Browsing by Author "Thoudam, Themis"

Now showing 1 - 8 of 8
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    Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease
    (Springer Nature, 2024-12-30) Li, Zhen; Gu, Min; Zaparte, Aline; Fu, Xiaoming; Mahen, Kala; Mrdjen, Marko; Li, Xinmin S.; Yang, Zhihong; Ma, Jing; Thoudam, Themis; Chandler, Kristina; Hesler, Maggie; Heathers, Laura; Gorse, Kiersten; Van, Thanh Trung; Wong, David; Gibson, Aaron M.; Wang, Zeneng; Taylor, Christopher M.; Quijada, Pearl; Makarewich, Catherine A.; Hazen, Stanley L.; Liangpunsakul, Suthat; Brown, J. Mark; Lefer, David J.; Welsh, David A.; Sharp, Thomas E., III; Medicine, School of Medicine
    The mechanism(s) underlying gut microbial metabolite (GMM) contribution towards alcohol-mediated cardiovascular disease (CVD) is unknown. Herein we observe elevation in circulating phenylacetylglutamine (PAGln), a known CVD-associated GMM, in individuals living with alcohol use disorder. In a male murine binge-on-chronic alcohol model, we confirm gut microbial reorganization, elevation in PAGln levels, and the presence of cardiovascular pathophysiology. Fecal microbiota transplantation from pair-/alcohol-fed mice into naïve male mice demonstrates the transmissibility of PAGln production and the CVD phenotype. Independent of alcohol exposure, pharmacological-mediated increases in PAGln elicits direct cardiac and vascular dysfunction. PAGln induced hypercontractility and altered calcium cycling in isolated cardiomyocytes providing evidence of improper relaxation which corresponds to elevated filling pressures observed in vivo. Furthermore, PAGln directly induces vascular endothelial cell activation through induction of oxidative stress leading to endothelial cell dysfunction. We thus reveal that the alcohol-induced microbial reorganization and resultant GMM elevation, specifically PAGln, directly contributes to CVD.
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    Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease
    (BMJ, 2024) Gao, Hui; Jiang, Yanchao; Zeng, Ge; Huda, Nazmul; Thoudam, Themis; Yang, Zhihong; Liangpunsakul, Suthat; Ma, Jing; Medicine, School of Medicine
    Alcohol-associated liver disease (ALD) is a growing global health concern and its prevalence and severity are increasing steadily. While bacterial endotoxin translocation into the portal circulation is a well-established key factor, recent evidence highlights the critical role of sterile inflammation, triggered by diverse stimuli, in alcohol-induced liver injury. This review provides a comprehensive analysis of the complex interactions within the hepatic microenvironment in ALD. It examines the contributions of both parenchymal cells, like hepatocytes, and non-parenchymal cells, such as hepatic stellate cells, Kupffer cells, neutrophils, and liver sinusoidal endothelial cells, in driving the progression of the disease. Additionally, we explored the involvement of key mediators, including cytokines, chemokines and inflammasomes, which regulate inflammatory responses and promote liver injury and fibrosis. A particular focus has been placed on extracellular vesicles (EVs) as essential mediators of intercellular communication both within and beyond the liver. These vesicles facilitate the transfer of signalling molecules, such as microRNAs and proteins, which modulate immune responses, fibrogenesis and lipid metabolism, thereby influencing disease progression. Moreover, we underscore the importance of organ-to-organ crosstalk, particularly in the gut-liver axis, where dysbiosis and increased intestinal permeability lead to microbial translocation, exacerbating hepatic inflammation. The adipose-liver axis is also highlighted, particularly the impact of adipokines and free fatty acids from adipose tissue on hepatic steatosis and inflammation in the context of alcohol consumption.
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    Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease
    (Springer Nature, 2023-03-27) Thoudam, Themis; Chanda, Dipanjan; Lee, Jung Yi; Jung, Min-Kyo; Sinam, Ibotombi Singh; Kim, Byung-Gyu; Park, Bo-Yoon; Kwon, Woong Hee; Kim, Hyo-Jeong; Kim, Myeongjin; Lim, Chae Won; Lee, Hoyul; Huh, Yang Hoon; Miller, Caroline A.; Saxena, Romil; Skill, Nicholas J.; Huda, Nazmul; Kusumanchi, Praveen; Ma, Jing; Yang, Zhihong; Kim, Min-Ji; Mun, Ji Young; Harris, Robert A.; Jeon, Jae-Han; Liangpunsakul, Suthat; Lee, In-Kyu; Pathology and Laboratory Medicine, School of Medicine
    Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca2+-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.
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    Mitochondrial quality control in alcohol-associated liver disease
    (Wolters Kluwer, 2024-10-24) Thoudam, Themis; Gao, Hui; Jiang, Yanchao; Huda, Nazmul; Yang, Zhihong; Ma, Jing; Liangpunsakul, Suthat; Medicine, School of Medicine
    Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD), a significant global health concern with limited therapeutic options. Understanding the key factors contributing to ALD pathogenesis is crucial for identifying potential therapeutic targets. Central to ALD pathogenesis is the intricate interplay between alcohol metabolism and cellular processes, particularly involving mitochondria. Mitochondria are essential organelles in the liver, critical for energy production and metabolic functions. However, they are particularly vulnerable to alcohol-induced damage due to their involvement in alcohol metabolism. Alcohol disrupts mitochondrial function, impairing ATP production and triggering oxidative stress, which leads to cellular damage and inflammation. Mitochondrial quality control mechanisms, including biogenesis, dynamics, and mitophagy, are crucial for maintaining optimal mitochondrial function. Chronic alcohol consumption disrupts mitochondrial quality control checkpoints, leading to mitochondrial dysfunction that impairs fatty acid oxidation and contributes to hepatic steatosis in ALD. Moreover, alcohol promotes the accumulation of damaged mitochondria and the release of proinflammatory components, exacerbating liver damage and inflammation. Preserving mitochondrial health presents a promising therapeutic approach to mitigate ALD progression. In this review, we provide a comprehensive overview of the effects of alcohol on mitochondrial function and quality control mechanisms, highlighting their role in ALD pathogenesis. Understanding these mechanisms may pave the way for the development of novel therapeutic interventions for ALD.
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    Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status
    (National Academy of Science, 2022) Thoudam, Themis; Chanda, Dipanjan; Sinam, Ibotombi Singh; Kim, Byung-Gyu; Kim, Mi-Jin; Oh, Chang Joo; Lee, Jung Yi; Kim, Min-Ji; Park, Soo Yeun; Lee, Shin Yup; Jung, Min-Kyo; Mun, Ji Young; Harris, Robert A.; Ishihara, Naotada; Jeon, Jae-Han; Lee, In-Kyu; Biochemistry and Molecular Biology, School of Medicine
    Dynamic regulation of mitochondrial morphology provides cells with the flexibility required to adapt and respond to electron transport chain (ETC) toxins and mitochondrial DNA-linked disease mutations, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here, we show that pyruvate dehydrogenase kinase 4 (PDK4) is genetically required for cells to undergo rapid mitochondrial fragmentation when challenged with ETC toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of mitochondrial stress. Importantly, we observed that the PDK4-mediated regulation of mitochondrial fission was independent of its canonical function, i.e., inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Phosphoproteomic screen for PDK4 substrates, followed by nonphosphorylatable and phosphomimetic mutations of the PDK4 site revealed cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 in the outer mitochondrial membrane to promote mitochondrial fission. Conversely, inhibition of the PDK4-SEPT2 axis could restore the balance in mitochondrial dynamics and reinvigorates cellular respiration in mitochondrial fusion factor, mitofusin 2-deficient cells. Furthermore, PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics and supports cancer cell growth. Our results identify the PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial function at the interface between cellular bioenergetics and mitochondrial dynamics.
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    PDK4 Augments ER–Mitochondria Contact to Dampen Skeletal Muscle Insulin Signaling During Obesity
    (American Diabetes Association, 2019-03) Thoudam, Themis; Ha, Chae-Myeong; Leem, Jaechan; Chanda, Dipanjan; Park, Jong-Seok; Kim, Hyo-Jeong; Jeon, Jae-Han; Choi, Yeon-Kyung; Liangpunsakul, Suthat; Huh, Yang Hoon; Kwon, Tae-Hwan; Park, Keun-Gyu; Harris, Robert A.; Park, Kyu-Sang; Rhee, Hyun-Woo; Lee, In-Kyu; Medicine, School of Medicine
    Background: Recent evidence in mobile health has demonstrated that, in some cases, apps are an effective way to improve health care delivery. Health care interventions delivered via mobile technology have demonstrated both practicality and affordability. Lately, cognitive behavioral therapy (CBT) interventions delivered over the internet have also shown a meaningful impact on patients with anxiety and depression. Objective: Given the growing proliferation of smartphones and the trust in apps to support improved health behaviors and outcomes, we were interested in comparing a mobile app with Web-based methods for the delivery of CBT. This study aimed to compare the usability of a CBT mobile app called MoodTrainer with an evidence-based website called MoodGYM. Methods: We used convenience sampling to recruit 30 students from a large Midwestern university and randomly assigned them to either the MoodGYM or MoodTrainer user group. The trial period ran for 2 weeks, after which the students completed a self-assessment survey based on Nielsen heuristics. Statistical analysis was performed to compare the survey results from the 2 groups. We also compared the number of modules attempted or completed and the time spent on CBT strategies. Results: The results indicate that the MoodTrainer app received a higher usability score when compared with MoodGYM. Overall, 87% (13/15) of the participants felt that it was easy to navigate through the MoodTrainer app compared with 80% (12/15) of the MoodGYM participants. All MoodTrainer participants agreed that the app was easy to use and did not require any external assistance, whereas only 67% (10/15) had the same opinion for MoodGYM. Furthermore, 67% (10/15) of the MoodTrainer participants found that the navigation controls were easy to locate compared with 80% (12/15) of the MoodGYM participants. MoodTrainer users, on average, completed 2.5 modules compared with 1 module completed by MoodGYM users. Conclusions: As among the first studies to directly compare the usability of a mobile app-based CBT with smartphone-specific features against a Web-based CBT, there is an opportunity for app-based CBT as, at least in our limited trial, it was more usable and engaging. The study was limited to evaluate usability only and not the clinical effectiveness of the app.
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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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    Upregulation of the ERRγ–VDAC1 axis underlies the molecular pathogenesis of pancreatitis
    (National Academy of Science, 2023) Chanda, Dipanjan; Thoudam, Themis; Sinam, Ibotombi Singh; Lim, Chae Won; Kim, Myeongjin; Wang, Jiale; Lee, Kyeong-Min; Ma, Jing; Saxena, Romil; Choi, Jinhyuk; Oh, Chang Joo; Lee, Hoyul; Jeon, Yong Hyun; Cho, Sung Jin; Jung, Hoe-Yune; Park, Keun-Gyu; Choi, Hueng-Sik; Suh, Jae Myoung; Auwerx, Johan; Ji, Baoan; Liangpunsakul, Suthat; Jeon, Jae-Han; Lee, In-Kyu; Medicine, School of Medicine
    Emerging evidence suggest that transcription factors play multiple roles in the development of pancreatitis, a necroinflammatory condition lacking specific therapy. Estrogen-related receptor γ (ERRγ), a pleiotropic transcription factor, has been reported to play a vital role in pancreatic acinar cell (PAC) homeostasis. However, the role of ERRγ in PAC dysfunction remains hitherto unknown. Here, we demonstrated in both mice models and human cohorts that pancreatitis is associated with an increase in ERRγ gene expression via activation of STAT3. Acinar-specific ERRγ haploinsufficiency or pharmacological inhibition of ERRγ significantly impaired the progression of pancreatitis both in vitro and in vivo. Using systematic transcriptomic analysis, we identified that voltage-dependent anion channel 1 (VDAC1) acts as a molecular mediator of ERRγ. Mechanistically, we showed that induction of ERRγ in cultured acinar cells and mouse pancreata enhanced VDAC1 expression by directly binding to specific site of the Vdac1 gene promoter and resulted in VDAC1 oligomerization. Notably, VDAC1, whose expression and oligomerization were dependent on ERRγ, modulates mitochondrial Ca2+ and ROS levels. Inhibition of the ERRγ-VDAC1 axis could alleviate mitochondrial Ca2+ accumulation, ROS formation and inhibit progression of pancreatitis. Using two different mouse models of pancreatitis, we showed that pharmacological blockade of ERRγ-VDAC1 pathway has therapeutic benefits in mitigating progression of pancreatitis. Likewise, using PRSS1R122H-Tg mice to mimic human hereditary pancreatitis, we demonstrated that ERRγ inhibitor also alleviated pancreatitis. Our findings highlight the importance of ERRγ in pancreatitis progression and suggests its therapeutic intervention for prevention and treatment of pancreatitis.