Abstract A67: Bi-phasic metabolic responses to in situ macrophage activation

Kam, Yoonseok; Swain, Pamela; Dranka, Brian P.

doi:10.1158/2326-6074.tumimm17-a67

Cited by 3 publications

(2 citation statements)

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“…Raw data were normalized to nuclei count and scaled up to 20 000 cells using the scale factor feature in Seahorse Wave software, as described in Kam et al . ( 29 ).…”

Section: Methodsmentioning

confidence: 99%

Simvastatin profoundly impairs energy metabolism in primary human muscle cells

Mäkinen

Datta

Nguyen

et al. 2020

Endocrine Connections

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Objectives: Simvastatin use is associated with muscular side effects, and increased risk for type 2 diabetes (T2D). In clinical use, simvastatin is administered in inactive lipophilic lactone-form, which is then converted to active acid-form in the body. Here, we have investigated if lactone- and acid-form simvastatin differentially affect glucose metabolism and mitochondrial respiration in primary human skeletal muscle cells. Methods: Muscle cells were exposed separately to lactone- and acid-form simvastatin for 48 h. After pre-exposure, glucose uptake and glycogen synthesis were measured using radioactive tracers; insulin signalling was detected with western blotting; and glycolysis, mitochondrial oxygen consumption and ATP production were measured with Seahorse XFe96 analyzer. Results: Lactone-form simvastatin increased glucose uptake and glycogen synthesis, whereas acid-form simvastatin did not affect glucose uptake and decreased glycogen synthesis. Phosphorylation of insulin signalling targets Akt substrate 160 kDa (AS160) and glycogen synthase kinase 3β (GSK3β) was upregulated with lactone-, but not with acid-form simvastatin. Exposure to both forms of simvastatin led to a decrease in glycolysis and glycolytic capacity, as well as to a decrease in mitochondrial respiration and ATP production. Conclusions: These data suggest that lactone- and acid-forms of simvastatin exhibit differential effects on non-oxidative glucose metabolism as lactone-form increases and acid-form impairs glucose storage into glycogen, suggesting impaired insulin sensitivity in response to acid-form simvastatin. Both forms profoundly impair oxidative glucose metabolism and energy production in human skeletal muscle cells. These effects may contribute to muscular side effects and risk for T2D observed with simvastatin use.

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“…Raw data were normalized to nuclei count and scaled up to 20 000 cells using the scale factor feature in Seahorse Wave software, as described in Kam et al . ( 29 ).…”

Section: Methodsmentioning

confidence: 99%

Simvastatin profoundly impairs energy metabolism in primary human muscle cells

Mäkinen

Datta

Nguyen

et al. 2020

Endocrine Connections

View full text Add to dashboard Cite

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“…Nevertheless, a rigid conclusion on ECAR cannot be made as the Mito Stress Test assay only allows for qualitative interpretation of cellular ECAR. Although the MTT assay has previously been reported as a normalizing tool for the Mito Stress Test assay [25], it is noteworthy that normalising the OCR and ECAR data to MTT readout may result in discrepancies when correlating cellular ATP to the absolute cell numbers [43,44], hence the limitation of this study. Therefore, cell viability assays that do not interfere with cell metabolism may be used as an alternative approach [44].…”

Section: Discussionmentioning

confidence: 99%

BZD9L1 Differentially Regulates Sirtuins in Liver-Derived Cells by Inducing Reactive Oxygen Species

Lee,

Tan,

Oon

2023

Biomedicines

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Growing evidence has highlighted that mitochondrial dysfunction contributes to drug-induced toxicities and leads to drug attrition and post-market withdrawals. The acetylation or deacetylation of mitochondrial proteins can affect mitochondrial functions as the cells adapt to various cellular stresses and other metabolic challenges. SIRTs act as critical deacetylases in modulating mitochondrial function in response to drug toxicity, oxidative stress, reactive oxygen species (ROS), and energy metabolism. We previously showed that a recently characterised SIRT inhibitor (BZD9L1) is non-toxic in rodents in a short-term toxicity evaluation. However, the impact of BZD9L1 on mitochondrial function is unknown. This work aims to determine the effects of BZD9L1 on mitochondrial function in human normal liver and kidney-derived cell lines using the Agilent Seahorse Cell Mito Stress Test to complement our short-term toxicity evaluations in vivo. The Mito Stress assay revealed that BZD9L1 could potentially trigger oxidative stress by inducing ROS, which promotes proton leak and reduces coupling efficiency in liver-derived THLE cells. However, the same was not observed in human kidney-derived HEK293 cells. Interestingly, BZD9L1 had no impact on SIRT3 protein expression in both cell lines but affected SOD2 and its acetylated form at 72 h in THLE cells, indicating that BZD9L1 exerted its effect through SIRT3 activity rather than protein expression. In contrast, BZD9L1 reduced SIRT1 protein expression and impacted the p53 protein differently in both cell lines. Although BZD9L1 did not affect the spare respiratory capacity in vitro, these findings call for further validation of mitochondrial function through assessment of other mitochondrial parameters to evaluate the safety of BZD9L1.

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Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight

et al. 2020

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Nitric Oxide (NO) is a soluble endogenous gas with various biological functions like signaling, and working as an effector molecule or metabolic regulator. In response to inflammatory signals, immune myeloid cells, like macrophages, increase production of cytokines and NO, which is important for pathogen killing. Under these proinflammatory circumstances, called “M1”, macrophages undergo a series of metabolic changes including rewiring of their tricarboxylic acid (TCA) cycle. Here, we review findings indicating that NO, through its interaction with heme and non-heme metal containing proteins, together with components of the electron transport chain, functions not only as a regulator of cell respiration, but also a modulator of intracellular cell metabolism. Moreover, diverse effects of NO and NO-derived reactive nitrogen species (RNS) involve precise interactions with different targets depending on concentration, temporal, and spatial restrictions. Although the role of NO in macrophage reprogramming has been in evidence for some time, current models have largely minimized its importance. It has, therefore, been hiding in plain sight. A review of the chemical properties of NO, past biochemical studies, and recent publications, necessitates that mechanisms of macrophage TCA reprogramming during stimulation must be re-imagined and re-interpreted as mechanistic results of NO exposure. The revised model of metabolic rewiring we describe here incorporates many early findings regarding NO biochemistry and brings NO out of hiding and to the forefront of macrophages immunometabolism.

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Abstract A67: Bi-phasic metabolic responses to in situ macrophage activation

Cited by 3 publications

References 0 publications

Simvastatin profoundly impairs energy metabolism in primary human muscle cells

Simvastatin profoundly impairs energy metabolism in primary human muscle cells

BZD9L1 Differentially Regulates Sirtuins in Liver-Derived Cells by Inducing Reactive Oxygen Species

Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight

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