Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 1, 2023

Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes can lead to liver cirrhosis hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism cellular stress, intrahepatic cell crosstalk, as well interplay between peripheral tissues remain elusive are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 a key factor regulating hepatic catabolism, stress responses, systemic homeostasis, NASH pathogenesis attenuated expression feature advanced NASH. Multiomics pharmacological intervention showed loss-of-function in hepatocytes disrupts metabolic transcriptional axis conjointly controlled by nutrient-sensing nuclear receptors ERRα PPARα, resulting suppression fatty acid oxidation, elevated ER apoptosis, immune infiltration, fibrogenesis, ultimately progression male mice. These results provide foundation developing alternative strategies co-targeting PPARα treatment

Language: Английский

---

Structure-guided approach to modulate small molecule binding to a promiscuous ligand-activated protein

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(10)

Published: Feb. 27, 2023

Ligand-binding promiscuity in detoxification systems protects the body from toxicological harm but is a roadblock to drug development due difficulty optimizing small molecules both retain target potency and avoid metabolic events. Immense effort invested evaluating metabolism of develop safer, more effective treatments, engineering specificity into or out promiscuous proteins their ligands challenging task. To better understand nature networks, we have used X-ray crystallography characterize structural feature pregnane X receptor (PXR), nuclear that activated by diverse (with different structures sizes) up-regulate transcription genes. We found large expand PXR's ligand-binding pocket, ligand-induced expansion occurs through specific unfavorable compound-protein clash likely contributes reduced binding affinity. Removing compound modification resulted favorable modes with significantly enhanced then engineered ligand-protein potent, PXR ligand, resulting marked reduction activation. Structural analysis showed remodeled, modified reposition pocket clashes, conformational changes result less modes. Thus, increases potential an event; therefore, candidates can be reduce safety liability binding.

Language: Английский

---

Vitamin B2 enables regulation of fasting glucose availability

eLife, Journal Year: 2023, Volume and Issue: 12

Published: July 7, 2023

Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding cause rare inborn errors of metabolism (IEMs) disrupt liver function and render fasting intolerance, hepatic steatosis, lipodystrophy. In our study, depleting pools in mice a vitamin B2-deficient diet (B2D) caused phenotypes associated organic acidemias other IEMs, including reduced body weight, hypoglycemia, fatty disease. Integrated discovery approaches revealed B2D tempered activation target genes the nuclear receptor PPARα, those gluconeogenesis. We also found PPARα knockdown recapitulated effects on glucose excursion disease mice. Finally, treatment agonist fenofibrate activated integrated stress response refilled amino acid substrates rescue availability overcome phenotypes. These findings identify metabolic responses nominate strategies management IEMs.

Language: Английский

---

Differential Disruption of Glucose and Lipid Metabolism Induced by Phthalates in Human Hepatocytes and White Adipocytes

Toxics, Journal Year: 2024, Volume and Issue: 12(3), P. 214 - 214

Published: March 14, 2024

Phthalic acid esters (PAEs), commonly used as plasticizers, are pervasive in the environment, leading to widespread human exposure. The association between phthalate exposure and metabolic disorders has been increasingly recognized, yet precise biological mechanisms not well-defined. In this study, we explored effects of monoethylhexyl (MEHP) monocyclohexyl (MCHP) on glucose lipid metabolism hepatocytes adipocytes. hepatocytes, MEHP MCHP were observed enhance uptake accumulation a dose-responsive manner, along with upregulating genes involved biosynthesis. Transcriptomic analysis indicated broader impact hepatic gene expression relative MCHP, but particularly promoted gluconeogenesis key enzymes G6PC FBP1. adipocytes, both increased droplet formation, mimicking Peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi). revealed that predominantly altered fatty pathways mature adipocytes (MA), whereas exhibited less impact. Metabolic perturbations from demonstrate shared activation PPARs pathway cell-type discrepancy might be attributed differential PPARγ. Our results indicate disrupt homeostasis liver adipose through involve PPAR adenosine monophosphate-activated protein kinase (AMPK) signaling pathways, highlighting nuanced cellular responses these environmental contaminants.

Language: Английский

---

Dynamic interplay of nuclear receptors in tumor cell plasticity and drug resistance: Shifting gears in malignant transformations and applications in cancer therapeutics

Cancer and Metastasis Reviews, Journal Year: 2024, Volume and Issue: 43(1), P. 321 - 362

Published: March 1, 2024

Language: Английский

---

Identification of a chromatin-bound ERRα interactome network in mouse liver

Molecular Metabolism, Journal Year: 2024, Volume and Issue: 83, P. 101925 - 101925

Published: March 26, 2024

Estrogen-related-receptor α (ERRα) plays a critical role in the transcriptional regulation of cellular bioenergetics and metabolism, perturbations its activity have been associated with metabolic diseases. While several coactivators corepressors ERRα identified to date, knowledge gap remains understanding extent which cooperates coregulators control gene expression. Herein, we mapped primary chromatin-bound interactome mouse liver. RIME (Rapid Immuno-precipitation Mass spectrometry Endogenous proteins) analysis using liver samples from two circadian time points was used catalog ERRα-interacting proteins on chromatin. The genomic crosstalk between cofactors precise programs explored through cross-examination genome-wide binding profiles chromatin immunoprecipitation-sequencing (ChIP-seq) studies. dynamic interplay newly uncovered cofactor Host cell factor C1 (HCFC1) further investigated by loss-of-function studies hepatocytes. Characterization hepatic led identification 48 interactors 42 were previously unknown including HCFC1. Interrogation available ChIP-seq highlighted oxidative phosphorylation (OXPHOS) under complex regulatory network multiple cofactors. HCFC1 found bind large set common genes, only small fraction showed their colocalization, predominately near start sites genes particularly enriched for components mitochondrial respiratory chain. Knockdown demonstrated inverse actions OXPHOS expression ultimately dictating impact respiration. Our work unveils repertoire partners comprised modifiers transcription factors thus advancing our how regulates programs.

Language: Английский

---

Kaempferol Improves Exercise Performance by Regulating Glucose Uptake, Mitochondrial Biogenesis, and Protein Synthesis via PI3K/AKT and MAPK Signaling Pathways

Foods, Journal Year: 2024, Volume and Issue: 13(7), P. 1068 - 1068

Published: March 30, 2024

Kaempferol is a natural flavonoid with reported bioactivities found in many fruits, vegetables, and medicinal herbs. However, its effects on exercise performance muscle metabolism remain inconclusive. The present study investigated kaempferol’s improving potential mechanisms vivo vitro. grip strength, exhaustive running time, distance of mice were increased the high-dose kaempferol group (p < 0.01). Also, reduced fatigue-related biochemical markers activities superoxide dismutase (SOD) glutathione peroxidase (GSH-Px) related to antioxidant capacity. also glycogen adenosine triphosphate (ATP) content liver skeletal muscle, as well glucose blood. In vitro, promoted uptake, protein synthesis, mitochondrial function decreased oxidative stress both 2D 3D C2C12 myotube cultures. Moreover, activated PI3K/AKT MAPK signaling pathways cells. It upregulated key targets function, synthesis. These findings suggest that improves alleviates physical fatigue by increasing biogenesis, synthesis decreasing ROS. Kaempferol’s molecular mechanism may be regulation pathways.

Language: Английский

---

Liver X Receptor Ligand GAC0001E5 Downregulates Antioxidant Capacity and ERBB2/HER2 Expression in HER2-Positive Breast Cancer Cells

Cancers, Journal Year: 2024, Volume and Issue: 16(9), P. 1651 - 1651

Published: April 25, 2024

The HER2-positive subtype accounts for approximately one-fifth of all breast cancers. Insensitivity and development acquired resistance to targeted therapies in some patients contribute their poor prognosis. HER2 overexpression is associated with metabolic reprogramming, facilitating cancer cell growth survival. Novel liver X receptor (LXR) ligand GAC0001E5 (1E5) has been shown inhibit proliferation by disrupting glutaminolysis inducing oxidative stress. In this study, cells were treated 1E5 determine potential inhibitory effects mechanisms action Similar previous observations other types, treatments inhibited LXR activity, expression, proliferation. Expression fatty acid synthesis genes, including synthase (FASN), was downregulated following treatment, results from co-treatment experiments an FASN inhibitor suggest that the same pathway 1E5. Treatments disrupted resulted increased Strikingly, transcript protein levels both significantly Taken together, these findings indicate therapeutic targeting reprogramming via modulation

Language: Английский

---

Journey through discovery of 75 years glucocorticoids: evolution of our knowledge of glucocorticoid receptor mechanisms in rheumatic diseases

Annals of the Rheumatic Diseases, Journal Year: 2024, Volume and Issue: 83(12), P. 1603 - 1613

Published: Aug. 6, 2024

For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding GCs binding nuclear receptors, mainly the glucocorticoid receptor (GR) their molecular mechanisms has changed dramatically. Initially, in late 1950s, were considered important regulators energy metabolism. By 1970s/1980s, they characterised as ligands for hormone-inducible transcription factors that regulate many aspects cell biology physiology. More recently, impact on cellular metabolism rediscovered. Our cell-type-specific GC actions crosstalk between various immune stromal cells arthritis models evolved by investigating conditional GR mutant mice using Cre/LoxP system. A major achievement studying complex, interplay is recent advent omics technologies at single-cell resolution, which will provide further unprecedented insights into types mediating responses. Alongside gene-encoded factors, anti-inflammatory metabolites participate resolving inflammation during are just being uncovered. The translation this knowledge therapeutic concepts help tackle inflammatory diseases reduce side effects. In review, we describe milestones preclinical research led current action years after first use arthritis.

Language: Английский

---

Palmitoyltransferase ZDHHC6 promotes colon tumorigenesis by targeting PPARγ-driven lipid biosynthesis via regulating lipidome metabolic reprogramming

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Aug. 16, 2024

The failure of proper recognition the intricate nature pathophysiology in colorectal cancer (CRC) has a substantial effect on progress developing novel medications and targeted therapy approaches. Imbalances processes lipid oxidation biosynthesis fatty acids are significant risk factors for development CRC. Therapeutic intervention that specifically targets peroxisome proliferator-activated receptor gamma (PPARγ) its downstream response element, to metabolism, been found promote growth tumors shown clinical advantages patients.

Language: Английский

---