Metabolic and Tissue-Specific Regulation of Acyl-CoA Metabolism

Ellis, Jessica M.; Bowman, Caitlyn E.; Wolfgang, Michael J.

doi:10.1371/journal.pone.0116587

Cited by 96 publications

(110 citation statements)

References 60 publications

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“…S8C) in TNBC. Considering that ACSL products, acyl-CoAs, are competed for by enzymes involved in LD storage, incorporation into lipid membranes, posttranslational modifications, and FAO (25,76), our data that ACSL activity inhibits FAO are consistent with a choice to direct acyl-CoAs toward storage in LDs. Accordingly, when ACSL activity is blocked, acyl-CoAs become limited and may preferentially enter FAO, and when ACSL activity is induced, acylCoAs become abundant and may preferentially enter LDs for storage.…”

Section: Low-lipid Content Favors Promigratory Phenotype Of Breast Casupporting

confidence: 65%

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Wright

Hou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

143

102

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Triple-negative breast cancer (TNBC) is notoriously aggressive with high metastatic potential, which has recently been linked to high rates of fatty acid oxidation (FAO). Here we report the mechanism of lipid metabolism dysregulation in TNBC through the prometastatic protein, CUB-domain containing protein 1 (CDCP1). We show that a "low-lipid" phenotype is characteristic of breast cancer cells compared with normal breast epithelial cells and negatively correlates with invasiveness in 3D culture. Using coherent anti-Stokes Raman scattering and two-photon excited fluorescence microscopy, we show that CDCP1 depletes lipids from cytoplasmic lipid droplets (LDs) through reduced acyl-CoA production and increased lipid utilization in the mitochondria through FAO, fueling oxidative phosphorylation. These findings are supported by CDCP1's interaction with and inhibition of acyl CoA-synthetase ligase (ACSL) activity. Importantly, CDCP1 knockdown increases LD abundance and reduces TNBC 2D migration in vitro, which can be partially rescued by the ACSL inhibitor, Triacsin C. Furthermore, CDCP1 knockdown reduced 3D invasion, which can be rescued by ACSL3 co-knockdown. In vivo, inhibiting CDCP1 activity with an engineered blocking fragment (extracellular portion of cleaved CDCP1) lead to increased LD abundance in primary tumors, decreased metastasis, and increased ACSL activity in two animal models of TNBC. Finally, TNBC lung metastases have lower LD abundance than their corresponding primary tumors, indicating that LD abundance in primary tumor might serve as a prognostic marker for metastatic potential. Our studies have important implications for the development of TNBC therapeutics to specifically block CDCP1-driven FAO and oxidative phosphorylation, which contribute to TNBC migration and metastasis.he transmembrane glycoprotein, CUB-domain containing protein 1 (CDCP1), is a driver of migration and invasion in multiple forms of carcinoma, including renal (1, 2), ovarian (3, 4), prostate (5), pancreatic (6, 7), colon (8-12), and triple-negative breast (TNBC) (13, 14) carcinomas, among others. Furthermore, CDCP1's role in tumor metastasis was confirmed in vivo in lung (15, 16), ovarian (17), prostate (5), and colon (9) cancers. Although CDCP1's role in TNBC metastasis has not been established to date, high CDCP1 expression has been validated as a prognostic marker of poor survival in TNBC when combined with positive node status (18).Our understanding of CDCP1's upstream regulators, its mechanism of activation, and downstream signaling continues to expand (recently reviewed in ref. 19). Studies by others (5) and our group (14) have demonstrated that CDCP1 cleavage is necessary for its activation, and recently, we have further shown that cleavage stimulates CDCP1 homodimerization (14). Homodimeric CDCP1 stimulates phosphorylation of protein kinase C δ (PKCδ) by Src kinase, leading to migration and invasion of TNBC cells in vitro (14). Adding to our knowledge of CDCP1's downstream signaling, we report that CDCP1 regulates lipid m...

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Section: Low-lipid Content Favors Promigratory Phenotype Of Breast Casupporting

confidence: 65%

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Wright

Hou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

143

102

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“…Fed mice were food deprived from 1 p.m.-3 p.m. to ensure consistent feeding patterns. For fasting studies, mice were deprived of food for 24 hours from 3p.m.-3 p.m. For the ketogenic diet studies, mice were placed on a ketogenic diet at 9 weeks of age (47). Serum was collected for all mice to measure free glycerol and TAG (Sigma), β-hydroxybutyrate (StanBio), total cholesterol, NEFA (Wako), and ALT (Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…All blood samples are reported as nmol/ml; tissue samples as pmol/mg. Liver fatty acid oxidation, TAG measurement and liver peroxidation was done as previously described (47, 48). …”

Section: Methodsmentioning

confidence: 99%

Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation

et al. 2016

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The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific knockout of carnitine palmitoyltransferase 2 (Cpt2L−/−), an obligate step in mitochondrial long-chain fatty acid β-oxidation. Fasting induced hepatic steatosis and serum dyslipidemia with an absence of circulating ketones while blood glucose remained normal. Systemic energy homeostasis was largely maintained in fasting Cpt2L−/− mice by adaptations in hepatic and systemic oxidative gene expression mediated in part by Pparα target genes including procatabolic hepatokines Fgf21, Gdf15 and Igfbp1. Feeding a ketogenic diet to Cpt2L−/− mice resulted in severe hepatomegaly, liver damage and death with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting.

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“…To test for direct metabolic effects, an ACOT7 protein engineered to harbor gain-of-function mutations [28] was overexpressed in liver and adipose tissue [41]. Despite measurable increases in thioesterase activity, overexpression in liver did not alter the flux of fatty acids for oxidation or incorporation into complex lipids.…”

Section: Type II Acotsmentioning

confidence: 99%

Deactivating Fatty Acids: Acyl-CoA Thioesterase-Mediated Control of Lipid Metabolism

Tillander

Alexson

Cohen

2017

Trends in Endocrinology & Metabolism

134

147

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The cellular uptake of free fatty acids (FFA) is followed by esterification to coenzyme A (CoA), generating fatty acyl-CoAs that are substrates for oxidation or incorporation into complex lipids. Acyl-CoA thioesterases constitute a family of enzymes that hydrolyze fatty acyl-CoAs to form FFA and CoA. Although biochemically and biophysically well characterized, the metabolic functions of these enzymes remain incompletely understood. Existing evidence suggests regulatory roles in controlling rates of peroxisomal and mitochondrial fatty acyl-CoA oxidation, as well as in the subcellular trafficking of fatty acids. Emerging data implicate acyl-CoA thioesterases in the pathogenesis of metabolic diseases, suggesting that better understanding their pathobiology could reveal unique targets in the management of obesity, diabetes and non-alcoholic fatty liver disease.

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Metabolic and Tissue-Specific Regulation of Acyl-CoA Metabolism

Cited by 96 publications

References 60 publications

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation

Deactivating Fatty Acids: Acyl-CoA Thioesterase-Mediated Control of Lipid Metabolism

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