ACLY
ATP-citrate synthase (EC 2.3.3.8) (ATP-citrate (pro-S-)-lyase) (ACL) (Citrate cleavage enzyme)
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Caloric restriction mimetics (CRMs) are promising molecules to prevent age-related diseases as they activate pathways driven by a true caloric restriction. Hydroxycitric acid (HCA) is considered a bona fide CRM since it depletes acetyl-CoA pools by acting as a competitive inhibitor of ATP citrate lyase (ACLY), ultimately repressing protein acetylation and promoting autophagy. Importantly, it can reduce inflammation and tumour development. In order to identify phenotypically relevant new HCA targets we have investigated HCA effects in Saccharomyces cerevisiae, where ACLY is lacking. Strikingly, the drug revealed a powerful anti-aging effect, another property proposed to mark bona fide CRMs. Chronological life span (CLS) extension but also resistance to acetic acid of HCA treated cells were associated to repression of cell apoptosis and necrosis. HCA also largely prevented cell deaths caused by a severe oxidative stress. The molecule could act widely by negatively modulating cell metabolism, similarly to citrate. Indeed, it inhibited both growth reactivation and the oxygen consumption rate of yeast cells in stationary phase. Genetic analyses on yeast CLS mutants indicated that part of the HCA effects can be sensed by Sch9 and Ras2, two conserved key regulators of nutritional and stress signal pathways of primary importance. Our data together with published biochemical analyses indicate that HCA may act with multiple mechanisms together with ACLY repression and allowed us to propose an integrated mechanistic model as a basis for future investigations.
Keywords
- Aging
- Apoptosis/necrosis
- Caloric restriction mimetics
- Hydroxycitric acid
- Oxidative stress
- Sch9 and Ras2 pathways
Methionine (Met) is one of the most important amino acids in fish feed. The effects of dietary Met on lipid deposition in fish varied a lot among different studies. The present study was aimed at investigating the effects of dietary Met supplementation on the lipid accumulation in tiger puffer, which have a unique lipid storage pattern. Crystalline L-Met was supplemented to a low-fishmeal control diet to obtain two experimental diets with a low (1.1% of dry weight, L-MET) or high Met level (1.6% of dry weight, H-MET). A 67-day feeding trial was conducted with juvenile tiger puffer (average initial weight, 13.83 g). Each diet was fed to triplicate tanks (30 fish in each tank). The results showed that the total lipid contents in whole-body and liver significantly increased with increasing dietary Met levels. The hepatosomatic index, weight gain, and total bile acid content in serum showed similar patterns in response to dietary Met treatments, while the lipid content in muscle was not affected. The hepatic contents of 18-carbon fatty acids were elevated by dietary Met supplementation. The Hepatic mRNA expression of lipogenetic gene such as FAS, GPAT, PPARγ, ACLY, and SCD1 was down-regulated, while the gene expression of lipolytic genes ACOX1 and HSL, as well as that of ApoB100, were up-regulated by increasing dietary Met levels. The hepatic lipidomics of experimental fish was also analyzed. In conclusion, increasing dietary Met levels (0.61%, 1.10%, and 1.60%) increased the hepatic lipid accumulation in tiger puffer. The mechanisms involved warrant further studies.
MeSH Terms
- Aging
- Animals
- Diet
- Dietary Supplements
- Fatty Acids
- Lipid Metabolism
- Liver
- Methionine
- Takifugu
Keywords
- Diet
- Lipid
- Methionine
- Takifugu rubripes
A recent prospective epidemiological study suggested that an increase in the nutritional uptake of the natural polyamine spermidine is associated with reduced overall and cancer-specific mortality. Here, we speculate through which mechanisms spermidine might exert such oncopreventive effects. ACLY, ATP citrate lyase; ATG, autophagy-related gene; CoA, coenzyme A; NSCLC, non-small cell lung cancer.
MeSH Terms
- Animals
- Antineoplastic Agents
- Humans
- Mice
- Neoplasms
- Spermidine
Keywords
- Aspirin
- Autophagy
- aging
- immunosurveillance
- inflammation
ATP citrate lyase (ACLY) is a key enzyme that is involved in de novo lipogenesis by catalyzing conversion of cytosolic citrate into acetyl CoA and oxaloacetate. Up-regulation of ACLY in various types of tumors enhances fatty acid synthesis and supplies excess acetyl CoA for histone acetylation. However, there is evidence that its enzymatic activity alone is insufficient to explain ACLY silencing-mediated growth arrest in tumor cells. In this study, we found that ACLY knockdown in primary human cells triggers cellular senescence and activation of tumor suppressor p53. Provision of acetyl CoA to ACLY knockdown cells did not alleviate ACLY silencing-induced p53 activation, suggesting an independent role for ACLY activity. Instead, ACLY physically interacted with the catalytic subunit of AMP-activated protein kinase (AMPK) and inhibited AMPK activity. The activation of AMPK under ACLY knockdown conditions may lead to p53 activation, ultimately leading to cellular senescence. In cancer cells, ACLY silencing-induced p53 activation facilitated DNA damage-induced cell death. Taken together, our results suggest a novel function of ACLY in cellular senescence and tumorigenesis.
MeSH Terms
- AMP-Activated Protein Kinases
- ATP Citrate (pro-S)-Lyase
- Acetyl Coenzyme A
- Animals
- Carcinogenesis
- Cellular Senescence
- Cytosol
- Gene Expression Regulation, Enzymologic
- Gene Knockdown Techniques
- HEK293 Cells
- Humans
- Neoplasms
- Rats
- Signal Transduction
- Tumor Suppressor Protein p53
Keywords
- AMP-activated protein kinase (AMPK)
- ATP-citrate lyase (ACLY)
- p53
- senescence
- tumor