; Mercan, Sercan; Rahman, Raza Ur; Gibhardt, Christine S.; Stejerean‐Todoran, Ioana; Reutlinger, K; Heßmann, Elisabeth; Singh, Shiv K.; Moeed, Abdul; Rehman, Abdul; Butt, Umer Javed; Bohnenberger, Hanibal; Stroebel, Philipp; Bremer, Sebastian; Neeße, Albrecht; Bogeski, Ivan; Ellenrieder, Volker

doi:10.1136/gutjnl-2021-325013

Cited by 30 publications

(12 citation statements)

References 59 publications

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“…45,57--59 Inflammatory cells could trigger several signals including inflammatory molecules, lipid messengers, ROS and endoplasmic reticulum stress, which perturbs hepatocytes and causes metabolic abnormality, which promotes NAFLD progression. 47,60,61 Works also demonstrate that NETs could promote HCC progression by inducing inflammatory microenvironments. 45,62 In this study, we found that GCN5L1 triggered ferroptosis and released HMGB1, which increased the infiltration of neutrophils and promoted the formation of NETs.…”

Section: Discussionmentioning

confidence: 99%

“…Several works have demonstrated that NETs promote inflammation, which might recruit multiple immune cells 45,57 . ‐ 59 Inflammatory cells could trigger several signals including inflammatory molecules, lipid messengers, ROS and endoplasmic reticulum stress, which perturbs hepatocytes and causes metabolic abnormality, which promotes NAFLD progression 47,60,61 . Works also demonstrate that NETs could promote HCC progression by inducing inflammatory microenvironments 45,62 .…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis‐induced formation of neutrophil extracellular traps

Xiong

Yan

et al. 2023

Clinical & Translational Med

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Background Mitochondria play central roles in metabolic diseases including nonalcoholic steatohepatitis (NASH). However, how mitochondria regulate NASH progression remains largely unknown. Our previous findings demonstrate that mitochondrial general control of amino acid synthesis 5 like 1 (GCN5L1) is associated with mitochondrial metabolism. Nevertheless, the roles of GCN5L1 in NASH are unclear. Aims and methods The GCN5L1 expression was detected in the fatty livers of NASH patients and animals. Hepatocyte‐specific GCN5L1 deficiency or overexpression mice were used to induce NASH models by feeding with a high‐fat/high‐cholesterol or methionine‐choline deficient diet. The molecular mechanisms underlying GCN5L1‐regulated NASH were further explored and verified in mice. Results and conclusions GCN5L1 expression was increased in NASH patients. Upregulated GCN5L1 level was also illustrated in NASH mice. Mice with hepatocyte‐specific GCN5L1 conditional knockout improved the inflammatory response compared to GCN5L1flox/flox mice. However, overexpression of mitochondrial GCN5L1 augmented the inflammatory response. Mechanically, GCN5L1 acetylated CypD and enhanced its binding with ATP5B, which induced the opening of mitochondrial permeability transition pores and the release of mitochondrial ROS into the cytoplasm. The increased ROS promoted ferroptosis of hepatocytes and induced accumulation of high mobility group box 1 in the microenvironment, which recruited neutrophils and induced the generation of neutrophil extracellular traps (NETs). NETs block impaired GCN5L1‐induced NASH progression. Furthermore, the upregulation of GCN5L1 in NASH was contributed by lipid overload‐induced endoplasmic reticulum stress. Together, mitochondrial GCN5L1 has a vital function in promoting NASH progression by regulating oxidative metabolism and the hepatic inflammatory microenvironment. Thus, GCN5L1 might be a potential intervention target in NASH treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis‐induced formation of neutrophil extracellular traps

Xiong

Yan

et al. 2023

Clinical & Translational Med

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“…TUDCA can treat cholestatic diseases mainly by increasing the bile flow and BA secretion, attributed to choleretic and cytoprotective effects on hepatocytes ( Paumgartner and Beuers, 2002 ), and its mechanism is mainly related to alleviating ERS ( Latif et al, 2022 ). However, in this study, the level of TUDCA was found to be elevated in NASH mice.…”

Section: Discussionmentioning

confidence: 99%

Kaempferol attenuates nonalcoholic steatohepatitis by regulating serum and liver bile acid metabolism

Lü

Shao²,

Zhang³

et al. 2022

Front. Pharmacol.

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Objective: Changes in bile acids (BAs) are increasingly recognized as potential targets for non-alcoholic steatohepatitis (NASH). Kaempferol has been proved to be anti-inflammatory and reduce the disorder of lipid metabolism. In order to analyze the BA profile in NASH mice and determine the predictive biomarkers of kaempferol treatment, serum-targeted metabolomics and liver tissue RNA sequencing (RNA-seq) were carried out.Design: Six normal control mice (NC group), eight HFD-fed mice (HFD group), and eight kaempferol-treated HFD-fed mice (HFD + KP group) were included in the present study. Ultra-performance liquid chromatography coupled to a tandem mass spectrometry system (UPLC-MS/MS) was used to quantify serum and liver BAs, and RNA-seq was used to quantify liver differentially expressed genes related to BA metabolism.Results: The serum levels of CA, βMCA, UDCA, and 12-DHCA, as well as ωMCA in both the serum and liver, were significantly decreased in the HFD group compared with those in the NC group, and kaempferol can increase the serum levels of βMCA, UDCA, and ωMCA and the liver level of 12-DHCA. The serum levels of TDCA, THDCA, TUDCA, TDCA/CA, and TDCA/DCA were significantly increased in the HFD group compared with those of the NC group, and kaempferol can decrease them. Furthermore, NASH mice had a higher liver level of total CA%, total CDCA%, primary BAs/secondary BAs, 12α-OH BAs/non-12α-OH Bas, and conjugated BAs/unconjugated BAs, and all decreased after kaempferol treatment. According to the RNA-seq results, we found that compared with the NC group, the mRNA expression of cholesterol-7α-hydroxylase (CYP7A1) in the HFD group was significantly increased, and the mRNA expression of sterol 12α‐hydroxylase (CYP8B1) and multidrug resistance-related protein 3 (MRP3) was significantly decreased, while kaempferol significantly promoted the mRNA expression of mitochondrial sterol 27-hydroxylase (CYP27A1) and Na+ -taurocholate cotransporting polypeptide (NTCP).Conclusion: βMCA, CA, UDCA, 12-DHCA, ωMCA, CDCA, TωMCA, TDCA, THDCA, TCDCA, and TUDCA in the serum, as well as 6,7-diketoLCA, 12-DHCA, and ωMCA in the liver, may be potential biomarkers for kaempferol to improve NASH. HFD-induced NASH may be associated with the increase of CYP7A1 and the decrease of CYP8B1, leading to increased BA synthesis, and the decrease of MRP3 leading to decreased BA synthesis, and kaempferol may alleviate NASH by increasing CYP27A1 and NTCP to enhance BA transport.

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“…Quantification of IF and IHC images was performed either using ImageJ Fiji 62 (by manually counting positive cells, measuring the fluorescence intensity of the entire field of view, or using semi-automatic macros as described previously 63 ), or using QuPath 64 v0.4.3. In QuPath, cell detection was performed using the built-in detection feature, obtaining intensity measurements per cell, per nucleus or per cytoplasm, which were used for positive cell quantification using single measurement classifications (or compound classifiers for double-positive cells).…”

Section: Methodsmentioning

confidence: 99%

Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer

Klein,

Tu,

Krebs

et al. 2023

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity. This intratumoral co-existence of classical and basal-like programs is evident in multi-scale transcriptomic and spatial analyses of resected, advanced-stage and chemotherapy-treated specimens and reciprocally linked to a diverse stromal immune microenvironment as well as worse clinical outcome. However, the underlying mechanisms of intratumoral subtype heterogeneity remain largely unclear. Here, by combining preclinical models, multi-center clinical, bulk and compartment-specific transcriptomic, proteomic, and bioimaging data from human specimens, we identified an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic CD68+macrophages as a driver of intratumoral subtype co-existence along with an immunosuppressive tumor microenvironment with T cell exclusion. Our ATAC-, ChIP-, and RNA-seq analyses revealed that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory immune signatures in tumor cells, antagonizing cJUN/AP1 signaling to favor a therapy-responsive classical neoplastic identity. Through the tumor microenvironment, this dichotomous regulation was further amplified via regional macrophage populations. Moreover, CD68+/TNF-α+cells associated with a reactive phenotype and reduced CD8+T cell infiltration in human PDAC tumors. Consequently, combined anti-TNF-α immunotherapy and chemotherapy resulted in reduced macrophage counts and promoted CD3+/CD8+T cell infiltration in basal-like PDAC, leading to improved survival in preclinical murine models. We conclude that tumor cell intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression.

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NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression

Cited by 30 publications

References 59 publications

Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis‐induced formation of neutrophil extracellular traps

Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis‐induced formation of neutrophil extracellular traps

Kaempferol attenuates nonalcoholic steatohepatitis by regulating serum and liver bile acid metabolism

Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer

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