A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity.

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 acetylation-defective 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-κB but blocked that with RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα 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.

Bile acid signal-induced phosphorylation of small heterodimer partner by protein kinase Cζ is critical for epigenomic regulation of liver metabolic genes.

Bile acids (BAs) are recently recognized key signaling molecules that control integrative metabolism and energy expenditure. BAs activate multiple signaling pathways, including those of nuclear receptors, primarily farnesoid X receptor (FXR), membrane BA receptors, and FXR-induced FGF19 to regulate the fed-state metabolism. Small heterodimer partner (SHP) has been implicated as a key mediator of these BA signaling pathways by recruitment of chromatin modifying proteins, but the key question of how SHP transduces BA signaling into repressive histone modifications at liver metabolic genes remains unknown. Here we show that protein kinase Cζ (PKCζ) is activated by BA or FGF19 and phosphorylates SHP at Thr-55 and that Thr-55 phosphorylation is critical for the epigenomic coordinator functions of SHP. PKCζ is coimmunopreciptitated with SHP and both are recruited to SHP target genes after bile acid or FGF19 treatment. Activated phosphorylated PKCζ and phosphorylated SHP are predominantly located in the nucleus after FGF19 treatment. Phosphorylation at Thr-55 is required for subsequent methylation at Arg-57, a naturally occurring mutation site in metabolic syndrome patients. Thr-55 phosphorylation increases interaction of SHP with chromatin modifiers and their occupancy at selective BA-responsive genes. This molecular cascade leads to repressive modifications of histones at metabolic target genes, and consequently, decreased BA pools and hepatic triglyceride levels. Remarkably, mutation of Thr-55 attenuates these SHP-mediated epigenomic and metabolic effects. This study identifies PKCζ as a novel key upstream regulator of BA-regulated SHP function, revealing the role of Thr-55 phosphorylation in epigenomic regulation of liver metabolism.

Nhe1 is essential for potassium but not calcium facilitation of cell motility and the monovalent cation requirement for chemotactic orientation in Dictyostelium discoideum.

In Dictyostelium discoideum, extracellular K+ or Ca2+ at a concentration of 40 or 20 mM, respectively, facilitates motility in the absence or presence of a spatial gradient of chemoattractant. Facilitation results in maximum velocity, cellular elongation, persistent translocation, suppression of lateral pseudopod formation, and myosin II localization in the posterior cortex. A lower threshold concentration of 15 mM K+ or Na or 5 mM Ca2+ is required for chemotactic orientation. Although the common buffer solutions used by D. discoideum researchers to study chemotaxis contain sufficient concentrations of cations for chemotactic orientation, the majority contain insufficient levels to facilitate motility. Here it has been demonstrated that Nhe1, a plasma membrane protein, is required for K+ but not Ca2+ facilitation of cell motility and for the lower K+ but not Ca2+ requirement for chemotactic orientation.

Western Spruce Budworm Effects on Forest Resilience.

Western spruce budworm (Choristoneura freemani Razowski) is the most destructive defoliator of forests in the western US. Forests in northern New Mexico experienced high levels of WSBW-caused defoliation and subsequent mortality between the 1980s and 2010s. The effects of severe western spruce budworm outbreaks on stand dynamics in the US Southwest are still relatively unknown, but understanding the impacts is important to the management and resilience of these forests. To begin addressing this knowledge gap, we conducted a study along two gradients: an elevational gradient from mixed-conifer to spruce-fir forests and a gradient of WSBW-caused defoliation intensity. We recorded overstory and understory stand conditions (size structure, species composition, damaging agents). Western spruce budworm was the primary damaging agent of host trees in all stands andcaused host tree mortality across all size classes, particularly in spruce-fir stands. Results indicate an unsustainable level of mortality in spruce-fir stands and a transition towards non-host species in mixed-conifer stands. Low levels of regeneration coupled with high overstory mortality rates indicate a potential lack of resilience in spruce-fir stands, whereas resilience to future western spruce budworm defoliation events may have increased in mixed-conifer stands affected by these outbreaks.

Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis.

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.

Epigenomic regulation of bile acid metabolism: emerging role of transcriptional cofactors.

The traditional role of bile acids is to simply facilitate absorption and digestion of lipid nutrients, but bile acids also act as endocrine signaling molecules that activate nuclear and membrane receptors to control integrative metabolism and energy balance. The mechanisms by which bile acid signals are integrated to regulate target genes are, however, largely unknown. Recently emerging evidence has shown that transcriptional cofactors sense metabolic changes and modulate gene transcription by mediating reversible epigenomic post-translational modifications (PTMs) of histones and chromatin remodeling. Importantly, targeting these epigenomic changes has been a successful approach for treating human diseases, especially cancer. Here, we review emerging roles of transcriptional cofactors in the epigenomic regulation of liver metabolism, especially focusing on bile acid metabolism. Targeting PTMs of histones and chromatin remodelers, together with the bile acid-activated receptors, may provide new therapeutic options for bile acid-related disease, such as cholestasis, obesity, diabetes, and entero-hepatic cancers.