Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and acetylationdefective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-jB but blocked that with RXRa, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRa target genes. A dysregulated acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders.
Tree-ring records were used to reconstruct spatial and temporal patterns of western spruce budworm (Choristoneura occidentalis Freeman) outbreaks in mixed conifer forests of southern Colorado. Reconstructions in 11 host stands showed a regionally synchronous pattern of at least 14 outbreaks during the past 350 years. Intervals between outbreaks were highly variable within stands, but at the regional scale outbreak intervals were more consistent. Spectral analyses of regional outbreak time series confirmed periodicities at about 25, 37, and 83 years. Comparison with an independent drought reconstruction indicated that outbreaks typically corresponded to increased moisture, while relatively little budworm activity occurred during dry periods. In contrast to other published reconstructions in Colorado and New Mexico, reconstructions from this study area did not exhibit significant 20th-century changes in the frequency of outbreak occurrence or magnitude of growth reduction. Sharply reduced growth during outbreaks was not clearly visible on the increment core samples, and budworm-induced reductions in tree-ring growth were usually detectable only after comparison with nonhost tree-ring series. This finding emphasizes that defoliation effects on ring growth can be highly relativistic. Hence, caution should be exercised in reconstructing insect outbreak histories based only on visual detection approaches, or without comparison with nonhost or nondefoliated tree-ring control series.
Farnesoid-X-Receptor (FXR) plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis. How activation of the FGF19 receptor at the membrane is transmitted to the nucleus for transcriptional regulation of BA levels and whether FGF19 signaling posttranslationally modulates FXR function remain largely unknown. Here we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase, Src, in response to postprandial FGF19, which is critical for its nuclear localization and transcriptional regulation of BA levels. Liver-specific expression of phospho-defective Y67F-FXR or Src downregulation in mice results in impaired homeostatic responses to acute BA feeding, and exacerbates cholestatic pathologies upon drug-induced hepatobiliary insults. Also, the hepatic FGF19-Src-FXR pathway is defective in primary biliary cirrhosis (PBC) patients. This study identifies Src-mediated FXR phosphorylation as a potential therapeutic target and biomarker for BA-related enterohepatic diseases.
Background: Small heterodimer partner (SHP) is a key mediator of bile acid signaling. Results: Bile acid signal-induced phosphorylation at Thr-55 by protein kinase C is important for SHP-mediated recruitment of chromatin modifiers and histone modifications. Conclusion: Thr-55 phosphorylation is critical for epigenomic regulation of liver metabolic genes. Significance: SHP Thr-55 phosphorylation may potentially provide a therapeutic target for bile acid-related diseases.
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