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"Kim, Chae"
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Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase
Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we report fasting-induced Fibroblast Growth Factor-21 (FGF21) signaling activates hepatic autophagy and lipid degradation via Jumonji-D3 (JMJD3/KDM6B) histone demethylase. Upon FGF21 signaling, JMJD3 epigenetically upregulates global autophagy-network genes, including
Tfeb
,
Atg7
,
Atgl
, and
Fgf21
, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increases its nuclear localization and interaction with the nuclear receptor PPARα to transcriptionally activate autophagy. Administration of FGF21 in obese mice improves defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and ULK1 is substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.
Fasting induces hepatic autophagy to preserve energy homeostasis. Here the authors report that fasting induced fibroblast growth factor 21 signalling induces autophagy by activating lysine-specific demethylase 6B, leading to histone demethylation mediated activation of autophagy genes.
Journal Article
Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A
Hepatic lipogenesis is normally tightly regulated but is aberrantly elevated in obesity. Fibroblast Growth Factor-15/19 (mouse FGF15, human FGF19) are bile acid-induced late fed-state gut hormones that decrease hepatic lipid levels by unclear mechanisms. We show that FGF15/19 and FGF15/19-activated Small Heterodimer Partner (SHP/NR0B2) have a role in transcriptional repression of lipogenesis. Comparative genomic analyses reveal that most of the SHP cistrome, including lipogenic genes repressed by FGF19, have overlapping CpG islands. FGF19 treatment or SHP overexpression in mice inhibits lipogenesis in a DNA methyltransferase-3a (DNMT3A)-dependent manner. FGF19-mediated activation of SHP via phosphorylation recruits DNMT3A to lipogenic genes, leading to epigenetic repression via DNA methylation. In non-alcoholic fatty liver disease (NAFLD) patients and obese mice, occupancy of SHP and DNMT3A and DNA methylation at lipogenic genes are low, with elevated gene expression. In conclusion, FGF15/19 represses hepatic lipogenesis by activating SHP and DNMT3A physiologically, which is likely dysregulated in NAFLD.
Hepatic lipogenesis is a tightly regulated process, which is elevated in obesity. Here the authors report that FGF15/19, bile acid-induced gut hormones, repress lipogenic genes in the late fed-state by activating small heterodimer partner (SHP) and promoting SHP-dependent recruitment of DNA methyltransferase DNMT3A to lipogenic genes.
Journal Article
Warcraft : the Sunwell trilogy. Volume 2, Shadows of ice
\"Kalec, a blue dragon that has taken human form to escape the forces that seek to destroy his race, and Anveena, a maiden with mysterious powers, go on a quest to save the entire High Elven Kingdom from the evil forces of the Undead Scourge.\"--Amazon.com
Book
Elucidating the role of metal ions in carbonic anhydrase catalysis
Why metalloenzymes often show dramatic changes in their catalytic activity when subjected to chemically similar but non-native metal substitutions is a long-standing puzzle. Here, we report on the catalytic roles of metal ions in a model metalloenzyme system, human carbonic anhydrase II (CA II). Through a comparative study on the intermediate states of the zinc-bound native CA II and non-native metal-substituted CA IIs, we demonstrate that the characteristic metal ion coordination geometries (tetrahedral for Zn
2+
, tetrahedral to octahedral conversion for Co
2+
, octahedral for Ni
2+
, and trigonal bipyramidal for Cu
2+
) directly modulate the catalytic efficacy. In addition, we reveal that the metal ions have a long-range (~10 Å) electrostatic effect on restructuring water network in the active site. Our study provides evidence that the metal ions in metalloenzymes have a crucial impact on the catalytic mechanism beyond their primary chemical properties.
Metalloenzymes often show different catalytic activities in the presence of non-native metal ions. Here, the authors report structures of carbonic anhydrase bound to zinc and several other metal ions and demonstrate that metal ion coordination geometries directly impact catalytic activity of the enzyme.
Journal Article
Making we the people : democratic constitutional founding in postwar Japan and South Korea
\"What does it mean to say that it is 'we the people' who 'ordain and establish' a constitution? Who are those sovereign people, and how can they do so? Interweaving history and theory, constitutional scholar Chaihark Hahm and political theorist Sung Ho Kim attempt to answer these perennial questions by revisiting the constitutional politics of postwar Japan and Korea. Together, these experiences demonstrate the infeasibility of the conventional assumption that there is a clearly bounded sovereign 'people' prior to constitution-making which may stand apart from both outside influence and troubled historical legacies. The authors argue that 'we the people' only emerges through a deeply transformative politics of constitutional founding and, as such, a democratic constitution and its putative author are mutually constitutive. Highly original and genuinely multidisciplinary, this book will be of interest to scholars of comparative constitutionalism as well as observers of ongoing constitutional debates in Japan and Korea\"-- Provided by publisher.
Book
Risk of adverse pregnancy outcomes by maternal occupational status: A national population‐based study in South Korea
Objective This study examined the association between maternal occupational status and adverse pregnancy outcomes in the general South Korean population. Methods We analyzed 1 825 845 employed and non‐employed women with a diagnostic code for pregnancy in the National Health Insurance Service (NHIS) database (2010–2019) of South Korea. Based on their employment status and type of occupation, we calculated risk ratios for three adverse outcomes: early abortive outcomes (miscarriage, ectopic pregnancy, and molar pregnancy), stillbirth, and no live birth (diagnosis of pregnancy with no record of live birth thereafter, which include early abortive outcomes and stillbirth) with adjusting for covariates. Results Overall, 18.0%, 0.7%, and 39.8% ended in early abortive outcomes, stillbirths, and no live births, respectively. The risk of early abortive outcomes and stillbirths was higher in non‐employed women than in employed women, while no live births were more frequent in employed women. Those in the health and social work industry showed the highest risk of no live births. Manufacturing jobs (1.030, 95% CI: 1.013, 1.047) and health/social work (1.029, 95% CI: 1.012, 1.046) were associated with an increased risk of early abortive outcomes compared with financial and insurance jobs. Consistently higher risks of no live births were observed in the manufacturing, wholesale/retail trade, education, health/social work, and public/social/personal service occupation. Conclusion Employment during pregnancy and several occupation types were associated with a higher risk of pregnancy loss. Additional research using detailed job activity data is needed to determine specific occupational causes of adverse pregnancy outcomes.
Journal Article
Warcraft : the Sunwell trilogy. Volume 3, Ghostlands
The mighty Sunwell, source of the high elves' magical might, had been thought lost... until now! In the ruins of the Ghostlands, a young blue dragon and his companions must fight to save one of their own from certain death. But here the dead refuse to rest easy!
Book
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.
FXR plays an important role in bile acid homeostasis by transcriptionally modulating several enterohepatic genes, including intestinal FGF19, that repress hepatic bile acid synthesis. Here the authors show that postprandial FGF19 regulates FXR transcriptional activity via its action on the tyrosine kinase Src, which phosphorylates FXR.
Journal Article