Fatty acid transport protein 4 is dispensable for intestinal lipid absorption in mice

Shim, Jien; Moulson, Casey L.; Newberry, Elizabeth P.; Lin, Meei-Hua; Xie, Yan; Kennedy, Susan; Miner, Jeffrey H.; Davidson, Nicholas O.

doi:10.1194/jlr.m800400-jlr200

Cited by 76 publications

(58 citation statements)

References 33 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although Fatp4 was previously thought to play a role in transport of fatty acids across the plasma membrane, more recent data have shown that Fatp4 is dispensable for fatty acid uptake in different cell types (5,10,11). Supporting this notion, uptake of radiolabeled fatty acids into adipose tissue in our study was undisturbed in Fatp4 AϪ/Ϫ mice.…”

Section: Discussionsupporting

confidence: 82%

Adipocyte-specific Inactivation of Acyl-CoA Synthetase Fatty Acid Transport Protein 4 (Fatp4) in Mice Causes Adipose Hypertrophy and Alterations in Metabolism of Complex Lipids under High Fat Diet

Lenz

Marx

Chamulitrat

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Fatp4 exhibits acyl-CoA synthetase activity and is thereby able to catalyze the activation of fatty acids for further metabolism. However, its actual function in most tissues remains unresolved, and its role in cellular fatty acid uptake is still controversial. To characterize Fatp4 functions in adipocytes in vivo, we generated a mouse line with adipocyte-specific inactivation of the Fatp4 gene (Fatp4 A؊/؊ ). Under standard conditions mutant mice showed no phenotypical aberrance. Uptake of radiolabeled palmitic and lignoceric acid into adipose tissue of Fatp4 A؊/؊ mice was unchanged. When exposed to a diet enriched in long chain fatty acids, Fatp4 A؊/؊ mice gained more body weight compared with control mice, although they were not consuming more food. Pronounced obesity was accompanied by a thicker layer of subcutaneous fat and greater adipocyte circumference, although expression of genes involved in de novo lipogenesis was not changed. However, the increase in total fat mass was contrasted by a significant decrease in various phospholipids, sphingomyelin, and cholesteryl esters in adipocytes. Livers of Fatp4-deficient animals under a high fat diet exhibited a higher degree of fatty degeneration. Nonetheless, no evidence for changes in insulin sensitivity and adipose inflammation was found. In summary, the results of this study confirm that Fatp4 is not crucial for fatty acid uptake into adipocytes. Instead, under the condition of a diet enriched in long chain fatty acids, adipocyte-specific Fatp4 deficiency results in adipose hypertrophy and profound alterations in the metabolism of complex lipids.The mechanism of fatty acid uptake into the cell is still under debate. In recent years there has been growing evidence for fatty acid uptake across the plasma membrane by specific protein transport systems rather than by mere diffusion processes (1). In line with this perception, there has been increasing interest in an evolutionarily conserved group of genes encoding fatty acid transport proteins (Fatps). 4 The Fatp family consists of six members (Fatp1-6) of which Fatp1 was first described and is the best characterized (2). A 60% homologue to that founding member of the Fatp family is Fatp4. Like other members of this gene family, it shows a tissue-specific expression pattern. It can be detected in skin, liver, adipose tissue, brain, skeletal muscle, and heart and is the only Fatp found in small intestine (3). For most of these tissues, the physiological function of Fatp4 is unknown. In several experiments, overexpression of Fatp4 in different cultured cell lines resulted in an increased cellular influx of fatty acids (4 -7). In line with these observations, Fatp4 was initially presumed to be a typical transmembrane transport protein (4). Meanwhile, there is emerging evidence that Fatp4 is not plasma membrane-associated but is localized to the endoplasmic reticulum (8) or other intracellular compartments (5, 9). Furthermore, like other members of the gene family, Fatp4 exhibits acyl-CoA synthetase activity and is t...

show abstract

Section: Discussionsupporting

confidence: 82%

Adipocyte-specific Inactivation of Acyl-CoA Synthetase Fatty Acid Transport Protein 4 (Fatp4) in Mice Causes Adipose Hypertrophy and Alterations in Metabolism of Complex Lipids under High Fat Diet

Lenz

Marx

Chamulitrat

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Overexpression studies have often led to different conclusions concerning effectors of fatty acid influx due to changes in protein levels and cellular location (6,31,32), and as such, we have focused our efforts on loss of function models. Our initial studies confirmed a major role of FATP1 in facilitating insulin-stimulated fatty acid uptake, whereas silencing of FATP4 had little influence on basal or insulin-stimulated fatty acid uptake (6).…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of Long-chain Acyl-CoA Synthetase 1 in 3T3-L1 Adipocytes

Lobo

Wiczer

Bernlohr

2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

ACSL1 (acyl-CoA synthetase 1), the major acyl-CoA synthetase of adipocytes, has been proposed to function in adipocytes as mediating free fatty acid influx, esterification, and storage as triglyceride. To test this hypothesis, ACSL1 was stably silenced (knockdown (kd)) in 3T3-L1 cells, differentiated into adipocytes, and evaluated for changes in lipid metabolism. Surprisingly, ACSL1-silenced adipocytes exhibited no significant changes in basal or insulin-stimulated long-chain fatty acid uptake, lipid droplet size, or tri-, di-, or monoacylglycerol levels when compared with a control adipocyte line. However, ACSL1 kd adipocytes displayed a 7-fold increase in basal and a ϳ15% increase in forskolin-stimulated fatty acid efflux without any change in glycerol release, indicating a role for the protein in fatty acid reesterification following lipolysis. Consistent with this proposition, ACSL1 kd cells exhibited a decrease in activation and phosphorylation of AMP-activated protein kinase and its primary substrate acetyl-CoA carboxylase. Moreover, ACSL1 kd adipocytes displayed an increase in phosphorylated protein kinase C and phosphorylated JNK, attenuated insulin signaling, and a decrease in insulin-stimulated glucose uptake. These findings identify a primary role of ACSL1 in adipocytes not in control of lipid influx, as previously considered, but in lipid efflux and fatty acid-induced insulin resistance.Fatty acid influx and efflux mechanisms and their regulation affect lipid storage and metabolism in adipocytes. Imbalances in adipose lipid metabolism have been shown to significantly contribute to the development of obesity and associated metabolic diseases, such as type 2 diabetes, hypertension, and cardiovascular disease (1-3). Although the molecular mechanisms involved in fatty acid efflux are still undefined, several proteins implicated in fatty acid influx have been proposed: CD36 (fatty acid translocase), acyl-CoA synthetases (fatty acid transport protein (FATP) 2 and acyl-CoA synthetase (ACSL) family members), plasma membrane fatty acid-binding protein, and caveolin-1 (4 -9).FATPs and long-chain ACSLs are membrane-bound enzymes that catalyze the ATP-dependent esterification of long chain (ACSL) and very long-chain (FATP) fatty acids to their acyl-CoA derivatives (10, 11). Both types of CoA synthetases have common ATP/AMP binding and fatty acid binding signature motifs. In mammals, six different isoforms of FATP (FATP1-FATP6) and five different isoforms of ACSL (ACSL1, -3, -4, -5, and -6) have been identified with tissue-specific expression patterns (12). White adipose tissue predominantly express FATP1, FATP4, and ACSL1, whereas brown adipose tissue in addition expresses ACSL5. Our recent results have confirmed a major role of FATP1 and CD36, but not FATP4, in insulin-stimulated LCFA uptake in 3T3-L1 adipocytes (6).ACSL1 is a ϳ78-kDa intrinsic membrane protein localized to multiple sites in a variety of different cells. In liver, ACSL1 has been shown to be localized to the endoplasmic reticulum and mitochond...

show abstract

“…Rather, consistent with the insulin-stimulated translocation of FATP1 to the plasma membrane ( 5 ), FATP1 is required for insulin-stimulated LCFA uptake ( 3,5 ). Functional studies of FATP4 have shown that the protein does not play a role in LCFA uptake in either enterocytes ( 23 ) or adipocytes ( 3 ) but in fat cells may function in fatty acid reesterifi cation following lipolysis ( 3 ).…”

mentioning

confidence: 99%

A novel role for fatty acid transport protein 1 in the regulation of tricarboxylic acid cycle and mitochondrial function in 3T3-L1 adipocytes

Wiczer

Bernlohr

2009

Journal of Lipid Research

View full text Add to dashboard Cite

Fatty acid transport protein 4 is dispensable for intestinal lipid absorption in mice

Cited by 76 publications

References 33 publications

Adipocyte-specific Inactivation of Acyl-CoA Synthetase Fatty Acid Transport Protein 4 (Fatp4) in Mice Causes Adipose Hypertrophy and Alterations in Metabolism of Complex Lipids under High Fat Diet

Adipocyte-specific Inactivation of Acyl-CoA Synthetase Fatty Acid Transport Protein 4 (Fatp4) in Mice Causes Adipose Hypertrophy and Alterations in Metabolism of Complex Lipids under High Fat Diet

Functional Analysis of Long-chain Acyl-CoA Synthetase 1 in 3T3-L1 Adipocytes

A novel role for fatty acid transport protein 1 in the regulation of tricarboxylic acid cycle and mitochondrial function in 3T3-L1 adipocytes

Contact Info

Product

Resources

About