The plasma lipidome varies with the severity of metabolic dysfunction-associated steatotic liver disease.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with many aspects of disturbed metabolic health. MASLD encompasses a wide spectrum of liver diseases, ranging from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), up to fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Limited noninvasive diagnostic tools are currently available to distinguish the various stages of MASLD and as such liver biopsy remains the gold standard for MASLD diagnostics.

The farnesoid X receptor activates transcription independently of RXR at non-canonical response elements.

The farnesoid X receptor (FXR) is a nuclear receptor (NR) known to obligately heterodimerize with the retinoid X receptor (RXR). FXR is expressed as four isoforms (α1-α4) that drive transcription from IR-1 (inverted repeat-1) response elements (REs). Recently, we found that FXR isoforms α2/α4 also activate transcription from non-canonical ER-2 (everted repeat-2) REs, mediating most metabolic effects of general FXR activation.

Dietary cystine restriction increases the proliferative capacity of the small intestine of mice.

Currently, over 88 million people are estimated to have adopted a vegan or vegetarian diet. Cysteine is a semi-essential amino acid, which availability is largely dependent on dietary intake of meat, eggs and whole grains. Vegan/vegetarian diets are therefore inherently low in cysteine.

Human liver organoids: From generation to applications.

In the last decade, research into human hepatology has been revolutionized by the development of mini human livers in a dish. These liver organoids are formed by self-organizing stem cells and resemble their native counterparts in cellular content, multicellular architecture, and functional features. Liver organoids can be derived from the liver tissue or pluripotent stem cells generated from a skin biopsy, blood cells, or renal epithelial cells present in urine.

Rifaximin stimulates nitrogen detoxification by PXR-independent mechanisms in human small intestinal organoids.

Background And Aims: Recurrent hepatic encephalopathy (HE) is characterized by hyperammonaemia in combination with neuropsychiatric abnormalities and is treated with lactulose and rifaximin. Rifaximin is a pregnane X receptor (PXR) agonist with low systemic and high intestinal bioavailability. The mechanisms by which it alleviates HE are unclear.

PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation.

Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ's ability to activate target genes in a cellular context is currently poorly understood.

Protein Condensation in the Nuclear Receptor Family; Implications for Transcriptional Output.

The nuclear receptor superfamily is a group of transcriptional regulators that orchestrate multiple vital processes such as inflammation, metabolism, and cell proliferation. In recent years, it has become clear that some nuclear receptors form condensates in living cells. These condensates contain high concentrations of proteins and can contain millions of molecules.

Post-Translational Modifications of FXR; Implications for Cholestasis and Obesity-Related Disorders.

The Farnesoid X receptor (FXR) is a nuclear receptor which is activated by bile acids. Bile acids function in solubilization of dietary fats and vitamins in the intestine. In addition, bile acids have been increasingly recognized to act as signaling molecules involved in energy metabolism pathways, amongst others activating FXR.

Ablation of liver results in an increased colonic mucus barrier in mice.

Background & Aims: The interorgan crosstalk between the liver and the intestine has been the focus of intense research. Key in this crosstalk are bile acids, which are secreted from the liver into the intestine, interact with the microbiome, and upon absorption reach back to the liver. The bile acid-activated farnesoid X receptor () is involved in the gut-to-liver axis.

Breast milk nutrients driving intestinal epithelial layer maturation via Wnt and Notch signaling: Implications for necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is an often lethal, inflammatory disease of the preterm intestine. The underdeveloped immune system plays an important role; however, the initial trigger for NEC development is likely a damaged intestinal epithelial layer. We hypothesize that due to incomplete maturation of different epithelial cell lineages, nutrients and bacteria are able to damage the epithelial cells and cause the (immature) inflammatory response, food intolerance and malabsorption seen in NEC.

Splice variants of metabolic nuclear receptors: Relevance for metabolic disease and therapeutic targeting.

Metabolic nuclear receptors are ligand-activated transcription factors which control a wide range of metabolic processes and signaling pathways in response to nutrients and xenobiotics. Targeting these NRs is at the forefront of our endeavours to generate novel treatment options for diabetes, metabolic syndrome and fatty liver disease. Numerous splice variants have been described for these metabolic receptors.

FXR Isoforms Control Different Metabolic Functions in Liver Cells via Binding to Specific DNA Motifs.

Background & Aims: The nuclear receptor subfamily 1 group H member 4 (NR1H4, also called FXR) is a ligand-activated transcription factor that, upon binding of bile acids, regulates the expression of genes involved in bile acid, fat, sugar, and amino acid metabolism. Transcript variants encode the FXR isoforms alpha 1, alpha 2, alpha 3, and alpha 4, which activate different genes that regulate metabolism. Little is known about the mechanisms by which the different isoforms regulate specific genes or how the expression of these genes affects the outcomes of patients given drugs that target FXR.

Farnesoid X receptor and bile acids regulate vitamin A storage.

The nuclear receptor Farnesoid X Receptor (FXR) is activated by bile acids and controls multiple metabolic processes, including bile acid, lipid, carbohydrate, amino acid and energy metabolism. Vitamin A is needed for proper metabolic and immune control and requires bile acids for efficient intestinal absorption and storage in the liver. Here, we analyzed whether FXR regulates vitamin A metabolism.

Steroidogenic control of liver metabolism through a nuclear receptor-network.

Objective: Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic tissues are largely unknown.

Methods And Results: Here, we show that in the liver, the classical steroidogenic enzyme Cyp17a1 forms an essential nexus for glucose and ketone metabolism during feed-fast cycles.

Dissecting the allosteric FXR modulation: a chemical biology approach using guggulsterone as a chemical tool.

Guggulsterone is a promiscuous ligand for endocrine and metabolic lipid receptors traditionally used to treat a number of diseases including diabesity, hyperlipidemia, atherosclerosis, and osteoarthritis. Although relatively weak, its activity at the farnesoid X receptor (FXR) is particularly intriguing as guggulsterone acts as an antagonist with a peculiar ability of gene selective modulation. We report here a chemical biology study with the aim to further characterize the biological action of guggulsterone at the FXR and to obtain further insights into the functional role played by noncanonical FXR binding pockets S2 and S3.

Identification of FDA-approved drugs targeting the Farnesoid X Receptor.

The farnesoid X receptor (FXR) belongs to the nuclear receptor family and is activated by bile acids. Multiple, chemically rather diverse, FXR agonists have been developed and several of these compounds are currently tested in clinical trials for NAFLD and cholestasis. Here, we investigated possible FXR-agonism or antagonism of existing FDA/EMA-approved drugs.

Progress and challenges of selective Farnesoid X Receptor modulation.

Bile acids are amphipathic molecules that were previously known to serve as fat solubilizers in the intestine in postprandial conditions. In the last two decades, bile acids have been recognized as signaling molecules regulating energy metabolism pathways via, amongst others, the farnesoid X receptor (FXR). Upon bile acid activation, FXR controls expression of genes involved in bile acid, lipid, glucose and amino acid metabolism.

Profiling of 3696 Nuclear Receptor-Coregulator Interactions: A Resource for Biological and Clinical Discovery.

Nuclear receptors (NRs) are ligand-inducible transcription factors that play critical roles in metazoan development, reproduction, and physiology and therefore are implicated in a broad range of pathologies. The transcriptional activity of NRs critically depends on their interaction(s) with transcriptional coregulator proteins, including coactivators and corepressors. Short leucine-rich peptide motifs in these proteins (LxxLL in coactivators and LxxxIxxxL in corepressors) are essential and sufficient for NR binding.

Protein fermentation in the gut; implications for intestinal dysfunction in humans, pigs, and poultry.

The amount of dietary protein is associated with intestinal disease in different vertebrate species. In humans, this is exemplified by the association between high-protein intake and fermentation metabolite concentrations in patients with inflammatory bowel disease. In production animals, dietary protein intake is associated with postweaning diarrhea in piglets and with the occurrence of wet litter in poultry.

Farnesoid X receptor: A "homeostat" for hepatic nutrient metabolism.

The Farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids (BAs). BAs are amphipathic molecules that serve as fat solubilizers in the intestine under postprandial conditions. In the post-absorptive state, BAs bind FXR in the hepatocytes, which in turn provides feedback signals on BA synthesis and transport and regulates lipid, glucose and amino acid metabolism.

Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation.

Fibroblast growth factor 19 (FGF19) is a gut-derived peptide hormone that is produced following activation of Farnesoid X Receptor (FXR). FGF19 is secreted and signals to the liver, where it contributes to the homeostasis of bile acid (BA), lipid and carbohydrate metabolism. FGF19 is a promising therapeutic target for the metabolic syndrome and cholestatic diseases, but enthusiasm for its use has been tempered by FGF19-mediated induction of proliferation and hepatocellular carcinoma.

Farnesoid X Receptor Activation Promotes Hepatic Amino Acid Catabolism and Ammonium Clearance in Mice.

Background & Aims: The nuclear receptor subfamily 1 group H member 4 (NR1H4 or farnesoid X receptor [FXR]) regulates bile acid synthesis, transport, and catabolism. FXR also regulates postprandial lipid and glucose metabolism. We performed quantitative proteomic analyses of liver tissues from mice to evaluate these functions and investigate whether FXR regulates amino acid metabolism.

Characterization of stem cell-derived liver and intestinal organoids as a model system to study nuclear receptor biology.

Nuclear receptors (NRs) are ligand-activated transcription factors regulating a large variety of processes involved in reproduction, development, and metabolism. NRs are ideal drug targets because they are activated by lipophilic ligands that easily pass cell membranes. Immortalized cell lines recapitulate NR biology poorly and generating primary cultures is laborious and requires a constant need for donor material.

Gut Microbial Diversity Is Reduced in Smokers with Crohn's Disease.

Background: Smoking has a negative impact on Crohn's disease (CD), but the mechanisms underlying this association are unclear. We compared the gut microbiota composition of smoking with nonsmoking patients with CD using a metagenomic approach.

Methods: Stool samples and clinical data were collected from current smokers and nonsmokers with CD from France and the Netherlands, matched for country, gender, age, disease activity, and body mass index.

Sulfide as a Mucus Barrier-Breaker in Inflammatory Bowel Disease?

The gut epithelium is covered by mucus consisting of mucin polymers connected via disulfide bonds. The mucus layer limits exposure of epithelial cells to toxins and bacteria. A recent study has shown that sulfide, produced by certain bacteria, reduces disulfide bonds in the mucus network.