TSC22D4 promotes TGFβ1-induced activation of hepatic stellate cells

Sakurai, Minako; Weber, Peter; Wolff, Gretchen; Wieder, Annika; Szendroedi, Julia; Herzig, Stephan; Üstünel, Bilgen Ekim

doi:10.1016/j.bbrc.2022.05.100

Cited by 5 publications

(4 citation statements)

References 32 publications

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“…Importantly, although 93% of these associations correspond to already known T2D independent signals, 7% of them are novel and will need a further and detailed inspection. According to previous findings, two of the 104 pairs have some functional connection with the disease [41][42][43][44][45][46] , thus, suggesting gene expression and gene pathways as one of the putative underlying molecular mechanisms to mediate the link between these pairs and T2D and, therefore, to possibly enhance the development of the disease.…”

Section: Discussionmentioning

confidence: 92%

“…Interestingly, diabetic hepatic fibrosis is a progressive liver disease and a chronic complication of diabetes mellitus, which is known to be mainly caused by the activation of quiescent hepatic stellate cells (HSCs) by high glucose stimulation 44 . The activation of these cells is known to be promoted by TSC22D4 45 , a gene that acts as a critical controller of diabetic hyperglycemia 46 , and has elevated levels in patients with T2D with non-alcoholic fatty liver disease or steatohepatitis. In summary, these results suggest that the association found between the interactions and Type 2 Diabetes can be mediated by the connection between variants with gene expression and their effects on gene pathways.…”

Section: Functional Interpretation Of the T2d-associated Pairsmentioning

confidence: 99%

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Exhaustive Variant Interaction Analysis using Multifactor Dimensionality Reduction

Gómez-Sánchez,

Alonso,

Pérez

et al. 2023

Preprint

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One of the main goals of human genetics is to understand the connections between genomic variation and the predisposition to develop a complex disorder. These disease-variant associations are usually studied in a single independent manner, disregarding the possible effect derived from the interaction between genomic variants. In particular, in a background of complex diseases, these interactions can be directly linked to the disorder and may play an important role in disease development. Although their study has been suggested to help to complete the understanding of the genetic bases of complex diseases, this still represents a big challenge due to large computing demands. Here, we have taken advantage of High-Performance Computing technologies to tackle this problem using a combination of machine learning methods and statistical approaches. As a result, we have created a containerized framework that uses Multifactor Dimensionality Reduction to detect pairs of variants associated with Type 2 Diabetes (T2D). This methodology has been tested in the Northwestern University NUgene project cohort using a dataset of 1,883,192 variant pairs with a certain degree of association with T2D.Out of the pairs studied, we have identified 104 significant pairs, two of which exhibit a potential functional relationship with T2D.

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Section: Discussionmentioning

confidence: 92%

Section: Functional Interpretation Of the T2d-associated Pairsmentioning

confidence: 99%

Exhaustive Variant Interaction Analysis using Multifactor Dimensionality Reduction

Gómez-Sánchez,

Alonso,

Pérez

et al. 2023

Preprint

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“…Previous studies demonstrate that glycosylation-dependent galectin-1/neuropilin-1 interactions promote liver fibrosis via the activation of TGF-β- and PDGF-like signals in HSCs [ 28 ]. A recent study showed that TGF-β-stimulated clone 22D4 (TSC22D4), a member of the TSC-22 family proteins, contributed to the TGF-β1-mediated activation of HSCs and promoted their proliferation and migration [ 29 ].…”

Section: Hepatic Parenchymal and Non-parenchymal Cells And Adipose Ti...mentioning

confidence: 99%

Autophagy Dysregulation in Metabolic Associated Fatty Liver Disease: A New Therapeutic Target

Chen

Lin

2022

IJMS

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Metabolic associated fatty liver disease (MAFLD) is one of the most common causes of chronic liver disease worldwide. To date, there is no FDA-approved treatment, so there is an urgent need to determine its pathophysiology and underlying molecular mechanisms. Autophagy is a lysosomal degradation pathway that removes damaged organelles and misfolded proteins after cell injury through endoplasmic reticulum stress or starvation, which inhibits apoptosis and promotes cell survival. Recent studies have shown that autophagy plays an important role in removing lipid droplets from hepatocytes. Autophagy has also been reported to inhibit the production of pro-inflammatory cytokines and provide energy for the hepatic stellate cells activation during liver fibrosis. Thyroid hormone, irisin, melatonin, hydrogen sulfide, sulforaphane, DA-1241, vacuole membrane protein 1, nuclear factor erythroid 2-related factor 2, sodium-glucose co-transporter type-2 inhibitors, immunity-related GTPase M, and autophagy-related gene 7 have been reported to ameliorate MAFLD via autophagic induction. Lipid receptor CD36, SARS-CoV-2 Spike protein and leucine aminopeptidase 3 play a negative role in the autophagic function. This review summarizes recent advances in the role of autophagy in MAFLD. Autophagy modulates major pathological changes, including hepatic lipid metabolism, inflammation, and fibrosis, suggesting the potential of modulating autophagy for the treatment of MAFLD.

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“…Recent studies have identified TSC22D4 as a crux heart in LF progress. Thus, combined TSC22D4 targeting against hepatocytes and HSCs may show superior efficacy against progressive liver disease [62] . GJA1 promotes the progress of LF though stimulating HSCs.…”

Section: Other Roles With Smad Signaling Pathwaymentioning

confidence: 99%

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

Zheng

Yang

Luo

et al. 2022

Preprint

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Liver fibrosis (LF) is a trauma repair process carried out by the liver in response to various acute and chronic liver injuries, featured by excessive proliferation as well as abnormal dismissal of extracellular matrix as the main pathological features, and its continuous development will deteriorate into cirrhosis, liver cancer as well as other illnesses. The occurrence of LF is closely related to Hepatic stellate cells (HSCs) stimulation, and intervention in HSCs proliferation is expected to reverse LF. Plant-based small molecule drugs have anti-LF effects, and their mechanisms of action are related to anti-inflammation, anti-oxidative stress, as well as inhibition of abnormal accumulation of extracellular matrix. Consequently, new agents for HSCs will be required to furnish a possible curative response. Small-molecule natural products might be attractive for LF therapy. That is because they not only have the effect against HSCs, but also have excellent qualities such as low toxic side effects and easy availability from the perspective of safety and cost. In this review, we provide an updated review of the signal transduction pathways involved in HSCs and small-molecule natural products targeting HSCs reported in the past 3 years at home and abroad, with the aim of providing new ideas for the development of plant-based small molecule drugs targeting HSCs to reverse LF.

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TSC22D4 promotes TGFβ1-induced activation of hepatic stellate cells

Cited by 5 publications

References 32 publications

Exhaustive Variant Interaction Analysis using Multifactor Dimensionality Reduction

Exhaustive Variant Interaction Analysis using Multifactor Dimensionality Reduction

Autophagy Dysregulation in Metabolic Associated Fatty Liver Disease: A New Therapeutic Target

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

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