Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

Bu, So Young; Mashek, Mara T.; Mashek, Douglas G.

doi:10.1074/jbc.m109.036665

Cited by 89 publications

(81 citation statements)

References 53 publications

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“…RNAi of ACSL3 in primary hepatocytes decreased the activity of PPAR ␥ and other lipogenic transcription factors ( 65 ). Although the incorporation of external fatty acids was not investigated, this offers an alternative explanation for the reduced uptake observed by us: Less active PPAR ␥ could decrease the overall capacity for cellular lipid metabolism and, consequently, fatty acid uptake.…”

Section: Lipid Droplet Biogenesismentioning

confidence: 86%

The N-terminal region of acyl-CoA synthetase 3 is essential for both the localization on lipid droplets and the function in fatty acid uptake

Poppelreuther

Rudolph

et al. 2012

Journal of Lipid Research

115

110

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This article is available online at http://www.jlr.org developed very early during evolution. Cytosolic lipid droplets (LDs) are the main reservoir of lipids and are common to many if not all eukaryotic cells ( 1 ). LDs have gained much recent interest because of their regulatory role in lipid homeostasis and their implication in metabolic diseases such as obesity and type 2 diabetes ( 2-4 ). They have a unique structure composed of a hydrophobic core surrounded by a phospholipid monolayer containing a specifi c protein composition. Perilipin family proteins and lipid metabolizing enzymes are the most abundant proteins ( 5, 6 ), and proteomic studies have identifi ed many additional constituents ( 7 ). Little is known how proteins are specifi cally targeted to lipid droplets ( 8, 9 ). The biogenesis of LDs likely involves the endoplasmic reticulum, but the mechanism has not been solved and is debated intensely ( 2,3,10 ).Triglycerides are the main species of neutral lipids stored within the LDs of most cell types. The predominant biosynthetic pathway requires three activated fatty acids for each triglyceride molecule. The fatty acids are taken up from the extracellular medium or are derived from endogenous metabolism by fatty acid synthase. In fact, addition of fatty acids is a very effi cient way to induce the formation of LDs ( 4 ). However, fatty acids are chemically quite inert and need to be activated by esterifi cation with CoA ( 11 ). This activation is catalyzed by the family of acylCoA synthetases ( 12 ); physiologically highly relevant are the long chain (ACSL1, -3, -4, -5, -6) and very long chain (ACSVL1, -2, -3, -4, -5, and -6) fatty acyl-CoA synthetase subfamilies ( 13 ). Apart from their obvious enzymatic role, additional functions have been suggested for ACS(V)L family proteins: metabolic channeling of fatty acids toward specifi c metabolic fates [e.g., phospholipid synthesis vs.Abstract Cytosolic lipid droplets (LDs) are storage organelles for neutral lipids derived from endogenous metabolism. Acyl-CoA synthetase family proteins are essential enzymes in this biosynthetic pathway, contributing activated fatty acids. Fluorescence microscopy showed that ACSL3 is localized to the endoplasmic reticulum (ER) and LDs, with the distribution dependent on the cell type and the supply of fatty acids. The N-terminus of ACSL3 was necessary and sufficient for targeting reporter proteins correctly, as demonstrated by subcellular fractionation and confocal microscopy. The N-terminal region of ACSL3 was also found to be functionally required for the enzyme activity. Selective permeabilization and in silico analysis suggest that ACSL3 assumes a hairpin membrane topology, with the N-terminal hydrophobic amino acids forming an amphipathic helix restricted to the cytosolic leafl et of the ER membrane. ACSL3 was effectively translocated from the ER to nascent LDs when neutral lipid synthesis was stimulated by the external addition of fatty acids. Cellular fatty acid uptake was increased by overexpression and reduced b...

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Section: Lipid Droplet Biogenesismentioning

confidence: 86%

The N-terminal region of acyl-CoA synthetase 3 is essential for both the localization on lipid droplets and the function in fatty acid uptake

Poppelreuther

Rudolph

et al. 2012

Journal of Lipid Research

115

110

View full text Add to dashboard Cite

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“…This enzyme is considered to catalyze the rate-limiting step in β-oxidation and to play a pivotal role in controlling TAG content in the liver 42 . ACSL3 has been shown to be involved in the formation of lipid droplets in conjunction with the increased production of acyl-CoAs 43 ; moreover, ACSL3 regulates lipogenic transcription factors to control glycerolipid synthesis 44 . Taking these findings together, it is logical to suggest that increases in the hydrolysis of TAG and subsequent β-oxidation of fatty acids, and a decrease in the synthesis of acyl-CoA supplied to TAG synthesis cause the reduced hepatic content of TAGs in SHRSP.…”

Section: Discussionmentioning

confidence: 99%

Altered Fatty Acid Profile in the Liver and Serum of Stroke-Prone Spontaneously Hypertensive Rats: Reduced Proportion of cis-Vaccenic Acid

et al. 2013

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“…Mouse primary hepatocytes were isolated as described previously (25,28). To address direct effects of adipocyte factors generated in response to PFKFB3/iPFK2 action, isolated WT hepatocytes were treated with iPFK2-OX-adipocyte-conditioned medium (iPFK2-OX-CM) or GFP-expressing adipocyte-conditioned medium (GFP-CM, control) in M199 medium at a 1:1 ratio for 48 h in the presence or absence of palmitate (250 M) for the last 24 h. Hepatocyte lipid accumulation was analyzed using Oil Red O staining and the colorimetric assay to quantify triglyceride content.…”

Section: Methodsmentioning

confidence: 99%

Targeted Overexpression of Inducible 6-Phosphofructo-2-kinase in Adipose Tissue Increases Fat Deposition but Protects against Diet-induced Insulin Resistance and Inflammatory Responses

Huo

Guo

et al. 2012

Journal of Biological Chemistry

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Background: Inducible 6-phosphofructo-2-kinase links metabolic and inflammatory responses. Results: Adipose overexpression of inducible 6-phosphofructo-2-kinase increases fat deposition, suppresses inflammatory responses, and improves insulin sensitivity in both adipose and liver tissues. Conclusion: Inducible 6-phosphofructo-2-kinase in adipocytes uniquely dissociates diet-induced inflammatory and metabolic responses in both adipose and liver tissues. Significance: Adipocyte-inducible 6-phosphofructo-2-kinase may underlie healthy obesity.

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Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

Cited by 89 publications

References 53 publications

The N-terminal region of acyl-CoA synthetase 3 is essential for both the localization on lipid droplets and the function in fatty acid uptake

The N-terminal region of acyl-CoA synthetase 3 is essential for both the localization on lipid droplets and the function in fatty acid uptake

Altered Fatty Acid Profile in the Liver and Serum of Stroke-Prone Spontaneously Hypertensive Rats: Reduced Proportion of cis-Vaccenic Acid

Targeted Overexpression of Inducible 6-Phosphofructo-2-kinase in Adipose Tissue Increases Fat Deposition but Protects against Diet-induced Insulin Resistance and Inflammatory Responses

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