Nuclear factor-κB regulates the expression of multiple genes encoding liver transport proteins

Abstract

Balasubramaniyan N, Ananthanarayanan M, Suchy FJ. Nuclear factor-B regulates the expression of multiple genes encoding liver transport proteins.

Role of FXR in Liver Inflammation During Nonalcoholic Steatohepatitis

“…Most importantly, it was demonstrated that pretreatment with FXR agonists (GW4064 and 6ECDCA) suppressed NF-κB agonist-induced inflammatory gene expression in an FXR-dependent manner in HepG2 cells and mouse primary hepatocytes [30]. NF-κB binding sites were identified on FXR and FXR target genes BSEP , SHP , MRP2 , MDR3 , and ABCG5/G8 ; specifically, NF-κB bound to the promoter of BSEP and actively suppressed transcription [37]. Overexpression of NF-κB recruited nuclear receptor co-repressor 2 (SMRT), and blocked FXR binding to its FXRE [37].…”

“…NF-κB binding sites were identified on FXR and FXR target genes BSEP , SHP , MRP2 , MDR3 , and ABCG5/G8 ; specifically, NF-κB bound to the promoter of BSEP and actively suppressed transcription [37]. Overexpression of NF-κB recruited nuclear receptor co-repressor 2 (SMRT), and blocked FXR binding to its FXRE [37]. Direct interaction between FXR and NF-κB was further confirmed in vivo , NF-κB recruitment to FXR and BSEP promoter was increased in models of disease and inflammation (bile-duct ligation and LPS-injection) [37], confirming previous observations of suppressed FXR signaling during inflammatory response [30, 38].…”

“…Overexpression of NF-κB recruited nuclear receptor co-repressor 2 (SMRT), and blocked FXR binding to its FXRE [37]. Direct interaction between FXR and NF-κB was further confirmed in vivo , NF-κB recruitment to FXR and BSEP promoter was increased in models of disease and inflammation (bile-duct ligation and LPS-injection) [37], confirming previous observations of suppressed FXR signaling during inflammatory response [30, 38]. NF-κB and SMRT recruitment to promoters of FXR and FXR-regulated genes may be a predominant adaptive mechanism in chronic inflammatory disease states characterized by decreased FXR and FXR-dependent signaling cascades.…”

Up‐regulation of miR‐let7a‐5p Leads to Decreased Expression of ABCC2 in Obstructive Cholestasis

“…We have previously shown that mixed lineage leukemia 3, a histone H3 lysine 4 lysine methyltransferase, is depressed after CBDL in mice, and this epigenetic mark is essential to activation of Abcc2 by the nuclear receptor FXR . We have also reported that transcription factor nuclear factor kappa B (NF‐κB) suppresses the transactivation of ABCC2 by FXR in vitro , and that NF‐κB activation in the context of obstructive cholestasis in mice establishes a repressive chromatin environment at the promoters of several FXR‐target genes, including the promoter of Abcc 2 through recruitment of HDACs and corepressors . It is likely that these and other mediators act in concert with let7a‐5p to repress ABCC2 expression in cholestasis, but the relative importance of each pathway during the progression of liver disease has not been defined.…”

“…Following protein transfer, the blots were blocked with 5% Nonfat Dry Blot Omniblok (American BioAnalytical, Natick, MA) in 1 × blocking buffer (diluted from 10 × Tris‐buffered saline with 0.5% Tween 20 [Kirkegaard & Perry Lab Inc., Gaithersburg, MD]). Following blocking, incubation with primary antibodies (to BSEP, MRP2, NTCP, FXR, and β‐actin) with secondary peroxidase‐conjugated antibodies and the washing steps was done as previously described . Signals developed with Clarity western ECL substrate (Bio‐Rad) were quantitated using the Bio‐Rad ChemiDoc System.…”