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

Abstract

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.

β‐Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis

“…The importance of this regulation is illustrated in mice lacking SHP, which show increased sensitivity to BDL secondary to increased basal expression of Cyp7a1 and increased bile flow (30, 31). The protective effect of SHP is also seen in several other studies where loss of SHP results in dysregulation of BA synthesis, while activation of SHP in hepatic stellate cells attenuates fibrosis (32, 33). Thus, the increased SHP expression seen in β-catenin KO after BDL is in line with previous reports describing an improvement in phenotype through reduction of BA synthesis and metabolism.…”

Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis

“…The critical antifibrotic role of Shp has been documented in the literature. An earlier study (47) demonstrated that disruption of Shp exacerbates bile duct ligation-induced cholestatic liver fibrosis, whereas Shp overexpression or increasing Shp expression by pharmacological compounds attenuates hepatic fibrosis induced either by hepatitis C virus infection (48) or by carbon tetrachloride and ␣-naphthyl-isothiocyanate (49). In addition, increasing Shp mRNA levels in HSCs by FXR ligands abrogates thrombin-and TGF-␤1-induced up-regulation of ␣1 collagen mRNA (50).…”

Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

“…Interestingly, the SHP interacting proteins are mainly nuclear receptors (such as FXR, ER, LXR, PXR, RAR, CAR, and PPAR) or other transcription factors (such as BMAL1, c-Jun, SREBP-1c, FOXO1, p65, and USF1), and dimerization with SHP usually leads to transcriptional repression of their target gene (117). These interactions regulate complex networks of metabolism, hemostasis and immune responses (52,117,118).…”