Targeting extracellular matrix remodeling in disease: Could resveratrol be a potential candidate?

Agarwal, Renu; Agarwal, Puneet

doi:10.1177/1535370216675065

Cited by 18 publications

(7 citation statements)

References 87 publications

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“…The TM4SF5-mediated inflammatory environment with profibrotic cytokines and chemokines may have alternatively transduced signaling in the SIRT1 reduced /SREBPs increased or SIRT1 increased /SOCSs reduced /pY 705 STAT3 increased axes. TM4SF5 promoted SREBP expression in fatty livers via SIRT1 downregulation, which is known to deacetylate and negatively regulate SREBP activity and expression [19]. SREBP-1a and SREBP-1c or SREBP-2 are known to be involved in FFA and cholesterol synthesis, respectively [20].…”

Section: Discussionmentioning

confidence: 99%

Differential TM4SF5‐mediated SIRT1 modulation and metabolic signaling in nonalcoholic steatohepatitis progression

Ryu

Kim

Kang

et al. 2020

The Journal of Pathology

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Nonalcoholic fatty liver disease is a chronic condition involving steatosis, steatohepatitis and fibrosis, and its progression remains unclear. Although the tetraspanin transmembrane 4 L six family member 5 (TM4SF5) is involved in hepatic fibrosis and cancer, its role in nonalcoholic steatohepatitis (NASH) progression is unknown. We investigated the contribution of TM4SF5 to liver pathology using transgenic and KO mice, diet-or drug-treated mice, in vitro primary cells, and in human tissue. TM4SF5-overexpressing mice exhibited nonalcoholic steatosis and NASH in an age-dependent manner. Initially, TM4SF5-positive hepatocytes and liver tissue exhibited lipid accumulation, decreased Sirtuin 1 (SIRT1), increased sterol regulatory-element binding proteins (SREBPs) and inactive STAT3 via suppressor of cytokine signaling (SOCS)1/3 upregulation. In older mice, TM4SF5 promoted inflammatory factor induction, SIRT1 expression and STAT3 activity, but did not change SOCS or SREBP levels, leading to active STAT3-mediated ECM production for NASH progression. A TM4SF5-associated increase in chemokines promoted SIRT1 expression and progression to NASH with fibrosis. Suppression of the chemokine CCL20 reduced immune cell infiltration and ECM production. Liver tissue from high-fat diet-or CCl 4-treated mice and human patients exhibited TM4SF5-dependent steatotic or steatohepatitic livers with links between TM4SF5-mediated SIRT1 modulation and SREBP or SOCS/STAT3 signaling axes. TM4SF5-mediated STAT3 activation in fibrotic NASH livers increased collagen I and laminin γ2. Both collagen I α1 and laminin γ2 suppression resulted in reduced SIRT1 and active STAT3, but no change in SREBP1 or SOCS, and abolished CCl 4-mediated mouse liver damage. TM4SF5-mediated signaling pathways that involve SIRT1, SREBPs and SOCS/STAT3 promoted progression to NASH. Therefore, TM4SF5 and its downstream effectors may be promising therapeutic targets to treat nonalcoholic fatty liver disease.

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Section: Discussionmentioning

confidence: 99%

Differential TM4SF5‐mediated SIRT1 modulation and metabolic signaling in nonalcoholic steatohepatitis progression

Ryu

Kim

Kang

et al. 2020

The Journal of Pathology

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“…3F). RES also downregulates intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) 42 , and inhibiting matrix metalloproteases (MMPs) secretion 43,44 , leading to the lower adhesion force in RES + DEP group (Fig. 3E).…”

Section: Discussionmentioning

confidence: 98%

A multi-scale approach to study biochemical and biophysical aspects of resveratrol on diesel exhaust particle-human primary lung cell interaction

Zhang

Tang

et al. 2019

Sci Rep

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Diesel exhaust particles (DEPs) are major air pollutants that lead to numerous human disorders, especially pulmonary diseases, partly through the induction of oxidative stress. Resveratrol is a polyphenol that ameliorates the production of reactive oxygen species (ROS) and delays aging-related processes. Herein we studied the cytoprotective effect of resveratrol on DEP-exposed human lung cells in a factorial experimental design. This work investigates biophysical features including cellular compositions and biomechanical properties, which were measured at the single-cell level using confocal Raman microspectroscopy (RM) and atomic force microscopy (AFM), respectively. Principal component analysis (PCA), hierarchical cluster analysis (HCA) and partial least square regression (PLS) analysis were applied to analyze Raman spectra with and without resveratrol protection. The health status of individual cells could be effectively predicted using an index derived from characteristic Raman spectral peak (e.g., 1006 cm−1) based on PLS model. AFM measurements indicated that cellular adhesion force was greatly reduced, while Young’s modulus was highly elevated in resveratrol treated DEP-exposed cells. Anti-oxidant resveratrol reduced DEP-induced ROS production and suppressed releases of several cytokines and chemokines. These findings suggest resveratrol may enhance resistance of human lung cells (e.g., SAEC) to air pollutants (e.g. DEPs).

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“…TM4SF5 promoted SREBPs expression in fatty livers via the down-regulation of SIRT1, which deacetylates and negatively regulates SREBPs activity and expression (Agarwal & Agarwal, 2017). SREBP-1a and SREBP-1c or SREBP-2 are involved in FFA or cholesterol synthesis, respectively (Moon, 2017).…”

Section: Discussionmentioning

confidence: 99%

Differential TM4SF5-mediated SIRT1 modulation and signaling for chronic liver disease

Ryu

Kim

Kang

et al. 2020

Preprint

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Here we show the roles of transmembrane 4 L six family member 5 (TM4SF5) in the progression of nonalcoholic steatosis (or NAFL) to steatohepatitis (NASH). The overexpression of TM4SF5 caused nonalcoholic steatosis and NASH in an age-dependent manner. Initially, TM4SF5-positive hepatocytes and livers exhibited lipid accumulation, decreased SIRT1, increased SREBPs levels, and inactive STAT3 via SOCS1/3 upregulation. In older animals, TM4SF5 under an inflammatory environment increased SIRT1 expression and STAT3 activity with no significant change to SOCSs and SREBPs levels, leading to active STAT3-mediated fibrotic extracellular matrix (ECM) production. Liver tissues from clinical human patients with NAFL or NASH also showed such a TM4SF5-SIRT1-STAT3-ECM relationship correlated with fibrosis score and age. Ligand-independent and TM4SF5-mediated STAT3 activity led to collagen I and laminins/laminin γ2 expression in hepatic stellate cells and hepatocytes, respectively. Laminin γ2 suppression abolished CCl4-mediated liver damage and ECM production and reduced SIRT1 and active-STAT3, but did not alter SREBP1 or SOCSs levels. These findings suggest that TM4SF5, CCL20, SIRT1, and/or laminin γ2 may be promising therapeutic targets against liver disease. the Tumor Microenvironment GCRC (2011-0030001) to JWL. Author contributions JR and EK performed most experiments; EK and MKK helped animal experiments; JWJ, SHN, JEK, DGS, and HJK helped with imaging experiments and with reagents; JHL, JHY, and HYK helped with clinical patient tissues; TS helped with the RNA-Seq analysis; SK helped with anti-TM4SF5 antibodies; JWL designed the experiments and wrote the manuscript. Conflict of interestsThe authors declare no competing interests. 26The paper explained PROBLEM: Nonalcoholic liver disease is a chronic disease with immuno-metabolic disorders during NAFLD progression to NASH/fibrosis, cirrhosis and cancer. The molecular mechanisms for the earlier progression to NASH/fibrosis remain unclear. RESULTS:Tm4sf5-engineered mice revealed that TM4SF5-dependent SIRT1 modulation and chemokines promoted NAFLD, NASH, and fibrosis in an age-dependent manner.TM4SF5/STAT3-mediated laminin expression in hepatocytes critically promoted the earlier progression toward NASH.

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Targeting extracellular matrix remodeling in disease: Could resveratrol be a potential candidate?

Cited by 18 publications

References 87 publications

Differential TM4SF5‐mediated SIRT1 modulation and metabolic signaling in nonalcoholic steatohepatitis progression

Differential TM4SF5‐mediated SIRT1 modulation and metabolic signaling in nonalcoholic steatohepatitis progression

A multi-scale approach to study biochemical and biophysical aspects of resveratrol on diesel exhaust particle-human primary lung cell interaction

Differential TM4SF5-mediated SIRT1 modulation and signaling for chronic liver disease

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