Hepatic Lcmr1 activates the transcription of G6pc and is needed for gluconeogenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE272627 | GEO | 2024/10/01
REPOSITORIES: GEO
Similar Datasets
Project description:Hepatic Lcmr1 activates the transcription of G6pc and is needed for gluconeogenesis
| PRJNA1137853 | ENA
Project description:Liver fibrosis is a strong predictor of long-term mortality in patients with non-alcoholic fatty liver disease; yet the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely under-stood. Using a cell type-resolved genomics approach, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a partial loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a net-work of NASH-activated transcription factors (TFs), as exemplified by Elf3 and Glis2. Indeed, Elf3 and Glis2 controlled hepatocyte identity and fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell (HSC) gene programs. Thus, interconnected TF networks not only promoted hepatocyte dysfunction, but also directed the intra-hepatic crosstalk with HSCs necessary for NASH and fibrosis progression implying molecular “hub-centered” targeting strategies to be superior to existing mono-target approaches as currently used in NASH therapy.
2021-07-13 | PXD025691 | Pride
Project description:Hepatic glucose production (HGP) maintains blood glucose levels during fasting but can also exacerbate diabetic hyperglycemia. HGP is dynamically controlled by a signaling/transcriptional network that regulates the expression/activity of gluconeogenic enzymes. A key mediator of gluconeogenic gene transcription is PGC-1?. PGC-1?'s activation of gluconeogenic gene expression is dependent upon its acetylation state, which is controlled by the acetyltransferase GCN5 and the deacetylase Sirt1. Nevertheless, whether other chromatin modifiers-particularly other sirtuins-can modulate PGC-1? acetylation is currently unknown. Herein, we report that Sirt6 strongly controls PGC-1? acetylation. Surprisingly, Sirt6 induces PGC-1? acetylation and suppresses HGP. Sirt6 depletion decreases PGC-1? acetylation and promotes HGP. These acetylation effects are GCN5 dependent: Sirt6 interacts with and modifies GCN5, enhancing GCN5's activity. Lepr(db/db) mice, an obese/diabetic animal model, exhibit reduced Sirt6 levels; ectopic re-expression suppresses gluconeogenic genes and normalizes glycemia. Activation of hepatic Sirt6 may therefore be therapeutically useful for treating insulin-resistant diabetes.
| S-EPMC3534905 | biostudies-literature
Project description:One of the causes of hyperglycemia in type 2 diabetes is elevated hepatic glucose production. AKT-FOXO1 pathway is primarily involved in the hormonal upregulation of this process, and pharmacological or genetic inhibition of this pathway prevents diabetes in animal models. Here we report that DYRK1B regulates FoxO1 function through phosphorylation to regulate hepatic glucose metabolism. DYRK1B expression is induced by fasting and in diabetic mice. DYRK1B promoted hepatic gluconeogenesis and glucose intolerance in in vivo and in vitro model systems. Liver-specific DYRK1B conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacted with and phosphorylated FoxO1, primarily at T467S468, which is required for its nuclear localization. DYRK1B inhibited AKT mediated FoxO1 phosphorylation at T24 and S256 and enhanced its nuclear retention. DYRK1B mediated phosphorylation of FoxO1 enhanced the expression of gluconeogenic genes and promoted gluconeogenesis. Treatment with DYRK1B pharmacological inhibitor AZ191 significantly lowered blood glucose levels in diabetic mice. We conclude that DYRK1B is a regulator of glucose metabolism, and its pharmacological inhibition could serve as therapeutic target for treating diabetes.
2025-04-30 | GSE263028 | GEO
Project description:One of the causes of hyperglycemia in type 2 diabetes is elevated hepatic glucose production. AKT-FOXO1 pathway is primarily involved in the hormonal upregulation of this process, and pharmacological or genetic inhibition of this pathway prevents diabetes in animal models. Here we report that DYRK1B regulates FoxO1 function through phosphorylation to regulate hepatic glucose metabolism. DYRK1B expression is induced by fasting and in diabetic mice. DYRK1B promoted hepatic gluconeogenesis and glucose intolerance in in vivo and in vitro model systems. Liver-specific DYRK1B conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacted with and phosphorylated FoxO1, primarily at T467S468, which is required for its nuclear localization. DYRK1B inhibited AKT mediated FoxO1 phosphorylation at T24 and S256 and enhanced its nuclear retention. DYRK1B mediated phosphorylation of FoxO1 enhanced the expression of gluconeogenic genes and promoted gluconeogenesis. Treatment with DYRK1B pharmacological inhibitor AZ191 significantly lowered blood glucose levels in diabetic mice. We conclude that DYRK1B is a regulator of glucose metabolism, and its pharmacological inhibition could serve as therapeutic target for treating diabetes.
2025-04-30 | GSE262106 | GEO
Project description:Hepatic fibrosis is a wound-healing response to chronic liver injury, which may result in cirrhosis and liver failure. The c-Jun N-terminal kinase-1 (JNK1) gene has been shown to be involved in liver fibrosis. Here, we aimed to investigate the molecular mechanism and identify the cell-type involved in mediating the JNK1-dependent effect on liver fibrogenesis Wild-type (WT), JNK1−/− and JNK1Δhepa (hepatocyte-specific deletion of JNK1) mice were subjected to bile duct ligation (BDL). Additionally, we performed bone marrow transplantations (BMT), isolated primary hepatic stellate cells (HSCs) and studied their activation in vitro. Serum markers of liver damage (liver transaminases, alkaline phosphatase and bilirubin) and liver histology revealed reduced injury in JNK1−/− compared to WT and JNK1Δhepa mice. Hepatocyte cell death and proliferation was reduced in JNK1−/− compared to WT and JNK1Δhepa. Parameters of liver fibrosis such as Sirius Red staining as well as Collagen IA1 and αSMA expression were down-regulated in JNK1−/− compared to WT and JNK1Δhepa livers, 4 weeks after BDL. To delineate the essential cell-type, we performed BMT of WT and JNK1-/- into JNK1-/- and WT mice, respectively. BMT experiments excluded bone marrow derived cells from having a major impact on the JNK1-dependent effect on fibrogenesis. Hence, we investigated primary HSCs from JNK1−/− livers showing reduced transdifferentiation compared with WT and JNK1Δhepa-derived HSCs. We conclude that JNK1 in HSCs plays a crucial role in hepatic fibrogenesis and thus represents a promising target for cell-directed treatment options for liver fibrosis. Control (JNK1f/f), JNK1 null (JNK1-/-) and hepatocyte-specific JNK1 null (JNK1Δhepa) mice were subjected to control, acute and chronic injury, i.e. sham or bile-duct ligation for 48h or 28 days resp., whereafter gene expression profiles were determined.
2013-11-27 | E-GEOD-40041 | biostudies-arrayexpress
Project description:We performed RNA sequencing analysis of hepatic gene expression a few hours after amlexanox treatment, and identified over 1700 differentially expressed genes. Pathway analysis of these differentially regulated genes revealed that the top two most enriched pathways were the adipocytokine signaling pathway and the Jak-STAT signaling pathway. RNA-seq analysis of hepatic gene expression was used to identify differentially expressed genes in response to Amlexanox treatment.
2015-04-17 | E-GEOD-57054 | biostudies-arrayexpress
Project description:Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B), a member of the CMGC group of kinase, is associated with metabolic syndrome. However, the molecular mechanisms involved remain elusive. In this study, we demonstrate that Dyrk1b expression is induced in liver by fasting and in diabetic mice. Using both in vivo and in vitro studies, we show that DYRK1B promotes hepatic gluconeogenesis and glucose intolerance. Liver-specific Dyrk1b conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacts with and phosphorylates FOXO1, primarily at Thr467/Ser468, which is essential for its nuclear localization. Additionally, DYRK1B inhibits AKT mediated FOXO1 phosphorylation at Thr24 and Ser256, thereby enhancing its nuclear retention. DYRK1B mediated phosphorylation enhances the expression of gluconeogenic genes and promotes gluconeogenesis. Further, a pharmacological inhibitor of DYRK1B significantly reduced blood glucose levels in diabetic mice. Collectively, these findings offer new insights into DYRK1B’s role in the glucose metabolism and identify it as a new therapeutic target for treating diabetes.
2025-05-07 | PXD052214 | Pride
Project description:DYRK1B phosphorylates FOXO1 to promote hepatic gluconeogenesis
| PRJNA1095472 | ENA
Project description:DYRK1B phosphorylates FOXO1 to promote hepatic gluconeogenesis
| PRJNA1090398 | ENA