Integrin Linked Kinase (ILK) and its Role in Liver Pathobiology

Martucci, Nicole J.; Michalopoulos, George K.; Mars, Wendy M.

doi:10.3727/105221621x16113475275710

Cited by 9 publications

(4 citation statements)

References 61 publications

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“…The profile comparison of lipid metabolism to humans also showed that known key elements like Fasn, Ilk, Ahsa1, Ughd, or Insig1 align with expression profiles from NASH, ALD, and HCC. These findings are also in line with recent literature, which associates these genes with liver diseases (36)(37)(38)(39).…”

Section: Multi-level Network Analysis Of Liver Tolerance Captures Hum...supporting

confidence: 93%

Tolerance of repeated toxic injuries of murine livers is associated with steatosis and inflammation

Hammad

Ogris

Othman

et al. 2022

Preprint

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The human liver has a remarkable capacity to regenerate and thus compensate over decades for fibrosis caused by toxic chemicals, drugs, alcohol, or malnutrition. To date, no protective mechanisms have been identified that help the liver tolerate these repeated injuries. In this study, we revealed dysregulation of lipid metabolism and mild inflammation as protective mechanisms by studying longitudinal multi-omic measurements of liver fibrosis-induced by repeated CCl4 injections in mice (n = 45). Based on comprehensive proteomics, transcriptomics, blood- and tissue-level profiling, we uncovered three phases of early disease development - Initiation, Progression, and Tolerance. Using a novel multi-omic network analysis, we identified multi-level mechanisms that are significantly dysregulated in the injury-tolerant response. A public data analysis and shows that these profiles are altered in human liver diseases, including fibrosis and early cirrhosis stages. Our findings mark the beginning of the Tolerance phase as the critical switching point in liver response to repetitive toxic doses. After fostering extracellular matrix accumulation as an acute response, we observe a deposition of tiny lipid droplets in hepatocytes only in the Tolerant phase. Our comprehensive study shows that lipid metabolism and mild inflammation may serve as biomarkers and are putative functional requirements to resist further disease progression.

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Section: Multi-level Network Analysis Of Liver Tolerance Captures Hum...supporting

confidence: 93%

Tolerance of repeated toxic injuries of murine livers is associated with steatosis and inflammation

Hammad

Ogris

Othman

et al. 2022

Preprint

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“…As a result of activating this signaling pathway, hepatic stellate cells (HSCs) become activated, motile, and synthesize more ECM components, including collagen type I, α-actin, and fibronectin ( Figure 5 C) [ 106 , 107 ]. Many cellular processes, including hepatocyte differentiation, growth, migration, and survival depend on ILK expression and its interaction with the extracellular matrix [ 108 ]. Researchers have shown that knocking down ILK results in dedifferentiated hepatocytes that can be regenerated by adding hydrated complex matrix preparations (Matrigel ® ), indicating that ILK contributes to maintaining extracellular microarchitecture.…”

Section: Resultsmentioning

confidence: 99%

Hypericum perforatum L. and the Underlying Molecular Mechanisms for Its Choleretic, Cholagogue, and Regenerative Properties

et al. 2023

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Any defects in bile formation, secretion, or flow may give rise to cholestasis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. As the pathogenesis of hepatic disorders is multifactorial, targeting parallel pathways potentially increases the outcome of therapy. Hypericum perforatum has been famed for its anti-depressive effects. However, according to traditional Persian medicine, it helps with jaundice and acts as a choleretic medication. Here, we will discuss the underlying molecular mechanisms of Hypericum for its use in hepatobiliary disorders. Differentially expressed genes retrieved from microarray data analysis upon treatment with safe doses of Hypericum extract and intersection with the genes involved in cholestasis are identified. Target genes are located mainly at the endomembrane system with integrin-binding ability. Activation of α5β1 integrins, as osmo-sensors in the liver, activates a non-receptor tyrosine kinase, c-SRC, which leads to the insertion of bile acid transporters into the canalicular membrane to trigger choleresis. Hypericum upregulates CDK6 that controls cell proliferation, compensating for the bile acid damage to hepatocytes. It induces ICAM1 to stimulate liver regeneration and regulates nischarin, a hepatoprotective receptor. The extract targets the expression of conserved oligomeric Golgi (COG) and facilitates the movement of bile acids toward the canalicular membrane via Golgi-derived vesicles. In addition, Hypericum induces SCP2, an intracellular cholesterol transporter, to maintain cholesterol homeostasis. We have also provided a comprehensive view of the target genes affected by Hypericum’s main metabolites, such as hypericin, hyperforin, quercitrin, isoquercitrin, quercetin, kaempferol, rutin, and p-coumaric acid to enlighten a new scope in the management of chronic liver disorders. Altogether, standard trials using Hypericum as a neo-adjuvant or second-line therapy in ursodeoxycholic-acid-non-responder patients define the future trajectories of cholestasis treatment with this product.

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“…The complex connects the ECM to the actin cytoskeleton and protects ILK from proteasomal degradation ( Legate et al, 2006 ). The ILK pathway is extensively involved in regulatory processes such as cell adhesion, apoptosis, proliferation, and migration ( Martucci et al, 2021 ). In cancer, ILK promotes EMT and enhances the migration and invasion of cancer cells ( McDonald and Dedhar, 2022 ).…”

Section: Ecm Stiffness-mediated Mechanical Signaling Pathwaymentioning

confidence: 99%

“…In cancer, ILK promotes EMT and enhances the migration and invasion of cancer cells ( McDonald and Dedhar, 2022 ). These cellular metabolism and behavior changes are facilitated by the activation of downstream signaling pathways such as AKT, Hippo, Wnt, and GSK-3β ( Martucci et al, 2021 ). ILK can promote the transition from fibroblasts to myofibroblasts in the dermis with the transcription factor Snail1/Slug ( Zoppi et al, 2018 ).…”

Section: Ecm Stiffness-mediated Mechanical Signaling Pathwaymentioning

confidence: 99%

Extracellular matrix stiffness—The central cue for skin fibrosis

Wang

Wen

et al. 2023

Front. Mol. Biosci.

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Skin fibrosis is a physiopathological process featuring the excessive deposition of extracellular matrix (ECM), which is the main architecture that provides structural support and constitutes the microenvironment for various cellular behaviors. Recently, increasing interest has been drawn to the relationship between the mechanical properties of the ECM and the initiation and modulation of skin fibrosis, with the engagement of a complex network of signaling pathways, the activation of mechanosensitive proteins, and changes in immunoregulation and metabolism. Simultaneous with the progression of skin fibrosis, the stiffness of ECM increases, which in turn perturbs mechanical and humoral homeostasis to drive cell fate toward an outcome that maintains and enhances the fibrosis process, thus forming a pro-fibrotic “positive feedback loop”. In this review, we highlighted the central role of the ECM and its dynamic changes at both the molecular and cellular levels in skin fibrosis. We paid special attention to signaling pathways regulated by mechanical cues in ECM remodeling. We also systematically summarized antifibrotic interventions targeting the ECM, hopefully enlightening new strategies for fibrotic diseases.

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Integrin Linked Kinase (ILK) and its Role in Liver Pathobiology

Cited by 9 publications

References 61 publications

Tolerance of repeated toxic injuries of murine livers is associated with steatosis and inflammation

Tolerance of repeated toxic injuries of murine livers is associated with steatosis and inflammation

Hypericum perforatum L. and the Underlying Molecular Mechanisms for Its Choleretic, Cholagogue, and Regenerative Properties

Extracellular matrix stiffness—The central cue for skin fibrosis

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