Document text
Principal Investigator: JANG H. YOUN
Organization: UNIVERSITY OF SOUTHERN CALIFORNIA
Fiscal Year: 2024
Award: $400,325
Funding agency: National Heart Lung and Blood Institute
Epoxyeicosatrienoic acids (EETs) are lipid mediators with beneficial effects on metabolic and cardiovascular (CV) health. EETs and other FFA epoxides are quickly metabolized to biologically less active diols by soluble epoxide hydrolase (sEH). Inhibition of sEH, which increases EETs, improves metabolic and CV health and is proposed as an effective strategy to treat diabetes and CV diseases. Despite its importance to health, how sEH is regulated in vivo is poorly understood, particularly in humans where sEH is difficult to study, largely due to limited access to individual tissues where sEH is expressed or lack of appropriate tools to assess sEH activity. sEH activity is often inferred in human studies by measuring FFA epoxide-diol ratios in the blood. As many as 15 FFA epoxide-diol pairs can be measured in blood. We recently developed a new method to estimate sEH activity in vivo, which combines metabolomic determination and simultaneous analysis of all measurable epoxide-diol pairs. This method⎯Simultaneous Analysis of Multiple Indices (SAMI)⎯markedly increases the power to detect changes (or group differences) in sEH activity. This is important, especially in human studies, as increased power allows detection of treatment effects with smaller sample sizes, reducing cost. One objective of this proposal is to evaluate the performance of our new metabolomic approach, SAMI, in detecting changes in sEH activity or EET metabolism under various conditions in animals, before it can be widely applied to human studies. Using SAMI, our recent study showed that sEH activity decreased profoundly after a meal in rats. Interestingly, this effect was completely abolished in animals with gut bacteria depleted by antibiotic treatment, suggesting that gut bacteria may be involved in the postprandial effect. Our preliminary data suggest the intriguing possibility that lithocholic acid (LCA), a secondary bile acid produced by gut bacteria, may be an endogenous inhibitor of sEH, mediating the postprandial regulation of sEH activity. Another objective of this proposal is to validate this novel mechanism of postprandial sEH regulation involving LCA. Thus, the proposed studies will explore a novel mechanism for sEH regulation in vivo and evaluate the performance of our new method to assess sEH activity based on plasma oxylipins. Successful completion of the proposed studies would facilitate studies of sEH regulation in vivo in animals and humans and lead to new therapeutic targets or strategies in the treatment of diabetes or CV diseases.
Terms: <Acids><Animals><Antibiotic Agents><Antibiotic Drugs><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Arachidonic Acids><Bile Acids><Blood><Blood Plasma><Blood Pressure><Blood Reticuloendothelial System><Body Tissues><Cardiovascular><Cardiovascular Abnormalities><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Common Rat Strains><Data><Deoxycholic Acid><Desoxycholic Acid><Detection><Development><Diabetes Mellitus><Dihydroxycholanoic Acid><Endothelium><Enzyme Gene><Enzymes><Epoxide Hydrases><Epoxide Hydratases><Epoxide hydrolase><Epoxides><Epoxy Compounds><Fats><Fatty acid glycerol esters><GI microbiota><Gastrointestinal microbiota><Genetic Polymorphism><Glycols><Health><Heart Vascular><Hepatic><Human><Hydrolase><Hydrolase Family Gene><Hydrolase Gene><In Vitro><Individual><Insulin Resistance><Intermediary Metabolism><Investigators><Isolithocholic Acid><Lithocholic Acid><Liver><Measurable><Measures><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Methods><Miscellaneous Antibiotic><Modern Man><Pathologic><Performance><Physiologic><Physiological><Plasma><Plasma Serum><Production><Rat><Rats Mammals><Rattus><Regulation><Research Personnel><Researchers><Reticuloendothelial System, Serum, Plasma><Role><Sample Size><Secondary to><Testing><Thesaurismosis><Time><Time Study><Tissues><bacteria in the gut><bacterial disease treatment><bacterial infectious disease treatment><blood glucose regulation><cardiovascular disorder><cardiovascular health><circulatory system><cost><developmental><diabetes><diabetic><dietary><diol><endothelial dysfunction><enteric microbial community><enteric microbiota><feeding><gastrointestinal microbial flora><glucose control><glucose homeostasis><glucose regulation><gut bacteria><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><hepatic body system><hepatic organ system><human disease><improved><in vivo><indexing><inhibitor><insulin resistant><insulin tolerance><intestinal flora><intestinal microbiota><intestinal microflora><intestinal tract microflora><lipid mediator><metabolism disorder><metabolism measurement><metabolomics><metabonomics><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><polymorphism><social role><tool><treatment effect>