ATP-citrate lyase: genetics, molecular biology and therapeutic target for dyslipidemia

Burke, Amy C.; Huff, Murray W.

doi:10.1097/mol.0000000000000390

Cited by 79 publications

(32 citation statements)

References 55 publications

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Section: Parental Genetic Insulin Resistance Impacts Body Weight Trajmentioning

confidence: 99%

“…ATP-citrate lyase (ACLY) is a cytosolic enzyme responsible for the production of acetyl-CoA -a substrate for de novo cholesterol and fatty acid synthesis (32)(33)(34)(35). ACLY is regulated by AKT signaling and has been a focus of recent clinical trials to treat hypercholesterolemia and NAFLD (33,35). On the other hand, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme for cholesterol synthesis and a target of statins (36), is increased in NAFLD and correlates with the histological severity of the disease (37).…”

Section: Parental Genetic Insulin Resistance Impacts Body Weight Trajmentioning

confidence: 99%

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Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice

Jesus

Orime

Kaminska

et al. 2020

Journal of Clinical Investigation

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Section: Parental Genetic Insulin Resistance Impacts Body Weight Trajmentioning

confidence: 99%

Section: Parental Genetic Insulin Resistance Impacts Body Weight Trajmentioning

confidence: 99%

Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice

Jesus

Orime

Kaminska

et al. 2020

Journal of Clinical Investigation

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“…Interestingly, genes associated with the fatty acid beta oxidation pathway are significantly upregulated in LAM. For example, expression of ACLY, a key enzyme in the shift from the TCA cycle to lipid formation that has been shown to cause lipid droplet accumulation 69 , is significantly higher in LAM than in microglia without lipid droplets. Similarly, RNA-Seq analysis of lipid droplet-rich microglia in LPS-treated young mice and in GRN -/mice revealed significant enrichment of pathways related to metabolism, including TCA cycle and fatty acid beta oxidation.…”

Section: What Causes Lipid Droplet Formation In Lam?mentioning

confidence: 99%

Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain

Marschallinger

Iram

Zardeneta

et al. 2019

Preprint

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Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call lipid droplet-accumulating microglia (LAM), are defective in phagocytosis, produce high levels of reactive oxygen species, and secrete proinflammatory cytokines. RNA sequencing analysis of LAM revealed a transcriptional profile driven by innate inflammation distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin, are causes of autosomal dominant forms of human neurodegenerative diseases. We thus propose that LAM contribute to agerelated and genetic forms of neurodegeneration.

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“…Therefore, there exists a clear need for a better understanding of the catalytic and allosteric biochemistry of the enzyme. Although a great deal of effort has gone into understanding the signaling cascades and post-translational modifications that tune ACLY function in the cell (36), limited knowledge about the molecular basis for ACLY function has held back the development of ACLY therapeutic treatments.…”

Section: Role Of Atp-citrate Lyase Multimerization In Catalysismentioning

confidence: 99%

ATP-citrate lyase multimerization is required for coenzyme-A substrate binding and catalysis

Bazilevsky¹,

Affronti

Wei

et al. 2019

Journal of Biological Chemistry

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Edited by Joel M. Gottesfeld ATP-citrate lyase (ACLY) is a major source of nucleocytosolic acetyl-CoA, a fundamental building block of carbon metabolism in eukaryotes. ACLY is aberrantly regulated in many cancers, cardiovascular disease, and metabolic disorders. However, the molecular mechanisms determining ACLY activity and function are unclear. To this end, we investigated the role of the uncharacterized ACLY C-terminal citrate synthase homology domain in the mechanism of acetyl-CoA formation. Using recombinant, purified ACLY and a suite of biochemical and biophysical approaches, including analytical ultracentrifugation, dynamic light scattering, and thermal stability assays, we demonstrated that the C terminus maintains ACLY tetramerization, a conserved and essential quaternary structure in vitro and likely also in vivo. Furthermore, we show that the C terminus, only in the context of the full-length enzyme, is necessary for full ACLY binding to CoA. Together, we demonstrate that ACLY forms a homotetramer through the C terminus to facilitate CoA binding and acetyl-CoA production. Our findings highlight a novel and unique role of the C-terminal citrate synthase homology domain in ACLY function and catalysis, adding to the understanding of the molecular basis for acetyl-CoA synthesis by ACLY. This newly discovered means of ACLY regulation has implications for the development of novel ACLY modulators to target acetyl-CoA-dependent cellular processes for potential therapeutic use.All three domains of life utilize acetyl-CoA as an essential metabolite for carbon transport. Acetyl-CoA is necessary for glycolysis, de novo lipogenesis, cholesterol synthesis, and protein acetylation (1). The dysregulation of this metabolite is an omnipresent feature and crucial component of diabetes, hypercholesterolemia, and oncogenesis (2). Among the majority of 2 The abbreviations used are: ACLY, ATP-citrate lyase; CS, citrate synthase; CSHD, citrate synthase homology domain; DSC, differential scanning calo-

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ATP-citrate lyase: genetics, molecular biology and therapeutic target for dyslipidemia

Cited by 79 publications

References 55 publications

Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice

Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice

Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain

ATP-citrate lyase multimerization is required for coenzyme-A substrate binding and catalysis

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