Inhibition of carnitine palmitoyltransferase in the rat small intestine reduces export of triacylglycerol into the lymph

Washington, LaTonya; Cook, George A.; Mansbach, Charles M.

doi:10.1194/jlr.m300123-jlr200

Cited by 27 publications

(11 citation statements)

References 51 publications

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“…the roles of CPT1a and CPT1b, is to increase the capacity of fatty acid flux into the mitochondria and to improve insulin sensitivity and glucose utilization by eliminating unoxidized fatty acids (Bruce et al 2009 ;Folmes & Lopaschuk, 2007). Although the role of CPT1c is far from fully elucidated, it has been suggested that CPT1c might alter the synthesis of ceramide and sphingolipids in neurons through facilitating the entry of palmitoyl CoA to the ER lumen (Sierra et al 2008 ;Washington et al 2003). The synthesis of ceramide and sphingolipids affects the lipid composition of the cell membrane, changing the environment and the activity of the membrane receptors (Chattopadhyay & Paila, 2007).…”

Section: Discussionmentioning

confidence: 99%

The effect of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex

Kim

et al. 2011

Int. J. Neuropsychopharm.

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Clozapine is an antipsychotic drug that has a greater efficacy than other medications in some contexts, especially for the treatment of treatment-resistant schizophrenia. However, clozapine induces more metabolic side-effects involving abnormality in lipid metabolism compared to other antipsychotics. AMP-activated protein kinase (AMPK) plays a central role in controlling lipid metabolism through modulating the downstream acetyl CoA carboxylase (ACC) and carnitine palmitoyl transferase 1 (CPT1) pathway. In this study, we investigated the effect of a single intraperitoneal injection of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex, which has been implicated as a target site for this antipsychotic drug. At 2 h after injection, the clinically relevant dose of clozapine had activated AMPK, with increased phosphorylation of AMPKα at Thr(172), and had inactivated ACC, with increased phosphorylation of ACC at Ser(79). In addition, clozapine activated the brain-specific isoform of CPT1, CPT1c, whose activity is inhibited by unphosphorylated ACC, in the rat frontal cortex. Immunohistochemistry and immunofluorescence analysis showed that clozapine induced an increase in number of p-AMPKα (Thr(172))- and p-ACC (Ser(79))-positive cells among the neurons of the rat frontal cortex. Taken together, these results show that clozapine activated the AMPK-ACC-CPT1 pathway in the neurons of the rat frontal cortex. These findings indicate that the antipsychotic agent clozapine affects the lipid regulatory system of neurons in the brain.

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Section: Discussionmentioning

confidence: 99%

The effect of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex

Kim

et al. 2011

Int. J. Neuropsychopharm.

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“…A carnitine acyltransferase system capable of transporting fatty acids from the cytosol across membranes via a fatty acylcarnitine intermediate has been identified at the ER (41)(42)(43). Carnitine acyltransferase enzymes have previously been demonstrated to have a role in TG synthesis in the ER lumen both in vivo in rat small intestine and with a cell-free system, providing evidence for a mechanism that could deliver fatty acid substrates across the ER membrane from the cytosol to the active site of DGAT1 in the ER lumen (44,45).…”

Section: Discussionmentioning

confidence: 99%

Topological Orientation of Acyl-CoA:Diacylglycerol Acyltransferase-1 (DGAT1) and Identification of a Putative Active Site Histidine and the Role of the N Terminus in Dimer/Tetramer Formation

McFie

Stone

Banman

et al. 2010

Journal of Biological Chemistry

133

125

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Acyl CoA:diacylglycerol acyltransferase (DGAT) is an integral membrane protein of the endoplasmic reticulum that catalyzes the synthesis of triacylglycerols. Two DGAT enzymes have been identified (DGAT1 and DGAT2) with unique roles in lipid metabolism. DGAT1 is a multifunctional acyltransferase capable of synthesizing diacylglycerol, retinyl, and wax esters in addition to triacylglycerol. Here, we report the membrane topology for murine DGAT1 using protease protections assays and indirect immunofluorescence in conjunction with selective permeabilization of cellular membranes. Topology models based on prediction algorithms suggested that DGAT1 had eight transmembrane domains. In contrast, our data indicate that DGAT1 has three transmembrane domains with the N terminus oriented toward the cytosol. The C-terminal region of DGAT1, which accounts for ϳ50% of the protein, is present in the endoplasmic reticulum lumen and contains a highly conserved histidine residue (His-426) that may be part of the active site. Mutagenesis of His-426 to alanine impaired the ability of DGAT1 to synthesize triacylglycerols as well as retinyl and wax esters in an in vitro acyltransferase assay. Finally, we show that the N-terminal domain of DGAT1 is not required for the catalytic activity of DGAT1 but, instead, may be involved in regulating enzyme activity and dimer/tetramer formation. Acyl coenzyme A:1,2-diacylglycerol acyltransferase (DGAT)2 is a membrane-bound enzyme that catalyzes the biosynthesis of triacylglycerols (TGs) (1). TGs are a class of neutral lipid that represents the major form of stored energy in eukaryotic organisms (2). However, excessive accumulation of TG in tissues can lead to obesity and insulin resistance, whereas increased TG in the blood is a risk factor for atherosclerosis (3)(4)(5).DGAT catalyzes the formation of an ester bond between a long chain fatty acid (fatty acyl coenzyme A (CoA)) and the free hydroxyl group of diacylglycerol (DG), generating TG. Two DGAT genes have now been identified, Dgat1 and Dgat2, which share no sequence homology. DGAT1 belongs to a large family of membrane-bound O-acyltransferases (MBOAT) that includes acyl-CoA:cholesterol acyltransferase-1 and -2 (ACAT-1 and -2), which catalyze cholesterol ester biosynthesis (6 -10). DGAT2 belongs to the DGAT2/acyl-CoA:monoacylglycerol acyltransferase gene family including monoacylglycerol acylCoA acyltransferases 1-3 and wax synthase (9, 11-16). Biochemical analyses have indicated that DGAT1 and DGAT2 have distinct roles in TG metabolism. When overexpressed in cells, DGAT2 yielded a much larger increase in intracellular triacylglycerol than DGAT1 (17). In in vitro assays, DGAT1, but not DGAT2, was capable of using a broad array of acyl acceptors to synthesize diacylglycerol, retinyl, and wax esters in addition to triacylglycerol (18).In vivo experiments in mice have also provided strong evidence that DGAT1 and DGAT2 do not serve redundant roles in lipid metabolism. Dgat1-deficient (Dgat1 Ϫ/Ϫ ) mice were viable with modest reductions in TG con...

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“…A working hypothesis is that following an oral fat load, CD36-rich membrane vesicles help shuttle FAs to ER enzymes required for TAG synthesis (Figure 8). For example Dgat1 (28) has been postulated to localize on the luminal side of the ER (29), and FA delivery to Dgat1 and other esterification enzymes could become limiting.…”

Section: Figurementioning

confidence: 99%

CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood

Drover

Ajmal²,

Nassir³

et al. 2005

J. Clin. Invest.

219

100

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CD36 mediates the transfer of fatty acids (FAs) across the plasma membranes of muscle and adipose cells, thus playing an important role in regulating peripheral FA metabolism in vivo. In the proximal intestine, CD36 is localized in abundant quantities on the apical surface of epithelial cells, a pattern similar to that of other proteins implicated in the uptake of dietary FAs. To define the role of CD36 in the intestine, we examined FA utilization and lipoprotein secretion by WT and CD36-null mice in response to acute and chronic fat feeding. CD36-null mice given a fat bolus by gavage or fed a high-fat diet accumulated neutral lipid in the proximal intestine, which indicated abnormal lipid processing. Using a model in which mice were equipped with lymph fistulae, we obtained evidence of defective lipoprotein secretion by directly measuring lipid output. The secretion defect appeared to reflect an impaired ability of CD36-null enterocytes to efficiently synthesize triacylglycerols from dietary FAs in the endoplasmic reticulum. In the plasma of intact mice, the reduced intestinal lipid secretion was masked by slow clearance of intestine-derived lipoproteins. The impaired clearance occurred despite normal lipoprotein lipase activity and likely reflected feedback inhibition of the lipase by FAs due to their defective removal from the plasma. We conclude that CD36 is important for both secretion and clearance of intestinal lipoproteins. CD36 deficiency results in hypertriglyceridemia both in the postprandial and fasting states and in humans may constitute a risk factor for diet-induced type 2 diabetes and cardiovascular disease.

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Inhibition of carnitine palmitoyltransferase in the rat small intestine reduces export of triacylglycerol into the lymph

Cited by 27 publications

References 51 publications

The effect of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex

The effect of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex

Topological Orientation of Acyl-CoA:Diacylglycerol Acyltransferase-1 (DGAT1) and Identification of a Putative Active Site Histidine and the Role of the N Terminus in Dimer/Tetramer Formation

CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood

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