Browsing by Author "Oshodi, Adepeju"

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    Serum metabolomic analysis reveals several novel metabolites in association with excessive alcohol use - an exploratory study
    (Elsevier, 2022) Liu, Danni; Yang, Zhihong; Chandler, Kristina; Oshodi, Adepeju; Zhang, Ting; Ma, Jing; Kusumanchi, Praveen; Huda, Nazmul; Heathers, Laura; Perez, Kristina; Tyler, Kelsey; Ross, Ruth Ann; Jiang, Yanchao; Zhang, Dabao; Zhang, Min; Liangpunsakul, Suthat; Medicine, School of Medicine
    Appropriate screening tool for excessive alcohol use (EAU) is clinically important as it may help providers encourage early intervention and prevent adverse outcomes. We hypothesized that patients with excessive alcohol use will have distinct serum metabolites when compared to healthy controls. Serum metabolic profiling of 22 healthy controls and 147 patients with a history of EAU was performed. We employed seemingly unrelated regression to identify the unique metabolites and found 67 metabolites (out of 556), which were differentially expressed in patients with EAU. Sixteen metabolites belong to the sphingolipid metabolism, 13 belong to phospholipid metabolism, and the remaining 38 were metabolites of 25 different pathways. We also found 93 serum metabolites that were significantly associated with the total quantity of alcohol consumption in the last 30 days. A total of 15 metabolites belong to the sphingolipid metabolism, 11 belong to phospholipid metabolism, and 7 metabolites belong to lysolipid. Using a Venn diagram approach, we found the top 10 metabolites with differentially expressed in EAU and significantly associated with the quantity of alcohol consumption, sphingomyelin (d18:2/18:1), sphingomyelin (d18:2/21:0,d16:2/23:0), guanosine, S-methylmethionine, 10-undecenoate (11:1n1), sphingomyelin (d18:1/20:1, d18:2/20:0), sphingomyelin (d18:1/17:0, d17:1/18:0, d19:1/16:0), N-acetylasparagine, sphingomyelin (d18:1/19:0, d19:1/18:0), and 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1). The diagnostic performance of the top 10 metabolites, using the area under the ROC curve, was significantly higher than that of commonly used markers. We have identified a unique metaboloic signature among patients with EAU. Future studies to validate and determine the kinetics of these markers as a function of alcohol consumption are needed.
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    Serum Metabolomic Profiling Identifies Key Metabolic Signatures Associated With Pathogenesis of Alcoholic Liver Disease in Humans
    (Wiley, 2019-02-20) Yang, Zhihong; Kusumanchi, Praveen; Ross, Ruth A.; Heathers, Laura; Chandler, Kristina; Oshodi, Adepeju; Thoudam, Themis; Li, Feng; Wang, Li; Liangpunsakul, Suthat; Medicine, School of Medicine
    Alcoholic liver disease (ALD) develops in a subset of heavy drinkers (HDs). The goals of our study were to (1) characterize the global serum metabolomic changes in well-characterized cohorts of controls (Cs), HDs, and those with alcoholic cirrhosis (AC); (2) identify metabolomic signatures as potential diagnostic markers, and (3) determine the trajectory of serum metabolites in response to alcohol abstinence. Serum metabolic profiling was performed in 22 Cs, 147 HDs, and 33 patients with AC using ultraperformance liquid chromatography-tandem mass spectrometry. Hepatic gene expression was conducted in Cs (n = 16) and those with AC (n = 32). We found progressive changes in the quantities of metabolites from heavy drinking to AC. Taurine-conjugated bile acids (taurocholic acid [TCA], 127-fold; taurochenodeoxycholic acid [TCDCA], 131-fold; and tauroursodeoxycholic acid, 56-fold) showed more striking elevations than glycine-conjugated forms (glycocholic acid [GCA], 22-fold; glycochenodeoxycholic acid [GCDCA], 22-fold; and glycoursodeoxycholic acid [GUDCA], 11-fold). This was associated with increased liver cytochrome P450, family 7, subfamily B, member 1 and taurine content (more substrates); the latter was due to dysregulation of homocysteine metabolism. Increased levels of GCDCA, TCDCA, GCA, and TCA positively correlated with disease progression from Child-Pugh A to C and Model for End-Stage Liver Disease scores, whereas GCDCA, GCA, and GUDCA were better predictors of alcohol abstinence. The levels of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor (FGF) 21 but not FGF19 were increased in HDs, and all three were further increased in those with AC. Conclusion: Serum taurine/glycine-conjugated bile acids could serve as noninvasive markers to predict the severity of AC, whereas GLP-1 and FGF21 may indicate a progression from heavy drinking to AC.
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    Stress-Responsive Gene FK506-Binding Protein 51 Mediates Alcohol-Induced Liver Injury Through the Hippo Pathway and Chemokine (C-X-C Motif) Ligand 1 Signaling
    (Wolters Kluwer, 2021) Kusumanchi, Praveen; Liang, Tiebing; Zhang, Ting; Ross, Ruth Ann; Han, Sen; Chandler, Kristina; Oshodi, Adepeju; Jiang, Yanchao; Dent, Alexander L.; Skill, Nicholas J.; Huda, Nazmul; Ma, Jing; Yang, Zhihong; Liangpunsakul, Suthat; Medicine, School of Medicine
    Background and aims: Chronic alcohol drinking is a major risk factor for alcohol-associated liver disease (ALD). FK506-binding protein 51 (FKBP5), a cochaperone protein, is involved in many key regulatory pathways. It is known to be involved in stress-related disorders, but there are no reports regarding its role in ALD. This present study aimed to examine the molecular mechanism of FKBP5 in ALD. Approach and results: We found a significant increase in hepatic FKBP5 transcripts and protein expression in patients with ALD and mice fed with chronic-plus-single binge ethanol. Loss of Fkbp5 in mice protected against alcohol-induced hepatic steatosis and inflammation. Transcriptomic analysis revealed a significant reduction of Transcriptional enhancer factor TEF-1 (TEA) domain transcription factor 1 (Tead1) and chemokine (C-X-C motif) ligand 1 (Cxcl1) mRNA in ethanol-fed Fkbp5-/- mice. Ethanol-induced Fkbp5 expression was secondary to down-regulation of methylation level at its 5' untranslated promoter region. The increase in Fkbp5 expression led to induction in transcription factor TEAD1 through Hippo signaling pathway. Fkbp5 can interact with yes-associated protein (YAP) upstream kinase, mammalian Ste20-like kinase 1 (MST1), affecting its ability to phosphorylate YAP and the inhibitory effect of hepatic YAP phosphorylation by ethanol leading to YAP nuclear translocation and TEAD1 activation. Activation of TEAD1 led to increased expression of its target, CXCL1, a chemokine-mediated neutrophil recruitment, causing hepatic inflammation and neutrophil infiltration in our mouse model. Conclusions: We identified an FKBP5-YAP-TEAD1-CXCL1 axis in the pathogenesis of ALD. Loss of FKBP5 ameliorates alcohol-induced liver injury through the Hippo pathway and CXCL1 signaling, suggesting its potential role as a target for the treatment of ALD.
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    Stress-responsive gene FKBP5 mediates alcohol-induced liver injury through the hippo pathway and CXCL1 signaling
    (Wiley, 2021-09) Kusumanchi, Praveen; Liang, Tiebing; Zhang, Ting; Ross, Ruth Ann; Han, Sen; Chandler, Kristina; Oshodi, Adepeju; Jiang, Yanchao; Dent, Alexander L.; Skill, Nicholas J.; Huda, Nazmul; Ma, Jing; Yang, Zhihong; Liangpunsakul, Suthat; Medicine, School of Medicine
    Chronic alcohol drinking is a major risk factor for alcohol-associated liver disease (ALD). FK506-binding protein 51 (FKBP5), a co-chaperone protein, is involved in many key regulatory pathways. It is known to be involved in stress-related disorders but there are no reports regarding its role in ALD. This present study aimed to examine the molecular mechanism of FKBP5 in ALD. We found a significant increase in hepatic FKBP5 transcripts and protein expression in patients with ALD and mice fed with chronic-plus-single binge ethanol. Loss of Fkbp5 in mice protected against alcohol-induced hepatic steatosis and inflammation. Transcriptomic analysis revealed a significant reduction of Tead1 and Cxcl1 mRNA in ethanol-fed Fkbp5-/- mice. Ethanol-induced Fkbp5 expression was secondary to downregulation of methylation level at its 5′ UTR promoter region. The increase in Fkbp5 expression led to induction in transcription factor Tead1 through Hippo signaling pathway. Fkbp5 can interact with YAP upstream kinase, MST1, affecting its ability to phosphorylate YAP and the inhibitory effect of hepatic YAP phosphorylation by ethanol leading to YAP nuclear translocation and TEAD1 activation. Activation of TEAD1 led to increased expression of its novel target, CXCL1, a chemokine-mediated neutrophil recruitment, causing hepatic inflammation and neutrophil infiltration in our mouse model. Conclusion We identified a novel FKBP5-YAP-TEAD1-CXCL1 axis in the pathogenesis of ALD. Loss of FKBP5 ameliorates alcohol-induced liver injury through the Hippo pathway and CXCL1 signaling, suggesting its potential role as a target for the treatment of ALD.