bims-meprid 2021-03-14 papers

Front Immunol. 2021 ;12 632526

Exploring the Role of ATP-Citrate Lyase in the Immune System.

Monica Dominguez, Bernhard Brüne, Dmitry Namgaladze.

Studies over the past decade have revealed that metabolism profoundly influences immune responses. In particular, metabolism causes epigenetic regulation of gene expression, as a growing number of metabolic intermediates are substrates for histone post-translational modifications altering chromatin structure. One of these substrates is acetyl-coenzyme A (CoA), which donates an acetyl group for histone acetylation. Cytosolic acetyl-CoA is also a critical substrate for de novo synthesis of fatty acids and sterols necessary for rapid cellular growth. One of the main enzymes catalyzing cytosolic acetyl-CoA formation is ATP-citrate lyase (ACLY). In addition to its classical function in the provision of acetyl-CoA for de novo lipogenesis, ACLY contributes to epigenetic regulation through histone acetylation, which is increasingly appreciated. In this review we explore the current knowledge of ACLY and acetyl-CoA in mediating innate and adaptive immune responses. We focus on the role of ACLY in supporting de novo lipogenesis in immune cells as well as on its impact on epigenetic alterations. Moreover, we summarize alternative sources of acetyl-CoA and their contribution to metabolic and epigenetic regulation in cells of the immune system.

Keywords: ATP-citrate lyase; acetyl-CoA; histone acetylation; macrophage; metabolism

DOI: https://doi.org/10.3389/fimmu.2021.632526

J Cell Physiol. 2021 Mar 08.

Acetyl-CoA synthases are essential for maintaining histone acetylation under metabolic stress during zygotic genome activation in pigs.

Wenjun Zhou, Zheng-Wen Nie, Dong-Jie Zhou, Xiang-Shun Cui.

ACSS1/2 converts acetate into acetyl-coenzyme A, which contributes to histone acetylation in the mitochondria and cytoplasm. Zygotic genome activation (ZGA) is critical for embryo development involving drastic histone modification. An efficient crRNAs-Cas13a targeting strategy was employed to investigate the ACSS1/2 function during ZGA. The results showed that nuclear accumulation of ACSS1 and ACSS2 occurs during ZGA. Knockdown of ACSS1/2 did not affect blastocyst formation when using a normal medium. On culturing embryos in a medium with acetate and no pyruvate (-P + Ace), knockdown of ACSS1 did not affect histone acetylation levels but significantly reduced ATP levels, whereas knockdown of ACSS2 significantly reduced histone acetylation levels in porcine embryos. Inhibition of fatty acid beta-oxidation by etomoxir significantly reduced ATP levels, which could be restored by acetate. The histone acetylation levels in the ACSS1 and ACSS2 knockdown groups both decreased considerably after etomoxir treatment. Moreover, acetate showed dose-dependent effects on SIRT1 and SIRT3 levels when under metabolic stress. The C-terminus of ACSS1 regulated the nuclear translocation. In conclusion, ACSS1/2 helps to maintain ATP and histone acetylation levels in porcine early embryos under metabolic stress during ZGA.

Keywords: ACSS1; ACSS2; ZGA; embryo development; histone acetylation; porcine

DOI: https://doi.org/10.1002/jcp.30355

Free Radic Biol Med. 2021 Mar 03. pii: S0891-5849(21)00139-8. [Epub ahead of print]

Mitochondrial Redox and TCA Cycle Metabolite Signaling in the Heart.

Ana Vujic, Amy N M Koo, Hiran A Prag, Thomas Krieg.

Mitochondria are essential signaling organelles that regulate a broad range of cellular processes and thereby heart function. Multiple mechanisms participate in the communication between mitochondria and the nucleus that maintain cardiomyocyte homeostasis, including mitochondrial reactive oxygen species (ROS) and metabolic shifts in TCA cycle metabolite availability. An increased rate of ROS generation can cause irreversible damage to the cell and proposed to be a leading cause of many pathologies, including accelerated aging and heart disease. Myocardial impairments are also characterised by specific coordinated metabolic changes and dysregulated inflammatory responses. Hence, the mitochondrial respiratory chain is an important mediator between health and disease in the heart. This review will first outline the sources of ROS in the heart, mitochondrial metabolite dynamics, and provide an overview of their implications for heart disease. In addition, we will concentrate our discussion around current cardioprotective strategies relevant to mitochondrial ROS. Thorough understanding of mitochondrial signaling and the complex interplay with vital signaling pathways in the heart might allow us to develop novel therapeutic approaches to cardiovascular disease.

Keywords: Cardiovascular disease; ROS; metabolism; mitochondria; redox signaling

DOI: https://doi.org/10.1016/j.freeradbiomed.2021.02.041

J Clin Invest. 2021 Mar 09. pii: 144703. [Epub ahead of print]

Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation.

Jin Xiang, Chang Chen, Rui Liu, Dongmei Gou, Lei Chang, Haijun Deng, Qingzhu Gao, Wanjun Zhang, Lin Tuo, Xuanming Pan, Li Liang, Jie Xia, Luyi Huang, Ke Yao, Bohong Wang, Zeping Hu, Ailong Huang, Kai Wang, Ni Tang.

Although cancer cells are frequently faced with nutrient- and oxygen-poor microenvironment, elevated hexosamine-biosynthesis pathway (HBP) activity and protein O-GlcNAcylation (a nutrient sensor) contribute to rapid growth of tumor and are emerging hallmarks of cancer. Inhibiting O-GlcNAcylation could be a promising anti-cancer strategy. The gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 (PCK1) was downregulated in hepatocellular carcinoma (HCC). However, little is known about the potential role of PCK1 in enhanced HBP activity and HCC carcinogenesis under glucose-limited conditions. In this study, PCK1 knockout markedly enhanced the global O-GlcNAcylation levels under low glucose condition. Mechanistically, metabolic reprogramming in PCK1-loss hepatoma cells led to oxaloacetate accumulation and increased de novo UTP synthesis contributing to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion of PCK1 also resulted in AMPK-GFAT1 axis inactivation promoting UDP-GlcNAc synthesis for elevated O-GlcNAcylation. Notably, lower expression of PCK1 promoted CHK2 threonine 378 O-GlcNAcylation counteracting its stability and dimer formation, increasing CHK2-dependent Rb phosphorylation and HCC cell proliferation. Moreover, aminooxyacetic acid hemihydrochloride and 6-diazo-5-oxo-L-norleucine blocked HBP-mediated O-GlcNAcylation and suppressed tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation.

Keywords: Gluconeogenesis; Liver cancer; Metabolism; Molecular biology; Oncology

DOI: https://doi.org/10.1172/JCI144703

Trends Endocrinol Metab. 2021 Mar 09. pii: S1043-2760(21)00043-6. [Epub ahead of print]

Acetyl-CoA and Metabolite Fluxes Regulate White Adipose Tissue Expansion.

Jessica B Felix, Aaron R Cox, Sean M Hartig.

White adipose tissue (WAT) depends on coordinated regulation of transcriptional and metabolic pathways to respond to whole-body energy demands. We highlight metabolites that contribute to biosynthetic reactions for WAT expansion. Recent studies have precisely defined how byproducts of carbohydrate and lipid metabolism affect physiological and endocrine functions in adipocytes. We emphasize the critical emerging roles of short-chain fatty acids (SCFAs) and tricarboxylic acid (TCA) cycle metabolites that connect lipogenesis to WAT energy balance and endocrine functions. These insights address how adipocytes use small molecules generated from central carbon metabolism to measure responses to nutritional stress.

Keywords: adipose tissue; insulin; lipid metabolism; metabolite; microenvironment

DOI: https://doi.org/10.1016/j.tem.2021.02.008