Regulation of triacylglycerol synthesis in permeabilized rat hepatocytes

Stals, H; Top, W.; Declercq, Peter

doi:10.1016/0014-5793(94)80615-2

Cited by 39 publications

(9 citation statements)

References 16 publications

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“…The lower affinity of DGAT for acyl-CoA as compared with other enzymes in the FA esterification pathway (Fig. 5) has been suggested from results of enzymatic assays in intact and permeabilized hepatocytes (42,43). However, the findings presented here mark the first demonstration of a key regulatory role for DGAT in vivo and point to the pivotal role of membrane FA transport in maintaining acyl-CoA at the levels required for optimal DGAT activity.…”

Section: Discussionsupporting

confidence: 56%

Defective Uptake and Utilization of Long Chain Fatty Acids in Muscle and Adipose Tissues of CD36 Knockout Mice

Coburn

Knapp

Febbraio

et al. 2000

Journal of Biological Chemistry

630

478

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The transmembrane protein CD36 has been identified in isolated cell studies as a putative transporter of long chain fatty acids. In humans, an association between CD36 deficiency and defective myocardial uptake of the fatty acid analog 15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid (BMIPP) has been reported. To determine whether this association represents a causal link and to assess the physiological role of CD36, we compared tissue uptake and metabolism of two iodinated fatty acid analogs BMIPP and 15-(p-iodophenyl) pentadecanoic acid (IPPA) in CD36 null and wild type mice. We also investigated the uptake and lipid incorporation of palmitate by adipocytes isolated from both groups. Compared with wild type, uptake of BMIPP and IPPA was reduced in heart (50 -80%), skeletal muscle (40 -75%), and adipose tissues (60 -70%) of null mice. The reduction was associated with a 50 -68% decrease in label incorporation into triglycerides and in 2-3-fold accumulation of label in diglycerides. Identical results were obtained from studies of [ 3 H]palmitate uptake in isolated adipocytes. The block in diglyceride to triglyceride conversion could not be explained by changes in specific activities of the key enzymes long chain acylCoA synthetase and diacylglycerol acyltransferase, which were similar in tissues from wild type and null mice. It is concluded that CD36 facilitates a large fraction of fatty acid uptake by heart, skeletal muscle, and adipose tissues and that CD36 deficiency in humans is the cause of the reported defect in myocardial BMIPP uptake. In CD36-expressing tissues, uptake regulates fatty acid esterification at the level of diacylglycerol acyltransferase by determining fatty acyl-CoA supply. The membrane transport step may represent an important control site for fatty acid metabolism in vivo.Studies with isolated and cultured cells have provided evidence for the existence of a protein-facilitated component in the membrane transport of long chain fatty acids (FA) 1 in adipose(1, 2), liver (3, 4), and muscle tissues (3, 5). Among the proteins proposed to enhance FA uptake is the transmembrane protein CD36. Expression of this protein in fibroblasts, which do not endogenously express CD36, was associated with an increase in FA uptake and incorporation into phospholipids (6). This increase reflected the appearance of a saturable, phloretinsensitive component exhibiting a transport K m within the physiologic range of unbound FA concentrations (7-10 nM) (7). The distribution of CD36 favors tissues with a high metabolic capacity for FA such as adipose, heart, and skeletal muscle (8). In muscle tissues, CD36 expression is most abundant in red oxidative fibers and is up-regulated with muscle stimulation concomitant with an increase in the V max of FA transport (9). Expression is also high in tissues experiencing large fluxes of FA such as capillary endothelia, mammary epithelia (10), or epithelia of the small intestine (11).Mice null for CD36 were recently developed and found to exhibit increased serum FA, triglyce...

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Section: Discussionsupporting

confidence: 56%

Defective Uptake and Utilization of Long Chain Fatty Acids in Muscle and Adipose Tissues of CD36 Knockout Mice

Coburn

Knapp

Febbraio

et al. 2000

Journal of Biological Chemistry

630

478

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“…DAG and FA released from phospholipids can be utilized for TG synthesis (38), and alterations in cellular PC content are sufficient to cause changes in TG metabolism (35). In rat hepatocytes, an elevated TG synthesis occurred as a result of excess DAG when CDP-choline was limiting PC synthesis and also where DGAT activity was maximal (39). It has also been established that mutations inhibiting CTP:phosphocholine cytidylyltransferase of the PC-Kennedy pathway in Chinese hamster ovary cells result in a redirection of DAG from phospholipids to TG (35).…”

Section: Discussionmentioning

confidence: 99%

The Development of a Metabolic Disease Phenotype in CTP:Phosphoethanolamine Cytidylyltransferase-deficient Mice

Fullerton

Hakimuddin

Bonen

et al. 2009

Journal of Biological Chemistry

150

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Phosphatidylethanolamine (PE) is an important inner membrane phospholipid mostly synthesized de novo via the PE-Kennedy pathway and by the decarboxylation of phosphatidylserine. CTP:phosphoethanolamine cytidylyltransferase (Pcyt2) catalyzes the formation of CDP-ethanolamine, which is often the rate regulatory step in the PE-Kennedy pathway. In the current investigation, we show that the reduced CDP-ethanolamine formation in Pcyt2 ؉/؊ mice limits the rate of PE synthesis and increases the availability of diacylglycerol. This results in the increased formation of triglycerides, which is facilitated by stimulated de novo fatty acid synthesis and increased uptake of pre-existing fatty acids. Pcyt2 ؉/؊ mice progressively accumulate more diacylglycerol and triglycerides with age and have modified fatty acid composition, predominantly in PE and triglycerides. Pcyt2 ؉/؊ additionally have an inherent blockage in fatty acid utilization as energy substrate and develop impaired tolerance to glucose and insulin at an older age. Accordingly, gene expression analyses demonstrated the up-regulation of the main lipogenic genes and down-regulation of mitochondrial fatty acid ␤-oxidation genes. These data demonstrate for the first time that to preserve membrane PE phospholipids, Pcyt2 deficiency generates compensatory changes in triglyceride and energy substrate metabolism, resulting in a progressive development of liver steatosis, hypertriglyceridemia, obesity, and insulin resistance, the main features of the metabolic syndrome.

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“…As fatty acids are known to activate DGAT [154], the sharp decline in NEFA supply to the liver upon refeeding of starved rats could result in the attenuation of DGAT activity (see below). Evidence from experiments on permeabilized hepatocytes indicates that phosphatidylcholine and TAG syntheses utilize the same pool of DAG [155], although, as discussed above, at least one additional pool of microsomal membrane DAG may exist [121,122,125]. Alternatively, altered DAG partitioning could involve acute changes in the activities of the enzymes that exert major control over the respective pathways through post-translational mechanisms.…”

Section: Partitioning Of Dag Between Phospholipid and Tag Synthesismentioning

confidence: 99%

Role of insulin in hepatic fatty acid partitioning: emerging concepts

Zammit

1996

Biochemical Journal

115

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Regulation of triacylglycerol synthesis in permeabilized rat hepatocytes

Cited by 39 publications

References 16 publications

Defective Uptake and Utilization of Long Chain Fatty Acids in Muscle and Adipose Tissues of CD36 Knockout Mice

Defective Uptake and Utilization of Long Chain Fatty Acids in Muscle and Adipose Tissues of CD36 Knockout Mice

The Development of a Metabolic Disease Phenotype in CTP:Phosphoethanolamine Cytidylyltransferase-deficient Mice

Role of insulin in hepatic fatty acid partitioning: emerging concepts

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