Thrombospondin-1 Exacerbates Acute Liver Failure and Hepatic Encephalopathy Pathology in Mice by Activating Transforming Growth Factor β1

Jefferson, Brandi; Ali, Malaika; Grant, Stephanie; Frampton, Gabriel; Ploof, Michaela; Andry, Sarah; DeMorrow, Sharon; McMillin, Matthew

doi:10.1016/j.ajpath.2019.10.003

Cited by 15 publications

(15 citation statements)

References 52 publications

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“…The expression of Thbs1 , the gene encoding thrombospondin-1, is also increased in eWAT after spaceflight. Thrombospondin-1 is an adipokine 51 that exacerbates hepatic dysfunction 52 . Thus, the increased expression of CD36 in the liver and thrombospondin-1 in eWAT might synergistically affect biological functions during space travel.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 plays a critical role in the metabolic response during and after spaceflight

et al. 2021

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Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. The volume of epididymal white adipose tissue (eWAT) in mice increases during spaceflight, a change that is attenuated by Nrf2 knockout. We conducted metabolome analyses of plasma from wild-type and Nrf2 knockout mice collected at pre-flight, in-flight and post-flight time points, as well as tissues collected post-flight to clarify the metabolic responses during and after spaceflight and the contribution of Nrf2 to these responses. Plasma glycerophospholipid and sphingolipid levels were elevated during spaceflight, whereas triacylglycerol levels were lower after spaceflight. In wild-type mouse eWAT, triacylglycerol levels were increased, but phosphatidylcholine levels were decreased, and these changes were attenuated in Nrf2 knockout mice. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of Nrf2 knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf2 plays critical roles in these responses.

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Section: Discussionmentioning

confidence: 99%

Nrf2 plays a critical role in the metabolic response during and after spaceflight

et al. 2021

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“…The downstream targets of THBS1 include ECM proteins and cell surface receptors. One receptor is transforming growth factor-β1 (TGF-β1), which plays a critical role in fibration and inflammation, exacerbating hepatic steatosis, fibrosis and failure ( Breitkopf et al., 2005 ; Bai et al., 2020 ; Jefferson et al., 2020 ). The upregulation of THBS1 can be stimulated by glucose, and the overexpression of THBS1 contributes to obesity-induced tissue inflammation and the development of metabolic syndrome ( Wang et al., 2003 ; Wang et al., 2004 ; Matsuo et al., 2015 ).…”

Section: Discussionmentioning

confidence: 99%

The Qingchangligan Formula Alleviates Acute Liver Failure by Regulating Galactose Metabolism and Gut Microbiota

Yin

Liu

Jiang

et al. 2022

Front. Cell. Infect. Microbiol.

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The Qingchangligan formula (QCLGF) is a traditional Chinese medicine that has significant clinical potential for patients with acute liver failure (ALF). However, the experimental evidence of the effect of QCLGF on ALF and the associated mechanisms remain elusive. We aimed to evaluate the function of QCLGF in ALF and the underlying mechanism. ALF was induced in rats by intraperitoneal injection of D-GalN (1100 mg/kg). The Qingchangligan formula was administered to the rats (6.725 g/kg · d) for 5 days, and the model group and the control group were given the same amount of physiological saline. Then 16S rRNA gene sequencing, high performance gas chromatography-mass spectrometry (GC-MS), and RNA-seq analysis were performed on the samples. The levels of ALT and AST in the ALF rats were abnormal (5322.08 ± 566.27 U/L and 7655.95 ± 1238.08 U/L, respectively) compared with the normal control (98.98 ± 6.90 U/L and 99.63 ± 10.94 U/L, respectively). The levels of ALT and AST in the QCLGF rats (2997.67 ± 469.24 U/L and 4158.40 ± 596.07 U/L, respectively) were closer the normal control group. Liver HE staining showed that the degree of liver damage in the QCLGF rats was lighter than that in the ALF rats. The overall structure of the gut microbiota after ALF was significantly altered, including Proteobacteria, Blautia, Romboutsia, Parabacteroides, UCG-008, Parasutterella, Ruminococcus, norank_f:Lachnospiraceae, the Eubacterium_xylanophilum_group, Oscillibacter, and Eisenbergiella. QCLGF balanced the structure and abundance of intestinal flora. The levels of D(+)galactose, isopropyl beta-D-1-thiogalactopyranoside and D-mannitol were lighter in the plasma of the ALF rats than in the normal control rats, but there were significantly elevated levels of those metabolites in the QCLGF rats. The gene expression changed significantly in the ALF rats. QCLGF regulated the expression of THBS1 and the KEGG pathways of carbohydrate metabolism, lipid metabolism, signal transduction, the immune system, and infectious disease: bacterial. QCLGF may alleviating intestinal flora disorder, regulating galactose metabolism and downregulating the expression of THBS1 to alleviate D-GalN induced acute liver failure.

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“…Other pathways initiated through TGF-β binding to TβRII involve non-Smad signals and include the ERK1/2 and MAPK p38 pathways [90]. The initiation of the non-Smad signaling pathways is very interesting since, as we discuss above, the MAPK family can also induce TSP-1 expression [34]; these findings indicate that TSP-1 is not only an activator of TGF-β1 but also the subject of TGF-β1 regulation [34,35,91]. Thus, a feedback cycle has been established for TSP-1 and TGF-β1.…”

Section: Transforming Growth Factor-β1 (Tgf-β1)mentioning

confidence: 93%

Thrombospondin-1: A Key Protein That Induces Fibrosis in Diabetic Complications

Zhang

Chen

et al. 2020

Journal of Diabetes Research

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Fibrosis accompanies most common pathophysiological features of diabetes complications in different organs. It is characterized by an excessive accumulation of extracellular matrix (ECM) components, the response to which contributes to inevitable organ injury. The extracellular protein thrombospondin-1 (TSP-1), a kind of extracellular glycoprotein, is upregulated by the increased activity of some transcription factors and results in fibrosis by activating multiple pathways in diabetes. The results of studies from our team and other colleagues indicate that TSP-1 is associated with the pathological process leading to diabetic complications and is considered to be the most important factor in fibrosis. This review summarizes the molecular mechanism of increased TSP-1 induced by hyperglycemia and the role of TSP-1 in fibrosis during the development of diabetes complications.

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Thrombospondin-1 Exacerbates Acute Liver Failure and Hepatic Encephalopathy Pathology in Mice by Activating Transforming Growth Factor β1

Cited by 15 publications

References 52 publications

Nrf2 plays a critical role in the metabolic response during and after spaceflight

Nrf2 plays a critical role in the metabolic response during and after spaceflight

The Qingchangligan Formula Alleviates Acute Liver Failure by Regulating Galactose Metabolism and Gut Microbiota

Thrombospondin-1: A Key Protein That Induces Fibrosis in Diabetic Complications

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