Hepatic cytochrome P-450 reductase-null mice show reduced transcriptional response to quercetin and reveal physiological homeostasis between jejunum and liver

Using mice deficient in hepatic cytochrome P-450 oxidoreductase (POR), which disables the liver cytochrome P-450 system, we examined the metabolism and biological response of the anticarcinogenic flavonoid, quercetin. Profiling circulating metabolites revealed similar profiles over 72 h in wild-type (WT) and POR-null (KO) mice, showing that hepatic P450 and reduced biliary secretion do not affect quercetin metabolism. Transcriptional profiling at 24 h revealed that two- to threefold more genes responded significantly to quercetin in WT compared with KO in the jejunum, ileum, colon, and liver, suggesting that hepatic P450s mediate many of the biological effects of quercetin, such as immune function, estrogen receptor signaling, and lipid, glutathione, purine, and amino acid metabolism, even though quercetin metabolism is not modified. The functional interpretation of expression data in response to quercetin (single dose of 7 mg/animal) revealed a molecular relationship between the liver and jejunum. In WT animals, amino acid and sterol metabolism was predominantly modulated in the liver, fatty acid metabolism response was shared between the liver and jejunum, and glutathione metabolism was modulated in the small intestine. In contrast, KO animals do not regulate amino acid metabolism in the liver or small intestine, they share the control of fatty acid metabolism between the liver and jejunum, and regulation of sterol metabolism is shifted from the liver to the jejunum and that of glutathione metabolism from the jejunum to the liver. This demonstrates that the quercetin-mediated regulation of these biological functions in extrahepatic tissues is dependent on the functionality of the liver POR. In conclusion, using a systems biology approach to explore the contribution of hepatic phase 1 detoxification on quercetin metabolism demonstrated the resiliency and adaptive capacity of a biological organism in dealing with a bioactive nutrient when faced with a tissue-specific molecular dysfunction.

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Plasma Metabolic Profiling Analysis of Gout Party on Acute Gout Arthritis Rats Based on UHPLC–Q–TOF/MS Combined with Multivariate Statistical Analysis

International Journal of Molecular Sciences ◽

10.3390/ijms20225753 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5753 ◽

Cited By ~ 2

Author(s):

Yuming Wang ◽

Chenghao Bi ◽

Wentao Pang ◽

Yuechen Liu ◽

Yu Yuan ◽

...

Keyword(s):

Fatty Acid ◽

Amino Acid ◽

Energy Metabolism ◽

Fatty Acid Metabolism ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Gouty Arthritis ◽

Enoic Acid ◽

Plasma Samples ◽

Tof Ms

Gout Party is a Chinese medicine prescription composed of Aconiti Lateralis Radix Praeparaia, Aconiti Radix Cocta, Cremastrae Pseudobulbus Pleiones Pseudobulbus, Smilacis Glabrae Rhizoma, Rehmanniae Radix, and Glycyrrhizae Radix et Rhizoma, which can relieve joint pain caused by gouty arthritis (GA) and rheumatoid, and has a therapeutic effect on acute gouty arthritis (AGA). However, little information is available on the molecular biological basis and therapeutic mechanism of Gout Party for the treatment of AGA. AGA model was established by injecting sodium urate, and colchicine served as a positive control drug. We established a metabolomic method based on ultra-high-performance liquid chromatography–tandem quadrupole/time-of-flight mass spectrometry (UHPLC–Q–TOF/MS) to analyze the plasma samples of model group rats and blank group rats. Multiple statistical analyses, including principal component analysis (PCA) and partial least square discrimination analysis (PLS-DA), were used to examine metabolite profile changes in plasma samples. Finally, we identified 2–ketobutyric acid, 3–hexenedioic acid, but–2–enoic acid, and so on; 22 endogenous metabolites associated with AGA. After successful molding, we found that 2–ketobutyric acid, 3–hexenedioic acid, but–2–enoic acid, argininic acid, galactonic acid, lactic acid, equol 4′–O–glucuronide, deoxycholic acid glycine conjugate, glycocholic acid, sphinganine 1–phosphate, LPE (0:0/20:3), LPE (0:0/16:0), LPC (15:0) decreased significantly (p < 0.05 or p < 0.01), alanine, erythrulose, 3–dehydrocarnitine, m–methylhippuric acid, 3–hydroxyoctanoic acid, p–cresol sulfate, estriol 3–sulfate 16–glucuronide, 10–hydroxy–9–(phosphonooxy)octadecenoate, docosahexaenoic acid increased significantly (p < 0.05 or p < 0.01). After Gout Party treatment, 14 biomarkers had a tendency to normal conditions. These above biomarkers were mainly involved in fatty acid metabolism, bile acid metabolism, amino acid metabolism, and energy metabolism pathways. These results suggested that Gout Party exerted therapeutic effects of treating AGA by improving energy metabolism disorder and amino acid metabolism dysfunction, and attenuating fatty acid metabolism abnormal and inflammation. The results of this experiment provided a reference for revealing the metabolic mechanism produced by Gout Party in the treatment of AGA, but the subsequent studies need to be further improved and supported by relevant cell experiments and clinical experiments.

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Small intestine proteomics coupled with serum metabolomics reveal disruption of amino acid metabolism in Chinese hamsters with type 2 diabetes mellitus

Journal of Proteomics ◽

10.1016/j.jprot.2020.103823 ◽

2020 ◽

Vol 223 ◽

pp. 103823

Author(s):

Chenyang Wang ◽

Jingjing Yu ◽

Ruihu Zhang ◽

Wentao Wang ◽

Zeya Shi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Small Intestine ◽

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Chinese Hamsters ◽

Serum Metabolomics

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Starvation causes disturbance in amino acid and fatty acid metabolism in Diporeia

Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology ◽

10.1016/j.cbpb.2011.12.011 ◽

2012 ◽

Vol 161 (4) ◽

pp. 348-355 ◽

Cited By ~ 16

Author(s):

Suman Maity ◽

Amber Jannasch ◽

Jiri Adamec ◽

Thomas Nalepa ◽

Tomas O. Höök ◽

...

Keyword(s):

Fatty Acid ◽

Amino Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism

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Remodeling of the Histoplasma Capsulatum Membrane Induced by Monoclonal Antibodies

Vaccines ◽

10.3390/vaccines8020269 ◽

2020 ◽

Vol 8 (2) ◽

pp. 269 ◽

Cited By ~ 2

Author(s):

Meagan C. Burnet ◽

Daniel Zamith-Miranda ◽

Heino M. Heyman ◽

Karl K. Weitz ◽

Erin L. Bredeweg ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Histoplasma Capsulatum ◽

Cellular Responses ◽

Mapk Signaling ◽

Yeast Cells ◽

Global Changes ◽

Sterol Metabolism

Antibodies play a central role in host immunity by directly inactivating or recognizing an invading pathogen to enhance different immune responses to combat the invader. However, the cellular responses of pathogens to the presence of antibodies are not well-characterized. Here, we used different mass spectrometry techniques to study the cellular responses of the pathogenic fungus Histoplasma capsulatum to monoclonal antibodies (mAb) against HSP60, the surface protein involved in infection. A proteomic analysis of H. capsulatum yeast cells revealed that mAb binding regulates a variety of metabolic and signaling pathways, including fatty acid metabolism, sterol metabolism, MAPK signaling and ubiquitin-mediated proteolysis. The regulation of the fatty acid metabolism was accompanied by increases in the level of polyunsaturated fatty acids, which further augmented the degree of unsaturated lipids in H. capsulatum’s membranes and energy storage lipids, such as triacylglycerols, phosphatidylcholines, phosphatidylethanolamines and phosphatidylinositols. MAb treatment also regulated sterol metabolism by increasing the levels of cholesterol and ergosterol in the cells. We also showed that global changes in the lipid profiles resulted in an increased susceptibility of H. capsulatum to the ergosterol-targeting drug amphotericin B. Overall, our data showed that mAb induction of global changes in the composition of H. capsulatum membranes can potentially impact antifungal treatment during histoplasmosis.

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Lactobacillus frumenti mediates energy production via fatty acid β-oxidation in the liver of early-weaned piglets

Journal of Animal Science and Biotechnology ◽

10.1186/s40104-019-0399-5 ◽

2019 ◽

Vol 10 (1) ◽

Author(s):

Zhichang Wang ◽

Jun Hu ◽

Wenyong Zheng ◽

Tao Yang ◽

Xinkai Wang ◽

...

Keyword(s):

Fatty Acid ◽

Amino Acid ◽

Gut Microbiota ◽

Oral Administration ◽

Energy Production ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Critical Role ◽

Guanosine Monophosphate ◽

Weaned Piglets

Abstract Background Early-weaning of piglets is often accompanied by severe disorders, especially diarrhea. The gut microbiota and its metabolites play a critical role in the maintenance of the physiologic and metabolic homeostasis of the host. Our previous studies have demonstrated that oral administration of Lactobacillus frumenti improves epithelial barrier functions and confers diarrhea resistance in early-weaned piglets. However, the metabolic response to L. frumenti administration remains unclear. Then, we conducted simultaneous serum and hepatic metabolomic analyses in early-weaned piglets administered by L. frumenti or phosphate-buffered saline (PBS). Results A total of 100 6-day-old crossbred piglets (Landrace × Yorkshire) were randomly divided into two groups and piglets received PBS (sterile, 2 mL) or L. frumenti (suspension in PBS, 108 CFU/mL, 2 mL) by oral administration once per day from 6 to 20 days of age. Piglets were weaned at 21 days of age. Serum and liver samples for metabolomic analyses were collected at 26 days of age. Principal components analysis (PCA) showed that L. frumenti altered metabolism in serum and liver. Numerous correlations (P < 0.05) were identified among the serum and liver metabolites that were affected by L. frumenti. Concentrations of guanosine monophosphate (GMP), inosine monophosphate (IMP), and uric acid were higher in serum of L. frumenti administration piglets. Pathway analysis indicated that L. frumenti regulated fatty acid and amino acid metabolism in serum and liver. Concentrations of fatty acid β-oxidation related metabolites in serum (such as 3-hydroxybutyrylcarnitine, C4-OH) and liver (such as acetylcarnitine) were increased after L. frumenti administration. Conclusions Our findings suggest that L. frumenti regulates lipid metabolism and amino acid metabolism in the liver of early-weaned piglets, where it promotes fatty acid β-oxidation and energy production. High serum concentrations of nucleotide intermediates, which may be an alternative strategy to reduce the incidence of diarrhea in early-weaned piglets, were further detected. These findings broaden our understanding of the relationships between the gut microbiota and nutrient metabolism in the early-weaned piglets.

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