Aggf1 attenuates hepatic inflammation and activation of hepatic stellate cells by repressing Ccl2 transcription

Liver injury represents a continuum of pathophysiological processes involving a complex interplay between hepatocytes, macrophages, and hepatic stellate cells. The mechanism whereby these intercellular interactions contribute to liver injury and fibrosis is not completely understood. We report here that angiogenic factor with G patch and FHA domains 1(Aggfl) was downregulated in the livers of cirrhotic patients compared to healthy controls and in primary hepatocytes in response to carbon tetrachloride(CC14) stimulation. Overexpression of Aggfl attenuated macrophage chemotaxis. Aggfl interacted with NF-κB to block its binding to the Ccl2 gene promoter and repressed Ccl2 transcription in hepatocytes. Macrophages cultured in the conditioned media collected from Aggfloverexpressing hepatocytes antagonized HSC activation. Taken together, our data illustrate a novel role for Aggfl in regulating hepatic inflammation and provide insights on the development of interventional strategies against cirrhosis.

MKL1 mediates TNF-α induced pro-inflammatory transcription by bridging the crosstalk between BRG1 and WDR5

Tumor necrosis factor alpha(TNF-a) is a cytokine that can potently stimulate the synthesis of a range of proinflammatory mediators in macrophages. The underlying epigenetic mechanism, however, is underexplored. Here we report that the transcriptional modulator megakaryocytic leukemia 1(MKL1) is associated with a histone H3 K4 methyltransferase activity. Re-ChIP assay suggests that MKL1 interacts with and recruits WDR5, a component of the COMPASS complex responsible for H3 K4 methylation, to the promoter regions of pro-inflammatory genes in macrophages treated with TNF-α. WDR5 enhances the ability of MKL1 to stimulate the promoter activities of proinflammatory genes. In contrast, silencing of WDR5 attenuates TNF-a induced production of pro-inflammatory mediators and erases the H3 K4 methylation from the gene promoters. Of interest, the chromatin remodeling protein BRG1 also plays an essential role in maintaining H3 K4 methylation on MKL1 target promoters by interacting with WDR5. MKL1 knockdown disrupts the interaction between BRG1 and WDR5. Together, our data illustrate a role for MKL1 in moderating the crosstalk between BRG1 and WDR5 to activate TNF-a induced pro-inflammatory transcription in macrophages.

A BBS4 mutation causes autosomal dominant polycystic liver disease

Autosomal dominant polycystic liver disease(ADPLD)refers to a condition characterized by the presence of numerous cholangiocytes-lined and fluid-filled cysts in the liver and the absence of polycystic kidney disease.1 Although patients with ADPLD may be asymptomatic,some patients suffer from abdominal pain,gastroesophageal reflux,and nausea,because of hepatomegaly.