The ACLY inhibitor SB204990 does not alter lysine histone acetylation in mouse liver

Motivation: Acetyl-coenzyme A is a fundamental component of cell metabolism, which plays a role in energy production, macromolecular biosynthesis and protein modification. Within the mitocondria, acetyl-coenzyme A condensation with oxaloacetate generates citrate, which can be exported to the cytosol, where is cleavaged by ATP-citrate lyase (ACLY), producing again acetyl-coenzyme A and oxaloacetate. In the nucleus and the cytoplasm acetyl-coenzyme A is used for important cellular functions such as histone acetylation or fatty acid synthesis. Silencing or inhibition of ACLY impairs tumor growth and produces blood lipid-lowering effects. Moreover, ACLY inhibitors are reasonably well tolerated in adult animals. Thus, ACLY inhibition could represent a therapeutic opportunity for the treatment of cancer and metabolic diseases, making its mechanistic understanding a promising field of study. Histone acetylation is a molecular mechanism that controls gene expression. Previous data has shown that global histone acetylation is latered in ACLY-deficient cell lines. Herein, we evaluated whether beneficial metabolic effects observed in mice exposed for 16 weeks to a pharmacological inhibitor of the ACLY are associated to modulations in histone acetylation in liver tissue lysates. Methods: An histone acid extraction wass conducted using the livers of mice exposed to 4 experimental conditions: standard diet, standard diet + SB (250 mg/Kg of food), high fat diet and high fat diet + SB (250 mg/Kg of food). Samples were procesed and western blots using specific antibodies of several histone-lysines were performed to evaluate potential modulations on histone acetylation levels between. Results and conclusions: Current data indicates that acetylation levels of H3K9, H3K14, H3K18, H3K56, H4K5, H4K8 are not significantly altered in the different experimental conditions. These results indicate that beneficial effects produced by ACLY inhibition are not caused by changes in histone acetylation in the liver

Evaluation of the effects of a hydrogen sulfide donor on neural plasticity.

The aging brain can exhibit significant modifications related with a progressive atrophy. Previous studies have shown that this atrophy may result from a combination of dendritic regression and neuronal death (1). Age-related memory and cognitive decline have been shown to coincide frequently with morphological changes which affect the neural plasticity and number of dendritic spines in the brains of both humans and animals (2). Furthermore, many neuropathologic conditions and neurodegenerative diseases exhibit abnormalities in dendritic tree structure. Animal studies have shown that even mild prolonged stress has been observed to induce the shrinkage of dendritic fields and the loss of dendritic spines (3).Recent evidence suggest that H2S is a gasotransmitter with neuroprotective properties. In addition, a few sulfur donors have shown beneficial therapeutic effects in experimental models of neurodegenerative diseases (4). Moreover, previous research in our lab suggests that a pharmacological treatment aimed at increasing intracellular H2S improves physical and metabolic health in mice. Nonetheless, the specific properties of these compounds maintaining neuron homeostasis and plasticity remain unknown.Here we aim to investigate whether modulation of intracellular H2S by a pharmacological intervention can improve neuronal plasticity in terms of morphological changes at the level of dendritic arborization and dendritic spine density. To this purpose, we will perform analyses in murine primary neuron cultures that will be treated with increasing concentrations of drug “δ”. Experimental conditions will be: untreated (0, vehicle solution), 10 μM, 50 μM, and 100 μM. Cells will be maintained for 12-14 days in culture, and will be treated with compound “δ” for 48 hours. Then cells will be fixed and MAP2 immunocytochemistry analyses will be performed. Photos will be taken under a fluorescence microscope and analyzed using software ImageJ to determine the percentage of arborized area and the dendritic spine density. The results will provide us with an insight into the potential of drug “δ” as a neuroprotective agent to prevent age-related loss of neuroplasticity

Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging

19 Páginas.-- 7 FigurasATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.This work was funded by grants from the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, co-funded by Fondos FEDER (PI15/00134, PI18/01590, CPII19/00023 to A.M.M.) and the Ministerio de Ciencia e Innovación (PID2021-123965OB-100 to A.M.M.). A.M.M. is funded by the Junta de Andalucía P20_00480, the Spanish Society of Diabetes, and CSIC 202220I059. M.S.K. is funded by the Nordea Foundation (#02-2017-1749), the Novo Nordisk Foundation (#NNF17OC0027812), the Neye Foundation, the Lundbeck Foundation (#R324-2019-1492), the Ministry of Higher Education and Science of Denmark (#0238-00003B). V.C.G. is funded by the Instituto de Salud Carlos III (CP19/00046), co-funded by FEDER. F.M. is funded by the CIBERDEM of the Instituto de Salud Carlos III. A.M.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We acknowledge the support of the group of basic research on diabetes of the Spanish Society of Diabetes.Peer reviewe

Effect of modulation of intracellular hydrogen sulfide production

Life expectancy has been significantly increased in recent years and thereby the diseases associated with aging. For hence, healthy aging is a current topic to investigate and try to promote. In a previous study in our laboratory, it has been observed that metabolism and physic health is improved in mice using pharmacological treatments aiming to increase intracellular H2S generation. To determine the underlying processes leading to these benefits, we evaluated modulations in metabolic pathways in the liver of these mice. We conducted a protein extraction using the livers of mice exposed to intracellular H2S generators using the following experimental groups: standard diet, standard diet + drug α, standard diet + drug β, high fat diet, high fat diet + drug α, high fat diet + drug β. Samples were processed and then western blots were performed using specific  antibodies to detect several proteins involved in energy, glucose and lipid metabolism. The purpose is to evaluate potential modulations on protein levels and post translational modulations that could contribute to the phenotype of these mice. The results will allow us to delineate whether intracellular H2S generators have the potential to modulate relevant pathways in order to generate new approaches for the treatment of age-related metabolic, physical and neurocognitive dysfunctions.   &nbsp

Thyroid hormones in diabetes, cancer, and aging

Thyroid function is central in the control of physiological and pathophysiological processes. Studies in animal models and human research have determined that thyroid hormones modulate cellular processes relevant for aging and for the majority of age-related diseases. While several studies have associated mild reductions on thyroid hormone function with exceptional longevity in animals and humans, alterations in thyroid hormones are serious medical conditions associated with unhealthy aging and premature death. Moreover, both hyperthyroidism and hypothyroidism have been associated with the development of certain types of diabetes and cancers, indicating a great complexity of the molecular mechanisms controlled by thyroid hormones. In this review, we describe the latest findings in thyroid hormone research in the field of aging, diabetes, and cancer, with a special focus on hepatocellular carcinomas. While aging studies indicate that the direct modulation of thyroid hormones is not a viable strategy to promote healthy aging or longevity and the development of thyromimetics is challenging due to inefficacy and potential toxicity, we argue that interventions based on the use of modulators of thyroid hormone function might provide therapeutic benefit in certain types of diabetes and cancers

Thyroid hormones in diabetes, cancer, and aging

Thyroid function is central in the control of physiological and pathophysiological processes. Studies in animal models and human research have determined that thyroid hormones modulate cellular processes relevant for aging and for the majority of age-related diseases. While several studies have associated mild reductions on thyroid hormone function with exceptional longevity in animals and humans, alterations in thyroid hormones are serious medical conditions associated with unhealthy aging and premature death. Moreover, both hyperthyroidism and hypothyroidism have been associated with the development of certain types of diabetes and cancers, indicating a great complexity of the molecular mechanisms controlled by thyroid hormones. In this review, we describe the latest findings in thyroid hormone research in the field of aging, diabetes, and cancer, with a special focus on hepatocellular carcinomas. While aging studies indicate that the direct modulation of thyroid hormones is not a viable strategy to promote healthy aging or longevity and the development of thyromimetics is challenging due to inefficacy and potential toxicity, we argue that interventions based on the use of modulators of thyroid hormone function might provide therapeutic benefit in certain types of diabetes and cancers.The authors receive financial support from the Institute of Health Carlos III and the Spanish Ministry of Science, Innovation and University, co‐funded by Fondos FEDER/Fondo social Europeo (PI18/01590 and CPII19/00023 to A.M‐M; CP19/00046 to V.C‐G, FI19/00162 to ASG, and BFU2017‐83588‐P to BRG), the Andalusian Regional Ministry of Health (C2‐0024‐2019 to A.M‐M and PI‐0272‐2017 to V.C‐G)