Adenosine triphosphate citrate lyase: Emerging target in the treatment of dyslipidemia

Lemus, Hernan Nicolás; Mendivil, Carlos O.

doi:10.1016/j.jacl.2015.01.002

Cited by 35 publications

(24 citation statements)

References 31 publications

(34 reference statements)

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“…The precursor of cholesterol is acetyl CoA which is mainly generated from fatty acid oxidation and pyruvate decarboxylation processes both of which occur in the mitochondria. Since acetyl CoA cannot enter the cytosol, an intermediate compound of the tricarboxylic acid (TCA) cycle, “citrate” exits the mitochondria to enter the cytosol where it reacts with Co-A to form acetyl-CoA and oxaloacetate by citrate lyase 47 . Furthermore, electron transport chain (ETC) and the TCA cycle are tightly regulated 48 .…”

Section: Discussionmentioning

confidence: 99%

Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer

Devarajan

Grijalva

et al. 2018

Cell Death Dis

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Ovarian cancer (OC) is most lethal malignancy among all gynecological cancer. Large bodies of evidences suggest that mitochondrial-derived ROS play a critical role in the development and progression of OC. Paraoxonase 2 (PON2) is a membrane-associated lactonase with anti-oxidant properties. PON2 deficiency aggravates mitochondrial ROS formation, systemic inflammation, and atherosclerosis. The role of PON2 in cancer development remains unknown. In this report, in human, we identified that PON2 expression is higher in early stages (but not in late stages) of OC when compared to normal tissue. Using a mouse xenograft model of OC, we demonstrate that overexpression of PON2 prevents tumor formation. Mechanistically, PON2 decreases OC cell proliferation by inhibiting insulin like growth factor-1 (IGF-1) expression and signaling. Intriguingly, PON2 reduces c-Jun-mediated transcriptional activation of IGF-1 gene by decreasing mitochondrial superoxide generation. In addition, PON2 impairs insulin like growth factor-1 receptor (IGF-1R) signaling in OC cells by altering cholesterol homeostasis, which resulted in reduced caveolin-1/IGF-1R interaction and IGF-1R phosphorylation. Taken together, we report for the first time that PON2 acts as a tumor suppressor in the early stage of OC by reducing IGF-1 production and its signaling, indicating PON2 activation might be a fruitful strategy to inhibit early stage ovarian tumor.

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Section: Discussionmentioning

confidence: 99%

Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer

Devarajan

Grijalva

et al. 2018

Cell Death Dis

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“…34 Considering its role in generating acetyl-CoA, which is the main substrate for lipogenesis and cholesterol synthesis, targeting ACLY has proven to be an effective therapy for treating hypercholesterolaemia and hyperlipidaemia. 206 Importantly, several ACLY inhibitors including ETC-1002 (Phase 2/3 clinical trials) and hydroxycitrate (randomised control trials) have shown high efficacy in lowering low-density lipoprotein-cholesterol and good tolerability in patients with cardiovascular disease and type 2 diabetes (Table 1), thus indicating that ACLY inhibition could represent a well-tolerated therapeutic strategy. [207][208][209][210][211] There is considerable interest in ACLY as a target for anticancer drugs; however, clinical trial studies in this context are far more limited when compared with dyslipidaemia cases.…”

Section: Therapeutically Exploiting Fatty Acid Metabolism In Cancermentioning

confidence: 99%

Reprogramming of fatty acid metabolism in cancer

2019

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A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K-AKT-mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.

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“…Bempedoic acid (ETC-1002) is a once-daily, orally administered prodrug that inhibits adenosine triphosphate citrate lyase (ACL), a key enzyme upstream of HMGCR involved in the synthesis of fatty acids and cholesterol [ 54 , 55 ]. It also activates 5′-adenosine monophosphate-activated protein kinase (AMPK), reducing the activity of acetyl-CoA carboxylase (ACC) and HMGCR, the rate-limiting enzymes of fatty acid and cholesterol synthesis, respectively [ 55 ].…”

Section: Nonstatin Lipid-lowering Therapiesmentioning

confidence: 99%

Management of Dyslipidemia in Type 2 Diabetes: Recent Advances in Nonstatin Treatment

Sugiyama

Saisho

2018

Diseases

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Dyslipidemia is a major risk factor for cardiovascular disease (CVD), which is the leading cause of morbidity and mortality in type 2 diabetes (T2DM). Statins have played a crucial role in its management, but residual risk remains since many patients cannot achieve their desired low-density lipoprotein cholesterol (LDL-C) level and up to 20% of patients are statin-intolerant, experiencing adverse events perceived to be caused by statins, most commonly muscle symptoms. Recently, great advances have been made in nonstatin treatment with ezetimibe, a cholesterol absorption inhibitor, and proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs), all showing a proven benefit with an excellent safety profile in cardiovascular outcome trials. This review summarizes the key aspects and the evolving role of these agents in the management of dyslipidemia in patients with T2DM, along with a brief introduction of novel drugs currently in development.

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Adenosine triphosphate citrate lyase: Emerging target in the treatment of dyslipidemia

Cited by 35 publications

References 31 publications

Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer

Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer

Reprogramming of fatty acid metabolism in cancer

Management of Dyslipidemia in Type 2 Diabetes: Recent Advances in Nonstatin Treatment

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