Acyl-CoA Metabolism and Partitioning

Grevengoed, Trisha J.; Klett, Eric L.; Coleman, Rosalind A.

doi:10.1146/annurev-nutr-071813-105541

Cited by 350 publications

(353 citation statements)

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“…It may be important to investigate whether a difference exists in the channeling of fatty acids toward the pathways of glycerolipid synthesis among the three experimental groups of animals because this process is considered to be associated with fatty acid degradation. [41][42][43][44][45] Among the enzymes that participate in the channeling of fatty acids in the liver, fat-free diet feeding increased the mRNA levels of long-chain acylCoA synthetase (ACSL) 5, glycerol-3-phosphate acyltransferase (GPAT) 1, and diglyceride acyltransferase (DGAT) 2; the clofibric acid treatment up-regulated the expression of genes for ACSL1, ACSL3, GPAT3, and DGAT1 (Fig. 5A).…”

Section: Resultsmentioning

confidence: 99%

“…Some of the isoforms of ACSL and GPAT are considered to channel fatty acids toward different metabolic pathways, such that changes in the expression of the isoforms of GPAT and ACSL may affect fatty acid degradation, [41][42][43] and a significant portion of fatty acids are initially channeled to TAG storage prior to hydrolysis by ATGL and are then degraded by β-oxidation. 32,44,45) These findings indicate that metabolic pathways other than fatty acid oxidation indirectly affect the differences noted in the degradation of MUFAs.…”

Section: Discussionmentioning

confidence: 99%

“…The present study also showed that fat-free diet feeding up-regulated the expression of Acsl5, Gpat1, and Dgat2 in the liver. Up-regulated ACSL5 and GPAT1 may reduce the degradation of MUFAs because these two enzymes reside on outer mitochondrial membranes, 41,49,51,52) channel increasingly generated MUFAs toward complex lipids (TAG, phospholipids, DAG, CE), and divert them away from CPT1-mediated entry into mitochondria. 43,52) DGTA2 co-localizes with SCD1 on the endoplasmic reticulum, and is primarily responsible for incorporating endogenously synthesized MUFAs into TAG.…”

Section: Discussionmentioning

confidence: 99%

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Fatty Acid β-Oxidation Plays a Key Role in Regulating <i>cis</i>-Palmitoleic Acid Levels in the Liver

Kawabata

Karahashi

Sakamoto

et al. 2016

Biological & Pharmaceutical Bulletin

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Different monounsaturated fatty acid (MUFA) species have distinct pathophysiological activities. cisPalmitoleic acid (16:1n-7) was previously reported to improve insulin sensitivity in animal studies. The proportions of hepatic MUFAs are generally considered to reflect changes in the activities of fatty acid modifications (∆9 desaturation and fatty acid elongation). However, hepatic levels of 16:1n-7 are markedly lower than those of oleic acid (18:1n-9). Nevertheless, no convincing explanation has yet been provided for the low level of 16:1n-7. We hypothesized that fatty acid degradation plays a key role in maintaining a low 16:1n-7 proportion in the liver. In order to corroborate the link between β-oxidation and the proportion of 16:1n-7, rats were fed a control diet, fed a fat-free diet to up-regulate fatty acid modifications, but not β-oxidation, or treated with clofibric acid to up-regulate fatty acid modifications and β-oxidation. The nutritional manipulation markedly increased the proportions of 16:1n-7, 18:1n-9, and cis-vaccenic acid (18:1n-7). Although the pharmacological manipulation enhanced fatty acid modifications to largely the same extent as the nutritional manipulation and markedly elevated the proportion of 18:1n-9, those of 16:1n-7 and 18:1n-7 remained largely unchanged. The oxidation rates of 16:1n-7, 18:1n-9, and 18:1n-7 in liver slices were in the following order: 16:1n-7>18:1n-7≑18:1n-9 in control livers, and were increased by the pharmacological manipulation and decreased by the nutritional manipulation. These results strongly suggest that β-oxidation, in concert with fatty acid modifications, plays a key role in regulating the MUFA profile and is crucially involved in maintaining low 16:1n-7 levels in the liver.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Fatty Acid β-Oxidation Plays a Key Role in Regulating <i>cis</i>-Palmitoleic Acid Levels in the Liver

Kawabata

Karahashi

Sakamoto

et al. 2016

Biological & Pharmaceutical Bulletin

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“…It shares sequence homology with the acyl-CoA synthetase (ACSL) family and is expressed intracellularly. FATP4 likely facilitates fatty acid uptake by trapping fatty acids as fatty acylCoAs ( 22 ). In mice, FATP4 is crucial for lipid homeostasis in the skin but its role in intestinal lipid absorption is dispensable ( 23 ).…”

mentioning

confidence: 99%

Intestinal triacylglycerol synthesis in fat absorption and systemic energy metabolism

Yen

Nelson

Yen

2015

Journal of Lipid Research

117

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cell membranes. The biosynthesis of TAG thus serves many physiological functions. Because it is highly reduced and anhydrous, TAG is the primary energy substrate stored in adipose tissues to sustain animals during fasting. TAG is also synthesized in the liver for the assembly and secretion of VLDL to transport neutral lipids to other tissues, as well as in the mammary gland for the formation of milk fat globules to deliver fatty acids and other lipid-soluble nutrients to mammalian neonates.In the intestine, TAG synthesis is prominent for its role in the absorption of dietary fat ( 2, 3 ). TAG forms the bulk of animal fats and plant oils. It accounts for approximately 95% of dietary fat, depending on the food sources, with the rest as phospholipids and trace amounts of sterols, lipid-soluble vitamins, and other lipophilic components. Because of its hydrophobicity, TAG does not traverse the cellular membrane. Its absorption involves hydrolysis to fatty acids and monoacylglycerol (MAG) in the intestinal lumen, lipid uptake by the enterocytes, resynthesis of TAG, and assembly and secretion of ApoB-containing chylomicrons for delivery of TAG and other lipid-soluble nutrients. Like with most nutrients, the absorption of TAG occurs mostly in the proximal half of the intestine and less so in the distal intestine, where specifi c compounds, such as bile acids and vitamin B12, are absorbed. The activity of TAG synthesis coincides with the absorption of dietary fat along the length of the intestine, and it is more active in Press, September 17, 2014 DOI 10.1194 Abbreviations: ACSL, acyl-CoA synthetase; AGPAT, 1-acylglycerol-3-phosphate acyltransferase; ATGL, adipose triglyceride lipase; CD36, cluster of differentiation; CGI-58, comparative gene identifi cation-58; Cideb, cell death-inducing DNA fragmentation factor 45 (DFF45) -like effector b; DAG, diacylglycerol; DGAT, acyl-CoA:diacylglycerol acyltransferase; ER, endoplasmic reticulum; FABP, fatty acid binding protein; GLP-1, glucagon-like peptide 1; GPAT, glycerol-3-phosphate acyltransferase; G3P, glycerol-3-phosphate; IFABP, intestine-type fatty acid binding protein; LFABP, liver-type fatty acid binding protein; MAG, monoacylglycerol; MBOAT, membrane-bound O-acyltransferase; MGAT, acylCoA:monoacylglycerol acyltransferase; MTP, microsomal triacylglycerol transfer protein; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; TAG, triacylglycerol (triglyceride ). Published, JLR Papers in

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“…This activation process requires ATP, CoA, and LCFAs. Activated fatty acids can then undergo degradation through ␤-oxidation, be utilized for cellular lipid synthesis, or serve as lipid anchors for protein modifications (3)(4)(5)(6)(7)(8).…”

mentioning

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SREBP2 Activation Induces Hepatic Long-chain Acyl-CoA Synthetase 1 (ACSL1) Expression in Vivo and in Vitro through a Sterol Regulatory Element (SRE) Motif of the ACSL1 C-promoter

Singh¹,

Kan²,

Dong

et al. 2016

Journal of Biological Chemistry

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Long-chain acyl-CoA synthetase 1 (ACSL1) plays a key role in fatty acid metabolism. To identify novel transcriptional modulators of ACSL1, we examined ACSL1 expression in liver tissues of hamsters fed a normal diet, a high fat diet, or a high cholesterol and high fat diet (HCHFD). Feeding hamsters HCHFD markedly reduced hepatic Acsl1 mRNA and protein levels as well as acyl-CoA synthetase activity. Decreases in Acsl1 expression strongly correlated with reductions in hepatic Srebp2 mRNA level and mature Srebp2 protein abundance. Conversely, administration of rosuvastatin (RSV) to hamsters increased hepatic Acsl1 expression. These new findings were reproduced in mice treated with RSV or fed the HCHFD. Furthermore, the RSV induction of acyl-CoA activity in mouse liver resulted in increases in plasma and hepatic cholesterol ester concentrations and reductions in free cholesterol amounts. Investigations on different ACSL1 transcript variants in HepG2 cells revealed that the mRNA expression of C-ACSL1 was specifically regulated by the sterol regulatory element (SRE)-binding protein (SREBP) pathway, and RSV treatment increased the C-ACSL1 abundance from a minor mRNA species to an abundant transcript. We analyzed 5-flanking sequence of exon 1C of the human ACSL1 gene and identified one putative SRE site. By performing a promoter activity assay and DNA binding assays, we firmly demonstrated the key role of this SRE motif in SREBP2-mediated activation of C-ACSL1 gene transcription. Finally, we demonstrated that knockdown of endogenous SREBP2 in HepG2 cells lowered ACSL1 mRNA and protein levels. Altogether, this work discovered an unprecedented link between ACSL1 and SREBP2 via the specific regulation of the C-ACSL1 transcript.In mammals, the predominant long-chain fatty acids (LCFAs) 3 have 16 and 18 carbons with different degrees of saturation. Prior to entering various metabolic pathways, free LCFAs must be esterified with coenzyme A by members of the long-chain acyl-CoA synthetase (ACSL) family (1, 2). This activation process requires ATP, CoA, and LCFAs. Activated fatty acids can then undergo degradation through ␤-oxidation, be utilized for cellular lipid synthesis, or serve as lipid anchors for protein modifications (3-8).The mammalian ACSL family consists of five distinct members, including ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6. These isoforms differ substantially in their substrate preference, tissue distribution, and subcellular compartmentation as well as in their responses to nutritional status (9), all of which contributes to the unique functions of each isoform in a particular tissue or a cell type.ACSL1 has been the most extensively studied isoform of this family since it was cloned from rat liver in 1990 (10) and has broad substrate specificity for saturated FAs of 16 and 18 chain lengths and unsaturated FAs of 16 -20 carbon atoms. ACSL1 is the abundant isoform in major metabolic tissues, including liver, heart, adipose, and muscle. Whereas in vitro studies carried out in different cell lines have reported ...

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Acyl-CoA Metabolism and Partitioning

Cited by 350 publications

References 208 publications

Fatty Acid β-Oxidation Plays a Key Role in Regulating <i>cis</i>-Palmitoleic Acid Levels in the Liver

Fatty Acid β-Oxidation Plays a Key Role in Regulating <i>cis</i>-Palmitoleic Acid Levels in the Liver

Intestinal triacylglycerol synthesis in fat absorption and systemic energy metabolism

SREBP2 Activation Induces Hepatic Long-chain Acyl-CoA Synthetase 1 (ACSL1) Expression in Vivo and in Vitro through a Sterol Regulatory Element (SRE) Motif of the ACSL1 C-promoter

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