Potential effect of ezetimibe against <i>Mycobacterium tuberculosis</i> infection in type II diabetes

Tsai, I-Fang; Kuo, Chiu-Ping; Lin, Andrew; Chien, Ming-Nan; Ho, Hsin‐Tsung; Wei, Tsai-Yin; Wu, Chien‐Liang; Lu, Yen‐Ta

doi:10.1111/resp.12948

Cited by 13 publications

(13 citation statements)

References 41 publications

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“…Therefore, reduction of plasma lipids may not be fully effective at controlling latent TB. In fact, our previous study showed that another lipid-lowering agent, ezetimibe, known to inhibit cholesterol uptake into cells, was associated with a lower risk of latent TB in patients with diabetes [29][30][31]. Our current study shows that fenofibrate not only sustains the availability of intracellular lipids but also enhances dormant genes known to involved in lipid metabolism.…”

Section: Discussionmentioning

confidence: 51%

Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment

Liu

Tsai

et al. 2020

JCM

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Background: Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that infects and persists in macrophages. This study aimed to investigate the effects of long-term fenofibrate treatment in patients with tuberculosis (TB), and the intracellular viability of Mtb in human macrophages. Methods: Epidemiological data from the National Health Insurance Research Database of Taiwan were used to present outcomes of TB patients treated with fenofibrate. In the laboratory, we assessed Mtb infection in macrophages treated with or without fenofibrate. Mtb growth, lipid accumulation in macrophages, and expression of transcriptional genes were examined. Results: During 11 years of follow-up, TB patients treated with fenofibrate presented a higher risk of mortality. Longer duration of fenofibrate use was associated with a significantly higher risk of mortality. Treatment with fenofibrate significantly increased the number of bacilli in human macrophages in vitro. Fenofibrate did not reduce, but induced an increasing trend in the intracellular lipid content of macrophages. In addition, dormant genes of Mtb, icl1, tgs1, and devR, were markedly upregulated in response to fenofibrate treatment. Our results suggest that fenofibrate may facilitate intracellular Mtb persistence. Conclusions: Our data shows that long-term treatment with fenofibrate in TB patients is associated with a higher mortality. The underlying mechanisms may partly be explained by the upregulation of Mtb genes involved in lipid metabolism, enhanced intracellular growth of Mtb, and the ability of Mtb to sustain a nutrient-rich reservoir in human macrophages, observed during treatment with fenofibrate. people, it still presents the highest incidence and mortality rate [2]. This disease is transmitted via inhalation of aerosolized bacilli, which then replicate within alveolar macrophages in lung tissue. In the host, immune cells can be recruited to the affected sites, and encase the invading mycobacteria, forming a structure known as the granuloma [3,4]. A granuloma is composed of infected alveolar macrophages, monocytes, multinucleated giant cells, epithelioid cells, and most notably, foamy macrophages [4,5]. The foamy aspect of these cells results from the accumulation of neutral lipids, typically triacylglycerides and esterified and non-esterified sterols. These foamy macrophages are nutrient-rich reservoirs for Mtb persistence [6,7].Published data support that regulating cholesterol in macrophages may affect the intracellular growth of Mtb [8,9]. However, questions remain regarding the use of hypolipidemic therapy for the treatment of Mtb infection [10]. By the activation of peroxisome proliferator activated receptor α (PPARα), mainly expressed in the liver, heart, monocytes, and macrophages, fenofibrate increases lipolysis and elimination of lipids from plasma [11][12][13]. It is commonly prescribed for the treatment of hypertriglyceridemia or mixed hyperlipidemia [13][14][15]. This study aimed to investigate epidemiological data to obtain outcomes of TB...

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Section: Discussionmentioning

confidence: 51%

Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment

Liu

Tsai

et al. 2020

JCM

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“…9 In contrast, nonstatin lipid-lowering agents are unknown to have anti-TB effects, except ezetimibe, which has recently presented potential benefits. 42 Since statin users and nonstatin users were both likely to have dyslipidaemia and the former were older and had more comorbidities than the latter in this study, statins' effect on TB cannot simply be explained by hyperlipidaemia itself or the healthy user effect. 16 Even after controlling for timerelated biases and balancing certain variables in the matched subcohort analysis, the results remained significant.…”

Section: Discussionmentioning

confidence: 78%

“…Moreover, combined with a standard anti‐TB regimen, statin accelerates bacillary clearance in the lungs of mice . In contrast, nonstatin lipid‐lowering agents are unknown to have anti‐TB effects, except ezetimibe, which has recently presented potential benefits . Since statin users and nonstatin users were both likely to have dyslipidaemia and the former were older and had more comorbidities than the latter in this study, statins' effect on TB cannot simply be explained by hyperlipidaemia itself or the healthy user effect .…”

Section: Discussionmentioning

confidence: 79%

Opposite effects of statins on the risk of tuberculosis and herpes zoster in patients with diabetes: A population‐based cohort study

Pan

Yen

Feng

et al. 2020

Brit J Clinical Pharma

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Aims It remains uncertain whether statin use is associated with the risks of tuberculosis (TB) and herpes zoster in patients with type 2 diabetes. This study aims to assess the effects of statins vs nonstatin lipid‐lowering agents on the risk of these infectious diseases in patients with diabetes. Methods Participants in the Taiwan National Health Insurance Research Database diagnosed with type 2 diabetes in 2001–2013 were classified as statin users, nonstatin users and lipid‐lowering drug‐free groups. Participants were observed for incident TB and herpes zoster from diabetes diagnosis until treatment crossover or December 2013. Statin user and nonstatin user were the time‐dependent variables in Cox regression analysis. Results Over 240 782 person‐years of observation, statin users (n = 17 696) were associated with a lower TB risk than nonstatin users (n = 5327) and the drug‐free group (n = 22 316) (adjusted hazard ratio [aHR]: 0.66; 95% confidence interval [CI]: 0.44–0.99 and aHR: 0.57; 95% CI: 0.44–0.73). Compared with nonstatin users, statin users showed a dose‐dependent association with TB risk (low‐potency statin users, aHR: 0.692; 95% CI: 0.455–1.053; high‐potency users, aHR: 0.491; 95% CI: 0.241–0.999). Statin users presented with a higher risk of herpes zoster than nonstatin users and the drug‐free group (aHR: 1.23; 95% CI: 1.01–1.50 and aHR: 1.20; 95% CI: 1.09–1.33). The risks of TB and herpes zoster were not statistically different between nonstatin users and the drug‐free group. Conclusion Compared with nonstatin drugs, statin use was specifically associated with a decreased risk of TB but a moderately increased risk of herpes zoster in this cohort study.

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Section: Therapeutic Targeting Of Host Immunometabolismmentioning

confidence: 99%

“…Another cholesterol-lowering drug, ezetimibe, has also shown potency against intracellular M.tb under hypoxic conditions (Tsai et al, 2017). Furthermore, the study also reported that patients receiving ezetimibe therapy exhibited a lower incidence of LTBI as well as intracellular lipid content, concomitant with reduced bacterial reservoirs (Tsai et al, 2017). However, like statins but via a different mechanism, ezetimibe also has anti-inflammatory properties which downregulates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression and monocyte chemotactic protein 1 (MCP-1) production albeit with a chance of increasing NO expression (Toshiyuki and Yasuchika, 2011).…”

Section: Therapeutic Targeting Of Host Immunometabolismmentioning

confidence: 99%

Immunometabolism and Pulmonary Infections: Implications for Protective Immune Responses and Host-Directed Therapies

et al. 2019

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BACKGROUND Central immune effector functions, e.g., the development of long-term immunological memory, homing to target tissues and effective immune-surveillance are, in part, determined by metabolic programming, which plays a role not only in cellular physiology yet also in immunopathology (Shehata et al., 2017; Gardiner, 2019). A better understanding of the dynamic role of metabolic programming may devise new ways of targeted therapeutic intervention(s). Preclinical and clinical studies in patients with non-communicable diseases link metabolic cellular impairment with immune dysfunction (Hotamisligil, 2017). A shift in metabolite requirement appears to govern the nature and dynamics of the immune response in the host-largely involving glucose or lipids and

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Potential effect of ezetimibe against Mycobacterium tuberculosis infection in type II diabetes

Abstract: Ezetimibe, which is a currently marketed drug, could hold promise as an adjunctive, host-directed therapy for TB.

Cited by 13 publications

References 41 publications

Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment

Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment

Opposite effects of statins on the risk of tuberculosis and herpes zoster in patients with diabetes: A population‐based cohort study

Immunometabolism and Pulmonary Infections: Implications for Protective Immune Responses and Host-Directed Therapies

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