Chronic inflammation, inflicted by the spillover of proinflammatory mediators, links metabolic dysfunction to nonalcoholic steatohepatitis (NASH). The epigenetic maneuverings that underscore accelerated synthesis of proinflammatory mediators in response to nutritional inputs are not clearly defined. Here we report that the ATP-dependent chromatin remodeling proteins Brahma-related gene 1 (Brg1) and Brahma (Brm) were up-regulated in vitro in cultured hepatocytes treated with free fatty acid or glucose and in vivo in animal models of NASH. Occupancy of Brg1 and Brm on the promoter regions of proinflammatory genes was increased in vitro in cells and ex vivo in liver tissues. Estradiol suppressed the induction and recruitment of Brg1/Brm by palmitate. Recruitment of Brg1 and Brm relied on nuclear factor kappa B/p65; reciprocally, Brg1 and Brm contributed to the stabilization of p65 binding. Importantly, overexpression of Brg1/Brm enhanced, whereas knockdown of Brg1/Brm attenuated, the induction of proinflammatory mediators in hepatocytes challenged with excessive nutrient. Mechanistically, Brg1 and Brm were involved in the maintenance of a chromatin microenvironment marked by active histone modifications and friendly to the access of the general transcriptional machinery. Finally, depletion of Brg1/Brm by short hairpin RNA attenuated the release of proinflammatory mediators in the liver and significantly ameliorated hepatic pathology in NASH mice. Conclusion : Our data illustrate a Brg1-dependent pathway that connects the epigenetic regulation of proinflammatory genes to the pathogenesis of NASH and point to a potential druggable target in the therapeutic intervention of NASH. (HEPATOLOGY 2013;58:576–588)

Chronic inflammation impairs metabolic homeostasis and is intimately correlated with the pathogenesis of type 2 diabetes. The pro-inflammatory cytokine IFN-γ is an integral part of the metabolic inflammation circuit and contributes significantly to metabolic dysfunction. The underlying mechanism, however, remains largely unknown. In the present study, we report that IFN-γ disrupts the expression of genes key to cellular metabolism and energy expenditure by repressing the expression and activity of SIRT1 at the transcription level. Further analysis reveals that IFN-γ requires class II transactivator (CIITA) to repress SIRT1 transcription. CIITA, once induced by IFN-γ, is recruited to the SIRT1 promoter by hypermethylated in cancer 1 (HIC1) and promotes down-regulation of SIRT1 transcription via active deacetylation of core histones surrounding the SIRT1 proximal promoter. Silencing CIITA or HIC1 restores SIRT1 activity and expression of metabolic genes in skeletal muscle cells challenged with IFN-γ. Therefore, our data delineate an IFN-γ/HIC1/CIITA axis that contributes to metabolic dysfunction by suppressing SIRT1 transcription in skeletal muscle cells and as such shed new light on the development of novel therapeutic strategies against type 2 diabetes.

CtBP2 has been demonstrated to possess tumor-promoting capacities by virtue of up-regulating epithelial-mesenchymal transition (EMT) and down-regulating apoptosis in cancer cells. As a result, cellular CtBP2 levels are considered a key factor determining the outcome of oncogenic transformation. How pro-tumorigenic and anti-tumorigenic factors compete for fine-tuning CtBP2 levels is incompletely understood. Here we report that the cyclin H/cyclin-dependent kinase 7 (CCNH/CDK7) complex interacted with CtBP2 in vivo and in vitro. Depletion of either CCNH or CDK7 decreased CtBP2 protein levels by accelerating proteasome-dependent CtBP2 clearance. Further analysis revealed that CCNH/CDK7 competed with the tumor repressor HIPK2 for CtBP2 binding and consequently inhibited phosphorylation and dimerization of CtBP2. Phosphorylation-defective CtBP2 interacted more strongly with CCNH/CDK7 and was more resistant to degradation. Finally, overexpression of CtBP2 increased whereas depletion of CtBP2 dampened the invasive and migratory potential of breast cancer cells. CtBP2 promoted the invasion and migration of breast cancer cells in a CCNH-dependent manner. Taken together, our data have delineated a novel pathway that regulates CtBP2 stability, suggesting that targeting the CCNH/CDK7-CtBP2 axis may yield a viable anti-tumor strategy.