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Jongsook Kim Kemper - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation of hepatic farnesoid x receptor by FGF19 signaling activated src maintains cholesterol levels and protects from atherosclerosis
Journal of Biological Chemistry, 2019Co-Authors: Sangwon Byun, Byron Kemper, Bo Kong, Hyunkyung Jung, Jinjing Chen, Jongsook Kim KemperAbstract:: The bile acid (BA) nuclear receptor, farnesoid X receptor (FXR/NR1H4), maintains metabolic homeostasis by transcriptional control of numerous genes, including an intestinal hormone, fibroblast growth factor-19 (FGF19; FGF15 in mice). Besides activation by BAs, the gene-regulatory function of FXR is also modulated by hormone or nutrient signaling-induced post-translational modifications. Recently, phosphorylation at Tyr-67 by the FGF15/19 signaling-activated nonreceptor tyrosine kinase Src was shown to be important for FXR function in BA homeostasis. Here, we examined the role of this FXR phosphorylation in cholesterol regulation. In both hepatic FXR-knockout and FXR-knockdown mice, reconstitution of FXR expression up-regulated cholesterol transport genes for its biliary excretion, including scavenger receptor class B member 1 (Scarb1) and ABC subfamily G member 8 (Abcg5/8), decreased hepatic and plasma cholesterol levels, and increased biliary and fecal cholesterol levels. Of note, these sterol-lowering effects were blunted by substitution of Phe for Tyr-67 in FXR. Moreover, consistent with Src's role in phosphorylating FXR, Src knockdown impaired cholesterol regulation in mice. In hypercholesterolemic apolipoprotein E-deficient mice, expression of FXR, but not Y67F-FXR, ameliorated atherosclerosis, whereas Src down-regulation exacerbated it. Feeding or treatment with an FXR agonist induced Abcg5/8 and Scarb1 expression in WT, but not FGF15-knockout, mice. Furthermore, FGF19 treatment increased occupancy of FXR at Abcg5/8 and Scarb1, expression of these genes, and cholesterol efflux from hepatocytes. These FGF19-mediated effects were blunted by the Y67F-FXR substitution or Src down-regulation or inhibition. We conclude that phosphorylation of hepatic FXR by FGF15/19-induced Src maintains cholesterol homeostasis and protects against atherosclerosis.
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small heterodimer partner and fibroblast growth factor 19 inhibit expression of npc1l1 in mouse intestine and cholesterol absorption
Gastroenterology, 2019Co-Authors: Sangwon Byun, Sunmi Seok, Byron Kemper, Eric H Xu, Jongsook Kim KemperAbstract:Background & Aims The nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in the liver and intestine. Postprandial fibroblast growth factor 19 (human FGF19, mouse FGF15) signaling increases the transcriptional activity of SHP. We studied the functions of SHP and FGF19 in the intestines of mice, including their regulation of expression of the cholesterol transporter NPC1L1 )NPC1-like intracellular cholesterol transporter 1) and cholesterol absorption. Methods We performed histologic and biochemical analyses of intestinal tissues from C57BL/6 and SHP-knockout mice and performed RNA-sequencing analyses to identify genes regulated by SHP. The effects of fasting and refeeding on intestinal expression of NPC1L1 were examined in C57BL/6, SHP-knockout, and FGF15-knockout mice. Mice were given FGF19 daily for 1 week; fractional cholesterol absorption, cholesterol and bile acid (BA) levels, and composition of BAs were measured. Intestinal organoids were generated from C57BL/6 and SHP-knockout mice, and cholesterol uptake was measured. Luciferase reporter assays were performed with HT29 cells. Results We found that the genes that regulate lipid and ion transport in intestine, including NPC1L1, were up-regulated and that cholesterol absorption was increased in SHP-knockout mice compared with C57BL/6 mice. Expression of NPC1L1 was reduced in C57BL/6 mice after refeeding after fasting but not in SHP-knockout or FGF15-knockout mice. SHP-knockout mice had altered BA composition compared with C57BL/6 mice. FGF19 injection reduced expression of NPC1L1, decreased cholesterol absorption, and increased levels of hydrophilic BAs, including tauro-α- and -β-muricholic acids; these changes were not observed in SHP-knockout mice. SREBF2 (sterol regulatory element binding transcription factor 2), which regulates cholesterol, activated transcription of NPC1L1. FGF19 signaling led to phosphorylation of SHP, which inhibited SREBF2 activity. Conclusions Postprandial FGF19 and SHP inhibit SREBF2, which leads to repression of intestinal NPC1L1 expression and cholesterol absorption. Strategies to increase FGF19 signaling to activate SHP might be developed for treatment of hypercholesterolemia.
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postprandial FGF19 induced phosphorylation by src is critical for fxr function in bile acid homeostasis
Nature Communications, 2018Co-Authors: Sangwon Byun, Byron Kemper, Eric H Xu, Bo Kong, Daniel Ryerson, Jongsook Kim KemperAbstract: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.
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a postprandial FGF19 shp lsd1 regulatory axis mediates epigenetic repression of hepatic autophagy
The EMBO Journal, 2017Co-Authors: Sangwon Byun, Byron Kemper, Yang Zhang, Bo Kong, Junichi Sadoshima, Jongsook Kim KemperAbstract:Abstract Lysosome‐mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient‐sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed‐state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP‐null mice or LSD1‐depleted mice. In addition, feeding‐mediated autophagy inhibition is attenuated in FGF15‐null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB‐bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1‐mediated demethylation of gene‐activation histone marks H3K4‐me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19‐SHP‐LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient‐rich postprandial conditions.
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A postprandial FGF19‐SHP‐LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy
The EMBO Journal, 2017Co-Authors: Sangwon Byun, Byron Kemper, Yang Zhang, Bo Kong, Junichi Sadoshima, Jian Ma, Jongsook Kim KemperAbstract:Abstract Lysosome‐mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient‐sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed‐state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP‐null mice or LSD1‐depleted mice. In addition, feeding‐mediated autophagy inhibition is attenuated in FGF15‐null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB‐bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1‐mediated demethylation of gene‐activation histone marks H3K4‐me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19‐SHP‐LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient‐rich postprandial conditions.
Yong Teng - One of the best experts on this subject based on the ideXlab platform.
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FGF19 amplification reveals an oncogenic dependency upon autocrine FGF19 fgfr4 signaling in head and neck squamous cell carcinoma
Oncogene, 2019Co-Authors: Liwei Lang, Xiangdong Zhao, Chloe Shay, Austin Y Shull, Yong TengAbstract:The fibroblast growth factor 19 gene FGF19 has previously been reported to be amplified in several cancer types and encodes for a key autocrine signaler known to promote tumorigenic growth. Thus, it is imperative to understand which cancers are oncogenically addicted to FGF19 amplification as well as the role it serves in these cancer types. We report for the first time high FGF19 amplification in head and neck squamous cell carcinomas (HNSCC), which is associated with increased autocrine secretion of FGF19 and poor patient outcome in HNSCC. FGF19 amplification corresponded with constitutive activation of FGF receptor 4 (FGFR4)-dependent ERK/AKT–p70S6K–S6 signaling activation in HNSCC cells, and addition of human recombinant FGF19 could promote cell proliferation and soft agar colony formation in HNSCC cells with low FGF19 expression through activation of FGFR4 and downstream signaling cascades. In contrast, FGF19 knockout counteracts the observed effects in HNSCC cells carrying high endogenous FGF19, with knockout of FGF19 significantly suppressing tumor growth in an orthotopic mouse model of HNSCC. Collectively, this study demonstrates that FGF19 gene amplification corresponds with an increased dependency upon FGF19/FGFR4 autocrine signaling in HNSCC, revealing a therapeutic target for this cancer type.
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interrupting the FGF19 fgfr4 axis to therapeutically disrupt cancer progression
Current Cancer Drug Targets, 2018Co-Authors: Liwei Lang, Austin Y Shull, Yong TengAbstract:: Coordination between the amplification of the fibroblast growth factor FGF19, overexpression of its corresponding receptor FGFR4, and hyperactivation of the downstream transmembrane enzyme β-klotho has been found to play pivotal roles in mediating tumor development and progression. Aberrant FGF19-FGFR4 signaling has been implicated in driving specific tumorigenic events including cancer cell proliferation, apoptosis resistance, and metastasis by activating a myriad of downstream signaling cascades. As an attractive target, several strategies implemented to disrupt the FGF19-FGFR4 axis have been developed in recent years, and FGF19-FGFR4 binding inhibitors are being intensely evaluated for their clinical use in treating FGF19-FGFR4 implicated cancers. Based on the established work, this review aims to detail how the FGF19-FGFR4 signaling pathway plays a vital role in cancer progression and why disrupting communication between FGF19 and FGFR4 serves as a promising therapeutic strategy for disrupting cancer progression.
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FGF19 amplification reveals an oncogenic dependency upon autocrine FGF19/FGFR4 signaling in head and neck squamous cell carcinoma
Oncogene, 2018Co-Authors: Liwei Lang, Xiangdong Zhao, Chloe Shay, Austin Y Shull, Yong TengAbstract:The fibroblast growth factor 19 gene FGF19 has previously been reported to be amplified in several cancer types and encodes for a key autocrine signaler known to promote tumorigenic growth. Thus, it is imperative to understand which cancers are oncogenically addicted to FGF19 amplification as well as the role it serves in these cancer types. We report for the first time high FGF19 amplification in head and neck squamous cell carcinomas (HNSCC), which is associated with increased autocrine secretion of FGF19 and poor patient outcome in HNSCC. FGF19 amplification corresponded with constitutive activation of FGF receptor 4 (FGFR4)-dependent ERK/AKT–p70S6K–S6 signaling activation in HNSCC cells, and addition of human recombinant FGF19 could promote cell proliferation and soft agar colony formation in HNSCC cells with low FGF19 expression through activation of FGFR4 and downstream signaling cascades. In contrast, FGF19 knockout counteracts the observed effects in HNSCC cells carrying high endogenous FGF19, with knockout of FGF19 significantly suppressing tumor growth in an orthotopic mouse model of HNSCC. Collectively, this study demonstrates that FGF19 gene amplification corresponds with an increased dependency upon FGF19/FGFR4 autocrine signaling in HNSCC, revealing a therapeutic target for this cancer type.
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fgfr4 provides the conduit to facilitate FGF19 signaling in breast cancer progression
Molecular Carcinogenesis, 2018Co-Authors: Xiangdong Zhao, Chloe Shay, Faliang Xu, Nestor P Dominguez, Yuanping Xiong, Zhongxun Xiong, Hong Peng, Yong TengAbstract:: Although genetic amplification and overexpression of the fibroblast growth factor 19 (FGF19) gene are found in human breast cancer, mechanisms that contribute to such functional alterations remain elusive. We report here that high expression of FGF19 is associated with the aggressive malignant behavior and poor survival outcome of breast cancer patients. FGF19 is particularly highly expressed in luminal molecular subtype of breast tumors and its expression levels are positively associated with its secretion levels from breast cancer cells. Genetic knockout of FGF19 significantly induces repression of breast tumor progression and metastasis in either an orthotopic mouse model of breast cancer or an experimental metastasis model. The FGF19 specific receptor, FGFR4, can be activated and subsequently upregulate AKT signaling in breast cancer cell upon FGF19, which is critical for oncogenic role of FGF19. Inactivation of FGFR4 by its inhibitor BLU9931 significantly attenuates FGF19-induced tumor-promoting activity, suggesting interruption of FGFR4 function is sufficient to affect FGF19-driven breast cancer. Overall, these insights support the idea that targeting FGFR4 in breast cancer cells overexpressing FGF19 may represent an effective strategy to suppress cancer development, progression, and metastasis.
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Making way for suppressing the FGF19/FGFR4 axis in cancer.
Future Medicinal Chemistry, 2018Co-Authors: Néstor Prieto-domínguez, Austin Y Shull, Yong TengAbstract:FGF19 is a noncanonical FGF ligand that can control a broad spectrum of physiological responses, which include bile acid homeostasis, liver metabolism and glucose uptake. Many of these responses are mediated by FGF19 binding to its FGFR4/β-klotho receptor complex and controlling activation of an array of intracellular signaling events. Overactivation of the FGF19/FGFR4 axis has been implicated in tumorigenic formation, progression and metastasis, and inhibitors of this axis have recently been developed for single agent use or in combination with other anticancer drugs. Considering the critical role of this receptor complex in cancer, this review focuses on recent developments and applications of FGF19/FGFR4-targeted therapeutics.
Sangwon Byun - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation of hepatic farnesoid x receptor by FGF19 signaling activated src maintains cholesterol levels and protects from atherosclerosis
Journal of Biological Chemistry, 2019Co-Authors: Sangwon Byun, Byron Kemper, Bo Kong, Hyunkyung Jung, Jinjing Chen, Jongsook Kim KemperAbstract:: The bile acid (BA) nuclear receptor, farnesoid X receptor (FXR/NR1H4), maintains metabolic homeostasis by transcriptional control of numerous genes, including an intestinal hormone, fibroblast growth factor-19 (FGF19; FGF15 in mice). Besides activation by BAs, the gene-regulatory function of FXR is also modulated by hormone or nutrient signaling-induced post-translational modifications. Recently, phosphorylation at Tyr-67 by the FGF15/19 signaling-activated nonreceptor tyrosine kinase Src was shown to be important for FXR function in BA homeostasis. Here, we examined the role of this FXR phosphorylation in cholesterol regulation. In both hepatic FXR-knockout and FXR-knockdown mice, reconstitution of FXR expression up-regulated cholesterol transport genes for its biliary excretion, including scavenger receptor class B member 1 (Scarb1) and ABC subfamily G member 8 (Abcg5/8), decreased hepatic and plasma cholesterol levels, and increased biliary and fecal cholesterol levels. Of note, these sterol-lowering effects were blunted by substitution of Phe for Tyr-67 in FXR. Moreover, consistent with Src's role in phosphorylating FXR, Src knockdown impaired cholesterol regulation in mice. In hypercholesterolemic apolipoprotein E-deficient mice, expression of FXR, but not Y67F-FXR, ameliorated atherosclerosis, whereas Src down-regulation exacerbated it. Feeding or treatment with an FXR agonist induced Abcg5/8 and Scarb1 expression in WT, but not FGF15-knockout, mice. Furthermore, FGF19 treatment increased occupancy of FXR at Abcg5/8 and Scarb1, expression of these genes, and cholesterol efflux from hepatocytes. These FGF19-mediated effects were blunted by the Y67F-FXR substitution or Src down-regulation or inhibition. We conclude that phosphorylation of hepatic FXR by FGF15/19-induced Src maintains cholesterol homeostasis and protects against atherosclerosis.
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small heterodimer partner and fibroblast growth factor 19 inhibit expression of npc1l1 in mouse intestine and cholesterol absorption
Gastroenterology, 2019Co-Authors: Sangwon Byun, Sunmi Seok, Byron Kemper, Eric H Xu, Jongsook Kim KemperAbstract:Background & Aims The nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in the liver and intestine. Postprandial fibroblast growth factor 19 (human FGF19, mouse FGF15) signaling increases the transcriptional activity of SHP. We studied the functions of SHP and FGF19 in the intestines of mice, including their regulation of expression of the cholesterol transporter NPC1L1 )NPC1-like intracellular cholesterol transporter 1) and cholesterol absorption. Methods We performed histologic and biochemical analyses of intestinal tissues from C57BL/6 and SHP-knockout mice and performed RNA-sequencing analyses to identify genes regulated by SHP. The effects of fasting and refeeding on intestinal expression of NPC1L1 were examined in C57BL/6, SHP-knockout, and FGF15-knockout mice. Mice were given FGF19 daily for 1 week; fractional cholesterol absorption, cholesterol and bile acid (BA) levels, and composition of BAs were measured. Intestinal organoids were generated from C57BL/6 and SHP-knockout mice, and cholesterol uptake was measured. Luciferase reporter assays were performed with HT29 cells. Results We found that the genes that regulate lipid and ion transport in intestine, including NPC1L1, were up-regulated and that cholesterol absorption was increased in SHP-knockout mice compared with C57BL/6 mice. Expression of NPC1L1 was reduced in C57BL/6 mice after refeeding after fasting but not in SHP-knockout or FGF15-knockout mice. SHP-knockout mice had altered BA composition compared with C57BL/6 mice. FGF19 injection reduced expression of NPC1L1, decreased cholesterol absorption, and increased levels of hydrophilic BAs, including tauro-α- and -β-muricholic acids; these changes were not observed in SHP-knockout mice. SREBF2 (sterol regulatory element binding transcription factor 2), which regulates cholesterol, activated transcription of NPC1L1. FGF19 signaling led to phosphorylation of SHP, which inhibited SREBF2 activity. Conclusions Postprandial FGF19 and SHP inhibit SREBF2, which leads to repression of intestinal NPC1L1 expression and cholesterol absorption. Strategies to increase FGF19 signaling to activate SHP might be developed for treatment of hypercholesterolemia.
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postprandial FGF19 induced phosphorylation by src is critical for fxr function in bile acid homeostasis
Nature Communications, 2018Co-Authors: Sangwon Byun, Byron Kemper, Eric H Xu, Bo Kong, Daniel Ryerson, Jongsook Kim KemperAbstract: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.
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a postprandial FGF19 shp lsd1 regulatory axis mediates epigenetic repression of hepatic autophagy
The EMBO Journal, 2017Co-Authors: Sangwon Byun, Byron Kemper, Yang Zhang, Bo Kong, Junichi Sadoshima, Jongsook Kim KemperAbstract:Abstract Lysosome‐mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient‐sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed‐state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP‐null mice or LSD1‐depleted mice. In addition, feeding‐mediated autophagy inhibition is attenuated in FGF15‐null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB‐bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1‐mediated demethylation of gene‐activation histone marks H3K4‐me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19‐SHP‐LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient‐rich postprandial conditions.
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A postprandial FGF19‐SHP‐LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy
The EMBO Journal, 2017Co-Authors: Sangwon Byun, Byron Kemper, Yang Zhang, Bo Kong, Junichi Sadoshima, Jian Ma, Jongsook Kim KemperAbstract:Abstract Lysosome‐mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient‐sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed‐state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP‐null mice or LSD1‐depleted mice. In addition, feeding‐mediated autophagy inhibition is attenuated in FGF15‐null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB‐bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1‐mediated demethylation of gene‐activation histone marks H3K4‐me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19‐SHP‐LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient‐rich postprandial conditions.
Bo Kong - One of the best experts on this subject based on the ideXlab platform.
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direct and indirect effects of fibroblast growth factor fgf 15 and FGF19 on liver fibrosis development
Hepatology, 2020Co-Authors: Justin D Schumacher, Bo Kong, Jason Wu, Daniel Rizzolo, Laura E Armstrong, Monica D Chow, Michael J GoedkenAbstract:: Farnesoid X receptor (FXR) induces fibroblast growth factor 15 (FGF15; human ortholog FGF19) in the gut to potently inhibit bile acid (BA) synthesis in the liver. FXR activation in hepatic stellate cells (HSCs) reduces liver fibrosis (LF). Fgf15-/- mice develop attenuated LF, but the underlying mechanisms for this protection are unclear. We hypothesized that FGF15/19 functions as a profibrotic mediator or mitogen to HSCs and increased BAs in Fgf15-/- mice leads to enhanced FXR activation in HSCs, subsequently reducing fibrogenesis. In this study, complimentary in vivo and in vitro approaches were used: (1) CCl4 -induced LF model in wild type (WT), Fgf15-/- , and Fgf15 transgenic (TG) mice with BA levels modulated by feeding cholestyramine- or cholic acid-containing diets; (2) analysis of primary HSCs isolated from WT and Fgf15-/- mice; and (3) treatment of a human HSC line, LX-2, with FXR activators and/or recombinant FGF19 protein. The results showed that Fgf15-/- mice had lower basal collagen expression, which was increased by BA sequestration. CCl4 induced fibrosis with similar severity in all genotypes; however, cholestyramine increased fibrosis severity only in Fgf15-/- mice. HSCs from Fgf15-/- mice showed increased FXR activity and reduced expression of profibrotic mediators. In LX-2 cells, FXR activation increased peroxisome proliferator-activated receptor gamma activity and reduced proliferation. FGF19 activated both signal transducer and activator of transcription 3 and c-Jun N-terminal kinase pathways and reduced nuclear factor kappa-light-chain-enhancer of activated B cells signaling without increasing fibrogenic gene expression or cell proliferation. Conclusion: FGF15/19 does not act as a direct profibrotic mediator or mitogen to HSCs in our models, and the protection against fibrosis by FGF15 deficiency may be mediated through increased BA activation of FXR in HSCs.
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phosphorylation of hepatic farnesoid x receptor by FGF19 signaling activated src maintains cholesterol levels and protects from atherosclerosis
Journal of Biological Chemistry, 2019Co-Authors: Sangwon Byun, Byron Kemper, Bo Kong, Hyunkyung Jung, Jinjing Chen, Jongsook Kim KemperAbstract:: The bile acid (BA) nuclear receptor, farnesoid X receptor (FXR/NR1H4), maintains metabolic homeostasis by transcriptional control of numerous genes, including an intestinal hormone, fibroblast growth factor-19 (FGF19; FGF15 in mice). Besides activation by BAs, the gene-regulatory function of FXR is also modulated by hormone or nutrient signaling-induced post-translational modifications. Recently, phosphorylation at Tyr-67 by the FGF15/19 signaling-activated nonreceptor tyrosine kinase Src was shown to be important for FXR function in BA homeostasis. Here, we examined the role of this FXR phosphorylation in cholesterol regulation. In both hepatic FXR-knockout and FXR-knockdown mice, reconstitution of FXR expression up-regulated cholesterol transport genes for its biliary excretion, including scavenger receptor class B member 1 (Scarb1) and ABC subfamily G member 8 (Abcg5/8), decreased hepatic and plasma cholesterol levels, and increased biliary and fecal cholesterol levels. Of note, these sterol-lowering effects were blunted by substitution of Phe for Tyr-67 in FXR. Moreover, consistent with Src's role in phosphorylating FXR, Src knockdown impaired cholesterol regulation in mice. In hypercholesterolemic apolipoprotein E-deficient mice, expression of FXR, but not Y67F-FXR, ameliorated atherosclerosis, whereas Src down-regulation exacerbated it. Feeding or treatment with an FXR agonist induced Abcg5/8 and Scarb1 expression in WT, but not FGF15-knockout, mice. Furthermore, FGF19 treatment increased occupancy of FXR at Abcg5/8 and Scarb1, expression of these genes, and cholesterol efflux from hepatocytes. These FGF19-mediated effects were blunted by the Y67F-FXR substitution or Src down-regulation or inhibition. We conclude that phosphorylation of hepatic FXR by FGF15/19-induced Src maintains cholesterol homeostasis and protects against atherosclerosis.
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postprandial FGF19 induced phosphorylation by src is critical for fxr function in bile acid homeostasis
Nature Communications, 2018Co-Authors: Sangwon Byun, Byron Kemper, Eric H Xu, Bo Kong, Daniel Ryerson, Jongsook Kim KemperAbstract: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.
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a postprandial FGF19 shp lsd1 regulatory axis mediates epigenetic repression of hepatic autophagy
The EMBO Journal, 2017Co-Authors: Sangwon Byun, Byron Kemper, Yang Zhang, Bo Kong, Junichi Sadoshima, Jongsook Kim KemperAbstract:Abstract Lysosome‐mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient‐sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed‐state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP‐null mice or LSD1‐depleted mice. In addition, feeding‐mediated autophagy inhibition is attenuated in FGF15‐null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB‐bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1‐mediated demethylation of gene‐activation histone marks H3K4‐me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19‐SHP‐LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient‐rich postprandial conditions.
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A postprandial FGF19‐SHP‐LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy
The EMBO Journal, 2017Co-Authors: Sangwon Byun, Byron Kemper, Yang Zhang, Bo Kong, Junichi Sadoshima, Jian Ma, Jongsook Kim KemperAbstract:Abstract Lysosome‐mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient‐sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed‐state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP‐null mice or LSD1‐depleted mice. In addition, feeding‐mediated autophagy inhibition is attenuated in FGF15‐null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB‐bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1‐mediated demethylation of gene‐activation histone marks H3K4‐me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19‐SHP‐LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient‐rich postprandial conditions.
Byron Kemper - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation of hepatic farnesoid x receptor by FGF19 signaling activated src maintains cholesterol levels and protects from atherosclerosis
Journal of Biological Chemistry, 2019Co-Authors: Sangwon Byun, Byron Kemper, Bo Kong, Hyunkyung Jung, Jinjing Chen, Jongsook Kim KemperAbstract:: The bile acid (BA) nuclear receptor, farnesoid X receptor (FXR/NR1H4), maintains metabolic homeostasis by transcriptional control of numerous genes, including an intestinal hormone, fibroblast growth factor-19 (FGF19; FGF15 in mice). Besides activation by BAs, the gene-regulatory function of FXR is also modulated by hormone or nutrient signaling-induced post-translational modifications. Recently, phosphorylation at Tyr-67 by the FGF15/19 signaling-activated nonreceptor tyrosine kinase Src was shown to be important for FXR function in BA homeostasis. Here, we examined the role of this FXR phosphorylation in cholesterol regulation. In both hepatic FXR-knockout and FXR-knockdown mice, reconstitution of FXR expression up-regulated cholesterol transport genes for its biliary excretion, including scavenger receptor class B member 1 (Scarb1) and ABC subfamily G member 8 (Abcg5/8), decreased hepatic and plasma cholesterol levels, and increased biliary and fecal cholesterol levels. Of note, these sterol-lowering effects were blunted by substitution of Phe for Tyr-67 in FXR. Moreover, consistent with Src's role in phosphorylating FXR, Src knockdown impaired cholesterol regulation in mice. In hypercholesterolemic apolipoprotein E-deficient mice, expression of FXR, but not Y67F-FXR, ameliorated atherosclerosis, whereas Src down-regulation exacerbated it. Feeding or treatment with an FXR agonist induced Abcg5/8 and Scarb1 expression in WT, but not FGF15-knockout, mice. Furthermore, FGF19 treatment increased occupancy of FXR at Abcg5/8 and Scarb1, expression of these genes, and cholesterol efflux from hepatocytes. These FGF19-mediated effects were blunted by the Y67F-FXR substitution or Src down-regulation or inhibition. We conclude that phosphorylation of hepatic FXR by FGF15/19-induced Src maintains cholesterol homeostasis and protects against atherosclerosis.
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small heterodimer partner and fibroblast growth factor 19 inhibit expression of npc1l1 in mouse intestine and cholesterol absorption
Gastroenterology, 2019Co-Authors: Sangwon Byun, Sunmi Seok, Byron Kemper, Eric H Xu, Jongsook Kim KemperAbstract:Background & Aims The nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in the liver and intestine. Postprandial fibroblast growth factor 19 (human FGF19, mouse FGF15) signaling increases the transcriptional activity of SHP. We studied the functions of SHP and FGF19 in the intestines of mice, including their regulation of expression of the cholesterol transporter NPC1L1 )NPC1-like intracellular cholesterol transporter 1) and cholesterol absorption. Methods We performed histologic and biochemical analyses of intestinal tissues from C57BL/6 and SHP-knockout mice and performed RNA-sequencing analyses to identify genes regulated by SHP. The effects of fasting and refeeding on intestinal expression of NPC1L1 were examined in C57BL/6, SHP-knockout, and FGF15-knockout mice. Mice were given FGF19 daily for 1 week; fractional cholesterol absorption, cholesterol and bile acid (BA) levels, and composition of BAs were measured. Intestinal organoids were generated from C57BL/6 and SHP-knockout mice, and cholesterol uptake was measured. Luciferase reporter assays were performed with HT29 cells. Results We found that the genes that regulate lipid and ion transport in intestine, including NPC1L1, were up-regulated and that cholesterol absorption was increased in SHP-knockout mice compared with C57BL/6 mice. Expression of NPC1L1 was reduced in C57BL/6 mice after refeeding after fasting but not in SHP-knockout or FGF15-knockout mice. SHP-knockout mice had altered BA composition compared with C57BL/6 mice. FGF19 injection reduced expression of NPC1L1, decreased cholesterol absorption, and increased levels of hydrophilic BAs, including tauro-α- and -β-muricholic acids; these changes were not observed in SHP-knockout mice. SREBF2 (sterol regulatory element binding transcription factor 2), which regulates cholesterol, activated transcription of NPC1L1. FGF19 signaling led to phosphorylation of SHP, which inhibited SREBF2 activity. Conclusions Postprandial FGF19 and SHP inhibit SREBF2, which leads to repression of intestinal NPC1L1 expression and cholesterol absorption. Strategies to increase FGF19 signaling to activate SHP might be developed for treatment of hypercholesterolemia.
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postprandial FGF19 induced phosphorylation by src is critical for fxr function in bile acid homeostasis
Nature Communications, 2018Co-Authors: Sangwon Byun, Byron Kemper, Eric H Xu, Bo Kong, Daniel Ryerson, Jongsook Kim KemperAbstract: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.
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a postprandial FGF19 shp lsd1 regulatory axis mediates epigenetic repression of hepatic autophagy
The EMBO Journal, 2017Co-Authors: Sangwon Byun, Byron Kemper, Yang Zhang, Bo Kong, Junichi Sadoshima, Jongsook Kim KemperAbstract:Abstract Lysosome‐mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient‐sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed‐state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP‐null mice or LSD1‐depleted mice. In addition, feeding‐mediated autophagy inhibition is attenuated in FGF15‐null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB‐bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1‐mediated demethylation of gene‐activation histone marks H3K4‐me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19‐SHP‐LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient‐rich postprandial conditions.
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A postprandial FGF19‐SHP‐LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy
The EMBO Journal, 2017Co-Authors: Sangwon Byun, Byron Kemper, Yang Zhang, Bo Kong, Junichi Sadoshima, Jian Ma, Jongsook Kim KemperAbstract:Abstract Lysosome‐mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient‐sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed‐state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP‐null mice or LSD1‐depleted mice. In addition, feeding‐mediated autophagy inhibition is attenuated in FGF15‐null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB‐bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1‐mediated demethylation of gene‐activation histone marks H3K4‐me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19‐SHP‐LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient‐rich postprandial conditions.