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    • br ACL Regulation and Role in Lipid Metabolism ACL is

    2023-12-12


    ACL Regulation and Role in Lipid Metabolism ACL is a ubiquitous enzyme at the nexus of nutrient catabolism and synthesis of cholesterol and fatty acids. In mammals, it is highly expressed in lipogenic tissues including adipose, liver, and lactating mammary glands [9]. In the presence of ATP and CoA, ACL catalyzes the cleavage of citrate to acetyl-CoA and oxaloacetate (see Figure I in Box 1). Fatty acids and cholesterol are the two fundamental building blocks supporting the synthesis of more complex lipids that serve several functions in cell physiology, including structural components of cellular membranes, energy transport and storage, bioactive signaling molecules, and substrates for post-translational modification of signaling proteins (Figure 1). The biosynthesis of lipids starts in the mitochondria where acetyl-CoA units derived from the metabolism of non-lipid nutrients are condensed with oxaloacetate (via the tricarboxylic fostamatinib cycle) to form citrate, and exported to the cytosol by the citrate transport protein. The subsequent cleavage of citrate back to acetyl-CoA by ACL in the cytosol is a requisite step for the de novo synthesis of cholesterol and fatty acids (Figure 1). Mevalonate, the product of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) within the cholesterol biosynthetic pathway, is also a building block for the synthesis of several important biological intermediates and products including isoprenoids, CoQ10, and dolichol, (reviewed in 10, 11; Figure 1). When nutrient availability exceeds biosynthetic and energy requirements, cells utilize this pathway for energy storage by esterifying lipids into cholesteryl esters and triglycerides [12]. Under certain conditions, such as those associated with metabolic reprogramming in mouse and human tumors 13, 14, 15, 16, 17 or in human liver following excessive alcohol consumption [18], ACL can be bypassed by direct activation of cytosolic acetate to acetyl-CoA by acetyl-CoA synthetase 2 (ACSS2). However, this pathway does not appear to completely compensate for the absence of ACL [19], nor to be quantitatively important for de novo synthesis of lipids in humans under normal physiological conditions 18, 20. While the pathways of de novo cholesterol and fatty acid biosynthesis are both dependent on the supply of cytosolic acetyl-CoA from ACL, they are largely subject to distinct regulatory mechanisms. Moreover, transcriptional regulation of the fatty acid synthesis pathways differs between white adipose and liver tissues [21]. In liver, ACL is coregulated along with all members of the lipogenic enzyme set, including enzymes required to generate NADPH-reducing equivalents [22]. The entire lipogenic enzyme set is essentially controlled by three transcriptions factors: sterol regulatory element binding protein 1c (SREBP-1c), carbohydrate-response element binding protein (ChREBP) 23, 24, and liver X receptors (LXRs) 25, 26. Although the expression of both SREBP-1c and ChREBP can be induced by LXR 24, 26 in rodent liver, the induction of gene expression is primarily mediated by SREBP-1c in response to elevated glucose and insulin (i.e., the fed state) [22] (Figure 1). By contrast, the cholesterol biosynthesis pathway is controlled by sterol-response element binding protein-2 (SREBP-2) and is activated in response to low intracellular cholesterol levels as observed with reduced dietary supply (reviewed in [27]; Figure 1). In addition to the transcriptional regulation of ACL, in vitro studies using purified enzyme and rat adipocytes have indicated that covalent activation of the enzyme can occur through phosphorylation at Ser454 by cAMP-dependent protein kinase and protein kinase B/Akt 28, 29, 30, 31, which desensitizes the enzyme to allosteric modulation in vitro[31]. However, in vivo evidence supporting the physiological relevance of Ser454 on lipid synthesis has not been established. In addition to ACL phosphorylation at Ser454, phosphorylation at Thr446 and Ser450 by glycogen synthase kinase 3 can also occur; however, this does not appear to affect enzyme activity [29]. Of note, ACL phosphorylation has been shown to play a role in modulating nuclear acetylation in cancer cells, macrophages, and T cells, resulting in the modulation of several cellular processes ranging from inflammation to DNA repair 32, 33, 34, 35. This raises the possibility that hormones signaling nutritional status, such as insulin, might affect these pathways in multiple cells types. Additional investigation seems warranted.