Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related nuclear receptors with overlapping regulatory functions in xenobiotic clearance but distinct roles in endobiotic metabolism. Car activation has been demonstrated to ameliorate hypercholesterolemia by regulating cholesterol metabolism and bile acid elimination, whereas PXR activation is associated with hypercholesterolemia and liver steatosis. Here we show a human CAR agonist/PXR antagonist, MI-883, which effectively regulates genes related to xenobiotic metabolism and cholesterol/bile acid homeostasis by leveraging CAR and PXR interactions in gene regulation. Through comprehensive analyses utilizing lipidomics, bile acid metabolomics, and transcriptomics in humanized PXR-CAR-CYP3A4/3A7 mice fed high-fat and high-cholesterol diets, we demonstrate that MI-883 significantly reduces plasma cholesterol levels and enhances fecal bile acid excretion. This work paves the way for the development of ligands targeting multiple xenobiotic nuclear receptors. Such ligands hold the potential for precise modulation of liver metabolism, offering new therapeutic strategies for metabolic disorders.

• MeSH
• Cholesterol metabolism   blood   MeSH
• Cytochrome P-450 CYP3A genetics   metabolism   MeSH
• Diet, High-Fat adverse effects   MeSH
• Hypercholesterolemia * drug therapy   metabolism   etiology   MeSH
• Hypolipidemic Agents * pharmacology   therapeutic use   MeSH
• Liver metabolism   drug effects   MeSH
• Constitutive Androstane Receptor MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Pregnane X Receptor * antagonists & inhibitors   metabolism   genetics   MeSH
• Receptors, Cytoplasmic and Nuclear * agonists   metabolism   genetics   antagonists & inhibitors   MeSH
• Bile Acids and Salts metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cholesterol MeSH
• Cytochrome P-450 CYP3A MeSH
• Hypolipidemic Agents * MeSH
• Constitutive Androstane Receptor MeSH
• Pregnane X Receptor * MeSH
• Receptors, Cytoplasmic and Nuclear * MeSH
• Bile Acids and Salts MeSH

Fatty acid isomers are responsible for an under-reported lipidome diversity across all kingdoms of life. Isomers of unsaturated fatty acids are often masked in contemporary analysis by incomplete separation and the absence of sufficiently diagnostic methods for structure elucidation. Here, we introduce a comprehensive workflow, to discover unsaturated fatty acids through coupling liquid chromatography and mass spectrometry with gas-phase ozonolysis of double bonds. The workflow encompasses semi-automated data analysis and enables de novo identification in complex media including human plasma, cancer cell lines and vernix caseosa. The targeted analysis including ozonolysis enables structural assignment over a dynamic range of five orders of magnitude, even in instances of incomplete chromatographic separation. Thereby we expand the number of identified plasma fatty acids two-fold, including non-methylene-interrupted fatty acids. Detection, without prior knowledge, allows discovery of non-canonical double bond positions. Changes in relative isomer abundances reflect underlying perturbations in lipid metabolism.

• MeSH
• Mass Spectrometry methods   MeSH
• Humans MeSH
• Lipidomics MeSH
• Fatty Acids * chemistry   MeSH
• Fatty Acids, Unsaturated chemistry   MeSH
• Ozone * chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Fatty Acids * MeSH
• Fatty Acids, Unsaturated MeSH
• Ozone * MeSH

Pancreatic cancer has the worst prognosis among all cancers. Cancer screening of body fluids may improve the survival time prognosis of patients, who are often diagnosed too late at an incurable stage. Several studies report the dysregulation of lipid metabolism in tumor cells, suggesting that changes in the blood lipidome may accompany tumor growth. Here we show that the comprehensive mass spectrometric determination of a wide range of serum lipids reveals statistically significant differences between pancreatic cancer patients and healthy controls, as visualized by multivariate data analysis. Three phases of biomarker discovery research (discovery, qualification, and verification) are applied for 830 samples in total, which shows the dysregulation of some very long chain sphingomyelins, ceramides, and (lyso)phosphatidylcholines. The sensitivity and specificity to diagnose pancreatic cancer are over 90%, which outperforms CA 19-9, especially at an early stage, and is comparable to established diagnostic imaging methods. Furthermore, selected lipid species indicate a potential as prognostic biomarkers.

• MeSH
• CA-19-9 Antigen blood   MeSH
• Ceramides blood   MeSH
• Humans MeSH
• Lipidomics methods   MeSH
• Lysophosphatidylcholines blood   MeSH
• Lipid Metabolism genetics   MeSH
• Multivariate Analysis MeSH
• Biomarkers, Tumor blood   genetics   MeSH
• Pancreatic Neoplasms blood   diagnosis   mortality   pathology   MeSH
• Proportional Hazards Models MeSH
• Sensitivity and Specificity MeSH
• Sphingomyelins blood   MeSH
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization MeSH
• Case-Control Studies MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CA-19-9 Antigen MeSH
• Ceramides MeSH
• Lysophosphatidylcholines MeSH
• Biomarkers, Tumor MeSH
• Sphingomyelins MeSH

Early detection of cancer is one of the unmet needs in clinical medicine. Peripheral blood analysis is a preferred method for efficient population screening, because blood collection is well embedded in clinical practice and minimally invasive for patients. Lipids are important biomolecules, and variations in lipid concentrations can reflect pathological disorders. Lipidomic profiling of human plasma by the coupling of ultrahigh-performance supercritical fluid chromatography and mass spectrometry is investigated with the aim to distinguish patients with breast, kidney, and prostate cancers from healthy controls. The mean sensitivity, specificity, and accuracy of the lipid profiling approach were 85%, 95%, and 92% for kidney cancer; 91%, 97%, and 94% for breast cancer; and 87%, 95%, and 92% for prostate cancer. No association of statistical models with tumor stage is observed. The statistically most significant lipid species for the differentiation of cancer types studied are CE 16:0, Cer 42:1, LPC 18:2, PC 36:2, PC 36:3, SM 32:1, and SM 41:1 These seven lipids represent a potential biomarker panel for kidney, breast, and prostate cancer screening, but a further verification step in a prospective study has to be performed to verify clinical utility.

• MeSH
• Early Detection of Cancer MeSH
• Adult MeSH
• Heparin chemistry   MeSH
• Mass Spectrometry MeSH
• Kidney metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipidomics * MeSH
• Lipids chemistry   MeSH
• Young Adult MeSH
• Biomarkers, Tumor metabolism   MeSH
• Prostatic Neoplasms metabolism   MeSH
• Breast Neoplasms metabolism   MeSH
• Area Under Curve MeSH
• Prospective Studies MeSH
• Prostate metabolism   MeSH
• Breast metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Reproducibility of Results MeSH
• Retrospective Studies MeSH
• ROC Curve MeSH
• Aged MeSH
• Models, Statistical MeSH
• Case-Control Studies MeSH
• Chromatography, Supercritical Fluid MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Heparin MeSH
• Lipids MeSH
• Biomarkers, Tumor MeSH