SHP-dependent and -independent induction of peroxisome proliferator-activated receptor-γ by the bile acid sensor farnesoid X receptor counter-regulates the pro-inflammatory phenotype of liver myofibroblasts

Renga, Barbara; Mencarelli, Andrea; Migliorati, Marco; Cipriani, Sabrina; D’Amore, Claudio; Distrutti, Eleonora; Fiorucci, Stefano

doi:10.1007/s00011-010-0306-1

Cited by 48 publications

(44 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, we investigated the influence of squalene on gene expression of three major MMPs (MMP-1, MMP-3 and MMP-9). As PPARγ agonists have been shown to inhibit LPS-mediated MMPs and pro-inflammatory cytokines (Renga et al, 2011;Wang et al, 2011), our study also undertook to explore whether squalene can affect PPARγ gene expression in LPS-treated cells. As shown in Fig.…”

Section: Squalene Down-regulates Mmps and Up-regulates Pparγ Gene Expmentioning

confidence: 99%

Squalene targets pro- and anti-inflammatory mediators and pathways to modulate over-activation of neutrophils, monocytes and macrophages

Cárdeno

Aparicio‐Soto

Paz

et al. 2015

Journal of Functional Foods

View full text Add to dashboard Cite

A B S T R A C TSqualene is a natural triterpene consumed as an integral part of the human diet. Increasing evidence demonstrates that squalene has antioxidant, cardioprotective and anticarcinogenic activities. Nevertheless, its anti-inflammatory properties remain unclear. The effects of squalene on lipopolysaccharide (LPS)-mediated inflammatory response in murine macrophages and human monocytes and neutrophils were investigated. Squalene reduced intracellular levels of ROS, nitrites, cytokines (TNF-α, IL-1β, IL-6 and IFN-γ) and proinflammatory enzymes (iNOS, COX-2 and MPO), including a decreased expression of TLR4and key proteins for signalling pathways mediated by NF-κB (IκBα), MAPKs (JNK) and MMPs (1, 3 and 9). In addition, squalene enhanced expression levels of anti-inflammatory enzymes (HO-1) and transcription factors (Nrf2 and PPARγ). This study establishes that squalene has significant potential for management of inflammatory conditions characterized by an overactivation of neutrophils/monocytes/macrophages and thereby for the efficient termination of the inflammatory response.

show abstract

Section: Squalene Down-regulates Mmps and Up-regulates Pparγ Gene Expmentioning

confidence: 99%

Squalene targets pro- and anti-inflammatory mediators and pathways to modulate over-activation of neutrophils, monocytes and macrophages

Cárdeno

Aparicio‐Soto

Paz

et al. 2015

Journal of Functional Foods

View full text Add to dashboard Cite

show abstract

“…Moreover, it has been demonstrated that the expression/activity of PPARs is positively modulated by the nuclear receptor FXR (Farnesoid X Receptor) [180]. These authors identified, in the PPAR gene promoter, a sequence containing FXR-responsive element (FXRE).…”

Section: Ppar In Hepatic Stellate Cellsmentioning

confidence: 99%

“…The same authors also demonstrated the role of FXR-PPAR crosstalk in inhibiting cytokine production and regulating inflammatory response of HSCs exposed to LPS. The cross-talk between these two nuclear receptors represses, in turn, the synthesis of collagen-and -SMA expression in activated HSCs [180].…”

Section: Ppar In Hepatic Stellate Cellsmentioning

confidence: 99%

Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment

Zardi¹,

Navarini²,

Sambataro³

et al. 2013

CMC

View full text Add to dashboard Cite

Abstr act: Complex molecular and cellular mechanisms are involved in the pathway of liver fibrosis. Activation and transformation of hepatic stellate cells (HSCs) are considered the two main reasons for the cause and development of liver fibrosis. The peroxisome proliferator-activated receptors (PPARs) belonging to the family of ligand-activated transcription factors play a key role in liver homeostasis, regulating adipogenesis and inhibiting fibrogenesis in HSCs. Normal transcriptional function of PPARs contributes to maintain HSCs in quiescent phase. A reduced expression of PPARs in HSCs greatly induces a progression of liver fibrosis and an increased production of collagen. Here, we discuss role and function of PPARs and we take into consideration molecular factors able to reduce PPARs activity in HSCs. Finally, although further validations are needed, we illustrate novel strategies available from in vitro and animal studies on how some PPARs-agonists have been proved effective as antifibrotic substances in liver disease.

show abstract

“…Further, fenofibrate, a PPARα agonist, increases SHP gene expression in the liver and protects from fibrosis induced by TGF-β1 and a methionine and choline-deficient diet through AMPK mediated induction of SHP gene expression9. Loss of SHP is also known to increase sensitivity to liver damage and fibrosis induced by bile duct ligation (BDL)10 establishing a major role for this gene in modulating transactivation of HSCs11.…”

mentioning

confidence: 99%

“…Because its mechanistic role in liver fibrosis811, identification of SHP ligands and molecular pathways regulated by SHP may lead to discovery of new treatments for liver diseases. Consistent with this concept, SHP ligands were actively searched1213.…”

mentioning

confidence: 99%

Decoding the role of the nuclear receptor SHP in regulating hepatic stellate cells and liver fibrogenesis

Cipriani

Carino

Masullo

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

The small heterodimer partner (SHP) is an orphan nuclear receptor that lacks the DNA binding domain while conserves a putative ligand-binding site, thought that endogenous ligands for this receptor are unknown. Previous studies have determined that SHP activation protects against development of liver fibrosis a process driven by trans-differentiation and activation of hepatic stellate cells (HSCs), a miofibroblast like cell type, involved in extracellular matrix (ECM) deposition. To dissect signals involved in this activity we generated SHP-overexpressing human and rat HSCs. Forced expression of SHP in HSC-T6 altered the expression of 574 genes. By pathway and functional enrichment analyses we detected a cluster of 46 differentially expressed genes involved in HSCs trans-differentiation. Using a isoxazole scaffold we designed and synthesized a series of SHP agonists. The most potent member of this group, ISO-COOH (EC50: 9 μM), attenuated HSCs trans-differentiation and ECM deposition in vitro, while in mice rendered cirrhotic by carbon tetrachloride (CCl4) or α-naphthyl-isothiocyanate (ANIT), protected against development of liver fibrosis as measured by morphometric analysis and expression of α-SMA and α1-collagen mRNAs. In aggregate, present results identify SHP as a counter-regulatory signal for HSCs transactivation and describe a novel class of SHP agonists endowed with anti-fibrotic activity.

show abstract

SHP-dependent and -independent induction of peroxisome proliferator-activated receptor-γ by the bile acid sensor farnesoid X receptor counter-regulates the pro-inflammatory phenotype of liver myofibroblasts

Abstract: The present study provides a molecular basis for the physiological cross-talk between FXR and PPARγ pathways in HSCs.

Cited by 48 publications

References 38 publications

Squalene targets pro- and anti-inflammatory mediators and pathways to modulate over-activation of neutrophils, monocytes and macrophages

Squalene targets pro- and anti-inflammatory mediators and pathways to modulate over-activation of neutrophils, monocytes and macrophages

Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment

Decoding the role of the nuclear receptor SHP in regulating hepatic stellate cells and liver fibrogenesis

Contact Info

Product

Resources

About