bims-medhac Biomed News
on Metabolism dependent histone acetylation
Issue of 2020‒06‒07
eleven papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Biochim Biophys Acta Proteins Proteom. 2020 May 30. pii: S1570-9639(20)30109-6. [Epub ahead of print] 140462
    Huergo LF, Araújo GAT, Santos ASR, Gerhardt ECM, Pedrosa FO, Souza EM, Forchhammer K.
      Malic enzymes participate in key metabolic processes, the MaeB-like malic enzymes carry a catalytic inactive phosphotransacetylase domain whose function remains elusive. Here we show that acetyl-CoA directly binds and inhibits MaeB-like enzymes with a saturable profile under physiological relevant acetyl-CoA concentrations. A MaeB-like enzyme from the nitrogen-fixing bacterium Azospirillum brasilense, namely AbMaeB1, binds both acetyl-CoA and unesterified CoASH in a way that inhibition of AbMaeB1 by acetyl-CoA is relieved by increasing CoASH concentrations. Hence, AbMaeB1 senses the acetyl-CoA/CoASH ratio. We revisited E. coli MaeB regulation to determine the inhibitory constant for acetyl-CoA. Our data support that the phosphotransacetylase domain of MaeB-like enzymes senses acetyl-CoA to dictate the fate of carbon distribution at the phosphoenol-pyruvate / pyruvate / oxaloacetate metabolic node.
    Keywords:  Acetyl-CoA; CoASH; Malic enzyme; Metabolic regulation; Phosphotransacetylase; TCA cycle
  2. Mol Pharmacol. 2020 Jun 02. pii: mol.119.119008. [Epub ahead of print]
    Butcher NJ, Burow R, Minchin RF.
      Arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic-metabolizing enzyme that also has a role in cancer cell growth and metabolism. Recently, it was reported that NAT1 undergoes lysine acetylation, an important post-translational modification that can regulate protein function. In the current study, we use site-directed mutagenesis to identify K100 and K188 as major sites of lysine acetylation in the NAT1 protein. Acetylation of ectopically expressed NAT1 in HeLa cells was decreased by C646, an inhibitor of the protein acetyltransferases p300/CBP. Recombinant p300 directly acetylated NAT1 in vitro. Acetylation of NAT1 was enhanced by the sirtuin inhibitor nicotinamide but not by the histone deacetylase inhibitor trichostatin A. Co-transfection of cells with NAT1 and either SIRT 1 or 2, but not SIRT3, significantly decreased NAT1 acetylation. NAT1 activity was evaluated in cells following nicotinamide treatment to enhance acetylation or co-transfection with SIRT1 to inhibit acetylation. The results indicated that NAT1 acetylation altered its enzyme kinetics, suggesting changes in acetyl coenzyme A binding. In addition, acetylation attenuated the allosteric effects of ATP on NAT1. Taken together, this study shows that NAT1 is acetylated by p300/CBP in situ and is deacetylated by the sirtuins SIRT1 and 2. It is hypothesized that post-translational modification of NAT1 by acetylation at K100 and K188 may modulate NAT1 effects in cells. SIGNIFICANCE STATEMENT: There is growing evidence that arylamine N-acetyltransferase 1 has an important cellular role, in addition to xenobiotic metabolism. Here, we show that NAT1 is acetylated at K100 and K188 and changes in protein acetylation equilibrium can modulate its activity in cells.
    Keywords:  Acetylation; N-acetyltransferases; Phase II drug metabolism
  3. Mol Cell. 2020 May 20. pii: S1097-2765(20)30308-7. [Epub ahead of print]
    He A, Chen X, Tan M, Chen Y, Lu D, Zhang X, Dean JM, Razani B, Lodhi IJ.
      Autophagy is activated by prolonged fasting but cannot overcome the ensuing hepatic lipid overload, resulting in fatty liver. Here, we describe a peroxisome-lysosome metabolic link that restricts autophagic degradation of lipids. Acyl-CoA oxidase 1 (Acox1), the enzyme that catalyzes the first step in peroxisomal β-oxidation, is enriched in liver and further increases with fasting or high-fat diet (HFD). Liver-specific Acox1 knockout (Acox1-LKO) protected mice against hepatic steatosis caused by starvation or HFD due to induction of autophagic degradation of lipid droplets. Hepatic Acox1 deficiency markedly lowered total cytosolic acetyl-CoA levels, which led to decreased Raptor acetylation and reduced lysosomal localization of mTOR, resulting in impaired activation of mTORC1, a central regulator of autophagy. Dichloroacetic acid treatment elevated acetyl-CoA levels, restored mTORC1 activation, inhibited autophagy, and increased hepatic triglycerides in Acox1-LKO mice. These results identify peroxisome-derived acetyl-CoA as a key metabolic regulator of autophagy that controls hepatic lipid homeostasis.
    Keywords:  Acox1; Autophagy; Lipid metabolism; NAFLD; Raptor; fatty acid oxidation; lipophagy; mTOR; peroxisomes
  4. Cell Rep. 2020 Jun 02. pii: S2211-1247(20)30671-9. [Epub ahead of print]31(9): 107701
    Becker LM, O'Connell JT, Vo AP, Cain MP, Tampe D, Bizarro L, Sugimoto H, McGow AK, Asara JM, Lovisa S, McAndrews KM, Zielinski R, Lorenzi PL, Zeisberg M, Raza S, LeBleu VS, Kalluri R.
      The mechanistic contributions of cancer-associated fibroblasts (CAFs) in breast cancer progression remain to be fully understood. While altered glucose metabolism in CAFs could fuel cancer cells, how such metabolic reprogramming emerges and is sustained needs further investigation. Studying fibroblasts isolated from patients with benign breast tissues and breast cancer, in conjunction with multiple animal models, we demonstrate that CAFs exhibit a metabolic shift toward lactate and pyruvate production and fuel biosynthetic pathways of cancer cells. The depletion or suppression of the lactate production of CAFs alter the tumor metabolic profile and impede tumor growth. The glycolytic phenotype of the CAFs is in part sustained through epigenetic reprogramming of HIF-1α and glycolytic enzymes. Hypoxia induces epigenetic reprogramming of normal fibroblasts, resulting in a pro-glycolytic, CAF-like transcriptome. Our findings suggest that the glucose metabolism of CAFs evolves during tumor progression, and their breast cancer-promoting phenotype is partly mediated by oxygen-dependent epigenetic modifications.
    Keywords:  breast cancer; cancer-associated fibroblasts; epigenetic alterations; hypoxia; metabolism
  5. J Biol Chem. 2020 Jun 03. pii: jbc.RA120.013583. [Epub ahead of print]
    Chen X, Shang L, Deng S, Li P, Chen K, Gao T, Zhang X, Chen Z, Zeng J.
      Feeding of rapeseed (canola) oil with a high erucic acid concentration is known to cause hepatic steatosis in animals. Mitochondrial fatty acid oxidation plays a central role in liver lipid homeostasis, so it is possible that hepatic metabolism of erucic acid might decrease mitochondrial fatty acid oxidation. However, the precise mechanistic relationship between erucic acid levels and mitochondrial fatty acid oxidation is unclear. Using male Sprague-Dawley rats, along with biochemical and molecular biology approaches, we report here that peroxisomal β-oxidation of erucic acid stimulates malonyl-CoA formation in the liver and thereby suppresses mitochondrial fatty acid oxidation. Excessive hepatic uptake and peroxisomal β-oxidation of erucic acid resulted in appreciable peroxisomal release of free acetate, which was then used in the synthesis of cytosolic acetyl-CoA. Peroxisomal metabolism of erucic acid also remarkably increased the cytosolic NADH:NAD+ ratio, suppressed sirtuin 1 (SIRT1) activity, and thereby activated acetyl-CoA carboxylase, which stimulated malonyl-CoA biosynthesis from acetyl-CoA. Chronic feeding of a diet including high-erucic-acid rapeseed oil diminished mitochondrial fatty acid oxidation and caused hepatic steatosis and insulin resistance in the rats. Of note, administration of a specific peroxisomal β-oxidation inhibitor attenuated these effects. Our findings establish a cross-talk between peroxisomal and mitochondrial fatty acid oxidation. They suggest that peroxisomal oxidation of long-chain fatty acids suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation, which might play a role in fatty acid-induced hepatic steatosis and related metabolic disorders.
    Keywords:  fatty acid oxidation; insulin resistance; mitochondrial metabolism; peroxisome; peroxisome proliferator-activated receptor (PPAR)
  6. Hepatology. 2020 Jun 04.
    Steensels S, Qiao J, Zhang Y, Maner-Smith KM, Kika N, Holman CD, Corey KE, Bracken WC, Ortlund EA, Ersoy BA.
      Obesity-induced pathogenesis of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is associated with increased de novo lipogenesis (DNL) and hepatic glucose production (HGP) due to excess fatty acids. Acyl-CoA thioesterase (Acot) family members control the cellular utilization of fatty acids by hydrolyzing (deactivating) acyl-CoA into non-esterified fatty acids and CoASH. Using C. elegans, we identified Acot9 as the strongest regulator of lipid accumulation within Acot family. Indicative of a maladaptive function, hepatic Acot9 expression was higher in obese patients with NAFLD and NASH compared to healthy obese controls. In the setting of excessive nutrition, global ablation of Acot9 protected mice against increases in weight gain, HGP, steatosis and steatohepatitis. Supportive of a hepatic function, the liver-specific deletion of Acot9 inhibited HGP and steatosis in mice without affecting diet-induced weight gain. By contrast, the rescue of Acot9 expression only in the livers of Acot9 knockout mice was sufficient to promote HGP and steatosis. Mechanistically, hepatic Acot9 localized to the inner mitochondrial membrane where it deactivated short-chain but not long-chain fatty acyl-CoA. This unique localization and activity of Acot9 directed acetyl-CoA away from protein lysine acetylation and towards the citric acid (TCA) cycle. Acot9-mediated exacerbation of triglyceride and glucose biosynthesis was attributable at least in part to increased TCA cycle activity, which provided substrates for HGP and DNL. β-oxidation and ketone body production, which depend on long-chain fatty acyl-CoA were not regulated by Acot9. Taken together, our findings indicate that Acot9 channels hepatic acyl-CoAs towards increased HGP and DNL under the pathophysiology of obesity. Therefore, Acot9 represents a novel target for the management of NAFLD.
    Keywords:  Thioesterase; citric acid cycle; non-alcoholic fatty liver disease
  7. Int J Mol Sci. 2020 Jun 03. pii: E4006. [Epub ahead of print]21(11):
    Evans LW, Athukorala M, Martinez-Guryn K, Ferguson BS.
      Cardiovascular diseases (CVD) are the main cause of death worldwide and create a substantial financial burden. Emerging studies have begun to focus on epigenetic targets and re-establishing healthy gut microbes as therapeutic options for the treatment and prevention of CVD. Phytochemicals, commonly found in fruits and vegetables, have been shown to exert a protective effect against CVD, though their mechanisms of action remain incompletely understood. Of interest, phytochemicals such as curcumin, resveratrol and epigallocatechin gallate (EGCG) have been shown to regulate both histone acetylation and microbiome re-composition. The purpose of this review is to highlight the microbiome-epigenome axis as a therapeutic target for food bioactives in the prevention and/or treatment of CVD. Specifically, we will discuss studies that highlight how the three phytochemicals above alter histone acetylation leading to global changes in gene expression and CVD protection. Then, we will expand upon these phytochemicals to discuss the impact of phytochemical-microbiome-histone acetylation interaction in CVD.
    Keywords:  Phytochemicals; heart; histone acetylation; histone deacetylase (HDAC), microbiome; microbiota
  8. Int J Mol Sci. 2020 May 31. pii: E3948. [Epub ahead of print]21(11):
    Amal H, Gong G, Yang H, Joughin BA, Wang X, Knutson CG, Kartawy M, Khaliulin I, Wishnok JS, Tannenbaum SR.
      BACKGROUND: Accumulating public health and epidemiological literature support the hypothesis that arsenic in drinking water or food affects the brain adversely.METHODS: Experiments on the consequences of nitric oxide (NO) formation in neuronal cell culture and mouse brain were conducted to probe the mechanistic pathways of nitrosative damage following arsenic exposure.
    RESULTS: After exposure of mouse embryonic neuronal cells to low doses of sodium arsenite (SA), we found that Ca2+ was released leading to the formation of large amounts of NO and apoptosis. Inhibition of NO synthase prevented neuronal apoptosis. Further, SA led to concerted S-nitrosylation of proteins significantly associated with synaptic vesicle recycling and acetyl-CoA homeostasis. Our findings show that low-dose chronic exposure (0.1-1 ppm) to SA in the drinking water of mice led to S-nitrosylation of proteomic cysteines. Subsequent removal of arsenic from the drinking water reversed the biochemical alterations.
    CONCLUSIONS: This work develops a mechanistic understanding of the role of NO in arsenic-mediated toxicity in the brain, incorporating Ca2+ release and S-nitrosylation as important modifiers of neuronal protein function.
    Keywords:  S-nitrosylation; acetyl-CoA; apoptosis; arsenic; brain cortex; brain disorders; mouse; nitric oxide; nitrosative stress; synaptic processes
  9. Cell. 2020 Jun 03. pii: S0092-8674(20)30621-8. [Epub ahead of print]
    Samata M, Alexiadis A, Richard G, Georgiev P, Nuebler J, Kulkarni T, Renschler G, Basilicata MF, Zenk FL, Shvedunova M, Semplicio G, Mirny L, Iovino N, Akhtar A.
      Before zygotic genome activation (ZGA), the quiescent genome undergoes reprogramming to transition into the transcriptionally active state. However, the mechanisms underlying euchromatin establishment during early embryogenesis remain poorly understood. Here, we show that histone H4 lysine 16 acetylation (H4K16ac) is maintained from oocytes to fertilized embryos in Drosophila and mammals. H4K16ac forms large domains that control nucleosome accessibility of promoters prior to ZGA in flies. Maternal depletion of MOF acetyltransferase leading to H4K16ac loss causes aberrant RNA Pol II recruitment, compromises the 3D organization of the active genomic compartments during ZGA, and causes downregulation of post-zygotically expressed genes. Germline depletion of histone deacetylases revealed that other acetyl marks cannot compensate for H4K16ac loss in the oocyte. Moreover, zygotic re-expression of MOF was neither able to restore embryonic viability nor onset of X chromosome dosage compensation. Thus, maternal H4K16ac provides an instructive function to the offspring, priming future gene activation.
    Keywords:  H4K16ac; MOF; X chromosome; ZGA; bookmarking; dosage compensation initiation; epigenetics; memory; nucleosome accessibility; pronuclei apposition; zygotic genome activation
  10. EMBO J. 2020 Jun 03. e103812
    Sánchez-González C, Nuevo-Tapioles C, Herrero Martín JC, Pereira MP, Serrano Sanz S, Ramírez de Molina A, Cuezva JM, Formentini L.
      It is controversial whether mitochondrial dysfunction in skeletal muscle is the cause or consequence of metabolic disorders. Herein, we demonstrate that in vivo inhibition of mitochondrial ATP synthase in muscle alters whole-body lipid homeostasis. Mice with restrained mitochondrial ATP synthase activity presented intrafiber lipid droplets, dysregulation of acyl-glycerides, and higher visceral adipose tissue deposits, poising these animals to insulin resistance. This mitochondrial energy crisis increases lactate production, prevents fatty acid β-oxidation, and forces the catabolism of branched-chain amino acids (BCAA) to provide acetyl-CoA for de novo lipid synthesis. In turn, muscle accumulation of acetyl-CoA leads to acetylation-dependent inhibition of mitochondrial respiratory complex II enhancing oxidative phosphorylation dysfunction which results in augmented ROS production. By screening 702 FDA-approved drugs, we identified edaravone as a potent mitochondrial antioxidant and enhancer. Edaravone administration restored ROS and lipid homeostasis in skeletal muscle and reinstated insulin sensitivity. Our results suggest that muscular mitochondrial perturbations are causative of metabolic disorders and that edaravone is a potential treatment for these diseases.
    Keywords:  ATP synthase; Acetyl-CoA; edaravone; insulin resistance; mitochondria
  11. J Exp Clin Cancer Res. 2020 Jun 05. 39(1): 103
    Di Martile M, Gabellini C, Desideri M, Matraxia M, Farini V, Valentini E, Carradori S, Ercolani C, Buglioni S, Secci D, Andreazzoli M, Del Bufalo D, Trisciuoglio D.
      BACKGROUND: Understanding the signalling pathways involved in angiogenesis, and developing anti-angiogenic drugs are one of the major focuses on cancer research. Herein, we assessed the effect of CPTH6, a lysine acetyltransferase inhibitor and anti-tumoral compound, on angiogenesis-related properties of both endothelial and cancer cells.METHODS: The in vitro effect of CPTH6 on protein acetylation and anti-angiogenic properties on endothelial and lung cancer cells was evaluated via wound healing, trans-well invasion and migration, tube formation, immunoblotting and immunofluorescence. Matrigel plug assay, zebrafish embryo and mouse xenograft models were used to evaluate in vivo anti-angiogenic effect of CPTH6.
    RESULTS: CPTH6 impaired in vitro endothelial angiogenesis-related functions, and decreased the in vivo vascularization both in mice xenografts and zebrafish embryos. Mechanistically, CPTH6 reduced α-tubulin acetylation and induced accumulation of acetylated microtubules in the perinuclear region of endothelial cells. Interestingly, CPTH6 also affected the angiogenesis-related properties of lung cancer cells, and conditioned media derived from CPTH6-treated lung cancer cells impaired endothelial cells morphogenesis. CPTH6 also modulated the VEGF/VEGFR2 pathway, and reshaped cytoskeletal organization of lung cancer cells. Finally, anti-migratory effect of CPTH6, dependent on α-tubulin acetylation, was also demonstrated by genetic approaches in lung cancer cells.
    CONCLUSION: Overall, this study indicates that α-tubulin acetylation could play a role in the anti-angiogenic effect of CPTH6 and, more in general, it adds information to the role of histone acetyltransferases in tumor angiogenesis, and proposes the inhibition of these enzymes as an antiangiogenic therapy of cancer.
    Keywords:  Acetylation; Endothelial cells; Lung cancer cells; Tubulin