Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205847 | GEO | 2023/08/18
REPOSITORIES: GEO
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Project description:Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis, with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics analysis and pharmacological intervention showed that loss of FBXW7 function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRa and PPARa, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression. These results provide the foundation for developing alternative strategies co-targeting ERRa and PPARa for the treatment of NASH.
2023-08-18 | GSE205845 | GEO
Project description:Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis, with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics analysis and pharmacological intervention showed that loss of FBXW7 function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRα and PPARα, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression. These results provide the foundation for developing alternative strategies co-targeting ERRα and PPARα for the treatment of NASH.
2023-08-18 | GSE205846 | GEO
Project description:Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression
| PRJNA847943 | ENA
Project description:Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression
| PRJNA847937 | ENA
Project description:Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression [RNA-Seq]
| PRJNA847944 | ENA
Project description:The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPARα but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPARα, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. We conclude that PPARα and FXR function coordinately to integrate liver energy balance.
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Project description:Autophagy is an evolutionarily conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis. Its acute regulation by nutrient-sensing signalling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors peroxisome proliferator-activated receptor-? (PPAR?) and farnesoid X receptor (FXR) are activated in the fasted and fed liver, respectively. Here we show that both PPAR? and FXR regulate hepatic autophagy in mice. Pharmacological activation of PPAR? reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPAR? knockout (Ppara(-/-), also known as Nr1c1(-/-)) mice, which are partially defective in the induction of autophagy by fasting. Pharmacological activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (Fxr(-/-), also known as Nr1h4(-/-)) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPAR? and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status.
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Project description:Skeletal muscle is a major site of postprandial glucose disposal. Inadequate insulin action in skeletal myocytes contributes to hyperglycemia in diabetes. Although glucose is known to stimulate insulin secretion by β cells, whether it directly engages nutrient signaling pathways in skeletal muscle to maintain systemic glucose homeostasis remains largely unexplored. Here we identified the Baf60c-Deptor-AKT pathway as a target of muscle glucose sensing that augments insulin action in skeletal myocytes. Genetic activation of this pathway improved postprandial glucose disposal in mice, whereas its muscle-specific ablation impaired insulin action and led to postprandial glucose intolerance. Mechanistically, glucose triggers KATP channel-dependent calcium signaling, which promotes HDAC5 phosphorylation and nuclear exclusion, leading to Baf60c induction and insulin-independent AKT activation. This pathway is engaged by the anti-diabetic sulfonylurea drugs to exert their full glucose-lowering effects. These findings uncover an unexpected mechanism of glucose sensing in skeletal myocytes that contributes to homeostasis and therapeutic action.
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Project description:Orphan nuclear receptors are important members of the nuclear receptor family and may regulate cell proliferation, metabolism, differentiation, and apoptosis. NR4As, a subfamily of orphan nuclear receptors, have been reported to play key roles in carbohydrate and lipid metabolism and energy homeostasis. Popularity of obesity has resulted in a series of metabolic diseases such as diabetes and its complications. While imbalance of energy intake and expenditure is the main cause of obesity, the concrete mechanism of obesity has not been fully understood. It has been reported that NR4As have significant regulatory effects on energy homeostasis and diabetes and are expected to become new targets for discovering drugs for metabolic syndrome. A number of studies have demonstrated that abnormalities in metabolism induced by altered levels of NR4As may contribute to numerous diseases, such as chronic inflammation, tumorigenesis, diabetes and its complications, atherosclerosis, and other cardiovascular diseases. However, systematic reviews focusing on the roles of NR4As in mediating energy homeostasis and diabetes remain limited. Therefore, this article reviews the structure and regulation of NR4As and their critical function in energy homeostasis and diabetes, as well as small molecules that may regulate NR4As. Our work is aimed at providing valuable support for the research and development of drugs targeting NR4As for the treatment of obesity and related metabolic diseases.
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Project description:Skeletal muscle is a major site of postprandial glucose disposal. Inadequate insulin action in this tissue contributes to hyperglycemia in type 1 and type 2 diabetes. While glucose is known to stimulate insulin secretion by pancreatic b cells, whether it directly engages nutrient-sensing pathways in skeletal muscle to regulate glucose metabolism remains largely unexplored. Here we identified the Baf60c-Deptor-AKT pathway as a target of muscle glucose sensing that augments insulin action in skeletal myocytes. Genetic activation of this pathway improves postprandial glucose disposal in mice, whereas the muscle-specific ablation impaired insulin action and led to glucose intolerance. Mechanistically, glucose triggers a rapid calcium response in myocytes that acts on the class IIa histone deacetylase HDAC5, leading to Baf60c induction and insulin-independent AKT activation. The pathway is engaged by the anti-diabetic drugs sulfonylureas, suggesting that its therapeutic activation may have beneficial effects on glycemic control in diabetes. We used microarrays to elucidate the role of of Baf60c in transcriptional regulation by glucose in skeletal myocytes.
2017-04-20 | GSE79925 | GEO