Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation

Chow, Jenny D.Y.; Lawrence, Robert; Healy, Marin E.; Dominy, John E.; Liao, Jason A.; Breen, David; Byrne, Frances L.; Kenwood, Brandon M.; Lackner, Carolin; Okutsu, Saeko; Mas, Valeria R.; Caldwell, Stephen H.; Tomsig, Jose L.; Cooney, Gregory J.; Puigserver, Pere; Turner, Nigel; James, David E.; Villén, Judit; Hoehn, Kyle L.

doi:10.1016/j.molmet.2014.02.004

Cited by 93 publications

(86 citation statements)

References 55 publications

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“…However, an increase in the acetylation of proteins in the nucleocytosolic space and hypoacetylation of mitochondrial proteins was observed in these mice (7). Interestingly, many enzymes in glucose metabolism and FA synthesis were altered in livers of double (Acc1/Acc2) KO mice (7). We have observed modifications in acetylation status of several proteins in the nuclear compartment (Fig.…”

Section: Discussionmentioning

confidence: 64%

“…For example, liver-specific double-Acc1 and -Acc2 knockout mice had no effect on the mitochondrial and cytosolic AcCoA levels in the liver. However, an increase in the acetylation of proteins in the nucleocytosolic space and hypoacetylation of mitochondrial proteins was observed in these mice (7). Interestingly, many enzymes in glucose metabolism and FA synthesis were altered in livers of double (Acc1/Acc2) KO mice (7).…”

Section: Discussionmentioning

confidence: 92%

“…Mice with Acc2 deletion demonstrated a significant upregulation of lipogenic enzymes [Acly, Acc1, FAS (Fasn), and Hmgcr] and their upstream transcription factor genes (such as SREBP1, SREBP2, and ChREBP) (1). Interestingly, no significant effect was observed in the expression of other regulatory genes such as SREBP-1c, Pgc-1␣, and Pgc-1␤ in double-KO (deletion of Acc1 and Acc2) mice (7).…”

Section: Discussionmentioning

confidence: 93%

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Lack of mitochondria-generated acetyl-CoA by pyruvate dehydrogenase complex downregulates gene expression in the hepatic de novo lipogenic pathway

Mahmood

Birkaya

Rideout

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 93%

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Lack of mitochondria-generated acetyl-CoA by pyruvate dehydrogenase complex downregulates gene expression in the hepatic de novo lipogenic pathway

Mahmood

Birkaya

Rideout

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…We have previously shown that attenuated expression of yeast ACC increases global acetylation of chromatin histones and alters transcriptional regulation (13). Moreover, chronic inhibition of ACC in mouse hepatocytes increases protein acetylation (14). The human genome encodes two tissue-specific ACC isoforms, ACC␣ (ACCA) and ACC␤ (ACCB) (15).…”

mentioning

confidence: 99%

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Galdieri¹,

Gatla

Vancurova

et al. 2016

Journal of Biological Chemistry

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Edited by Alex TokerAMP-activated protein kinase (AMPK) is an energy sensor and master regulator of metabolism. AMPK functions as a fuel gauge monitoring systemic and cellular energy status. Activation of AMPK occurs when the intracellular AMP/ATP ratio increases and leads to a metabolic switch from anabolism to catabolism. AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), which catalyzes carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in de novo synthesis of fatty acids. AMPK thus regulates homeostasis of acetylCoA, a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Nucleocytosolic concentration of acetyl-CoA affects histone acetylation and links metabolism and chromatin structure. Here we show that activation of AMPK with the widely used antidiabetic drug metformin or with the AMP mimetic 5-aminoimidazole-4-carboxamide ribonucleotide increases the inhibitory phosphorylation of ACC and decreases the conversion of acetyl-CoA to malonyl-CoA, leading to increased protein acetylation and altered gene expression in prostate and ovarian cancer cells. Direct inhibition of ACC with allosteric inhibitor 5-(tetradecyloxy)-2-furoic acid also increases acetylation of histones and non-histone proteins. Because AMPK activation requires liver kinase B1, metformin does not induce protein acetylation in liver kinase B1-deficient cells. Together, our data indicate that AMPK regulates the availability of nucleocytosolic acetyl-CoA for protein acetylation and that AMPK activators, such as metformin, have the capacity to increase protein acetylation and alter patterns of gene expression, further expanding the plethora of metformin's physiological effects.Acetylation is one of the epigenetic post-translational modifications of histones; it affects chromatin structure and regulates diverse cellular functions, such as gene expression, DNA replication and repair, and cellular proliferation (1, 2). Acetylation and deacetylation of chromatin histones, mediated by histone acetyltransferases (HATs) 3 and histone deacetylases (HDACs), respectively, represent the major mechanisms for epigenetic gene regulation. The dynamic balance between histone acetylation and deacetylation, mediated by the activities of HATs and HDACs, is stringently regulated in healthy cells but is often dysregulated in cancer (3, 4).Histone acetylation depends on intermediary metabolism for supplying acetyl-CoA in the nucleocytosolic compartment (5). In mammalian cells, the nucleocytosolic enzyme ATP-citrate lyase is the major source of acetyl-CoA for histone acetylation (6). Another mechanism for generation of acetyl-CoA in the nucleus involves translocation of pyruvate dehydrogenase from mitochondria to the nucleus (7). In yeast, global histone acetylation depends on nucleocytosolic acetyl-CoA produced by acetyl-CoA synthetase (5). In both yeast and mammalian cells, the nucleocytosolic acetyl-CoA is the link among cellular energy, carbon metabolism, histone acetylation, ...

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“…Values were normalized to an internal standard and then to protein concentration. For measurement of cholesterol, total lipids were extracted from the VCCC using an adapted Folch method as previously described 173 . Samples were then assayed for total cholesterol using the fluorometric Amplex Red Cholesterol Assay kit (Thermo Fisher).…”

Section: Measurement Of Glycerolipids Phospholipid Derivatives and Smentioning

confidence: 99%

Signaling Microdomains within the Myoendothelial Junction

Biwer

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Communication between endothelial and smooth muscle cells is critical to maintain homeostatic vascular tone and blood pressure. In resistance arteries, the cells make direct cytoplasmic contact via cellular extensions that project through the thin extracellular matrix of the internal elastic lamina that separates them. These structures are termed myoendothelial junctions (MEJ). There are a number of proteins and signaling processes localized to this part of the arterial wall that regulate bi-directional communication between the endothelium and smooth muscle. In particular, a number of proteins localized to the MEJ mediate calcium signaling and there is localized calcium release from the endoplasmic reticulum via the inositol (1, 4, 5) trisphosphate receptor that can influence vascular tone and negative feedback. There is a detailed description of the creation and isolation of in vitro MEJ using the vascular cell co-culture technique, which has allowed for deeper exploration of signaling molecules and processes occurring at the MEJ. Smooth muscle cells and endothelial cells grow on opposite sides of a filter inset, and the MEJ form within the holes of the filter. This model can be used to immunofluorescently label proteins or the cellular fractions can be individually isolated to investigate protein expression and phosphorylation via western blotting. Using this unique model, we show the in vitro MEJ has a unique lipid composition that is rich in diacylglycerol and phosphatidylserine. This likely facilitates localization of signaling molecules such as protein kinase C and selective activation of endothelial nitric oxide synthase. Additionally, the multifunctional protein calreticulin is highly expressed at the MEJ of resistance arteries and endothelial deletion of calreticulin results in impaired MEJ calcium signaling, thus vasoconstriction to phenylephrine and blood pressure. Our data suggests that EC monolayer Calr could be iii functionally different than MEJ-localized Calr, which may be located outside the ER.Further work will need to be done in order to clarify and confirm MEJ Calr function and how it affects calcium signaling at the MEJ specifically in response to phenylephrine. In summary, the MEJ is an important signaling microdomain strategically located in the wall of resistance arteries to mediate heterocellular communication.

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Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation

Cited by 93 publications

References 55 publications

Lack of mitochondria-generated acetyl-CoA by pyruvate dehydrogenase complex downregulates gene expression in the hepatic de novo lipogenic pathway

Lack of mitochondria-generated acetyl-CoA by pyruvate dehydrogenase complex downregulates gene expression in the hepatic de novo lipogenic pathway

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Signaling Microdomains within the Myoendothelial Junction

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