77 9 Loss of virulence in ACL mutants may

Loss of virulence in ACL mutants may be caused by defect in vegetative growth and conidial germination, and reduced trichothecene production. However, supplement of potassium acetate restored the defects in germination rate and vegetative growth, but not virulence in wheat heads (Table 2, Fig. 2B), suggesting that other factors also are involved in the loss of virulence of the 77 9 mutants. Nevertheless, reduced trichothecene production in the mutants may partially account for the loss of virulence (Proctor et al., 1995). In conclusion, we show that both sub-units of ACL are required for both fungal development and virulence in G. zeae. We have demonstrated that the defects in the ACL deletion mutants were caused by the reduction of histone acetylation rather than the level of lipid biosynthesis. To our knowledge, this study is the first report to link the biological functions of ACL in ascomycete fungi to the level of histone acetylation. Future work will be focused on the characterization of other enzymes that are potentially involved in the production of cytosolic acetyl-CoA, as well as the elucidation of the networks involved, in order to understand the mechanisms that link metabolism and gene regulation in filamentous fungi.
Acknowledgments
Alterations of lipoprotein metabolism are highly prevalent risk factors for cardiovascular disease, and their appropriate treatment has the potential to generate a major public health impact. There is now abundant evidence to support the concept that among the different lipoprotein fractions, tight control of plasma low-density lipoprotein (LDL) cholesterol (LDL-C) has the most impact on hard outcomes in both primary and secondary cardiovascular (CV) prevention., Statins, a family of medications that work as inhibitors of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase (the rate-limiting enzyme in the cholesterol biosynthesis pathway), are currently the mainstay of hypercholesterolemia treatment, and their use has consistently shown to reduce CV morbidity and mortality., , Despite the overall safety and efficacy of these medications, statin intolerance remains a major clinical issue. The most important unwanted effects of statins can be grouped into 3 categories: (1) overt myopathy and/or myalgia, even without significant elevations of plasma creatine phosphokinase, ; (2) asymptomatic increases in liver transaminases, ; and (3) an increase in the risk of developing type 2 diabetes mellitus, or a slight impairment in glycated hemoglobin A1c among patients already diagnosed with type 2 diabetes mellitus., Although these adverse effects are only seldom severe or life threatening, they do compromise patient adherence or treatment continuation and therefore the expected CV benefit of therapy. Furthermore, despite the wide availability and clinical use of statins, the percentage of patients who reach LDL-C goals remains worryingly low., This may be related to the dose-dependent nature of statin-related adverse effects, which prevents strict dose escalation when necessary. To overcome the limitations inherent to statin intolerance, and to provide patients with the full benefit that can be derived from LDL-C reduction, new families of cholesterol-lowering medications are being developed, exploiting molecular targets different from HMG-CoA reductase. One such pharmacologic family is proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, but concerns still remain about subcutaneous administration, cost, and the potential for neurocognitive side effects. Recently, an entirely new approach to cholesterol lowering has been developed. Adenosine triphosphate citrate lyase and its role in lipid synthesis Adenosine triphosphate (ATP) citrate lyase (ACL) is a cytosolic enzyme most highly expressed in lipogenic tissues such as liver and white adipose tissue. ACL catalyzes a reaction in which 2 carbons from citrate are transferred to CoA, with consumption of 1 ATP molecule and generation of acetyl CoA and oxaloacetate. ACL is thus a major contributor to the cytosolic pool of acetyl CoA, the fundamental building block for the biosynthesis of both fatty acids and cholesterol. X-ray diffraction analyses of ACL have revealed that it is conformed by 4 polypeptide chains of similar size. Recent studies have identified the binding site of both citrate and ATP to ACL, as well as two thirds of the enzyme's complete 3-dimensional structure. The ACL gene is under transcriptional regulation by sterol regulatory element binding protein 1 (SREBP-1). The mature protein seems to be stabilized by posttranslational phosphorylation of specific serine and threonine residues, although the relevance of these modifications has not been tested in vivo.