Molecular cloning of rat mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase and detection of the corresponding mRNA and of those encoding the remaining enzymes comprising the ketogenic 3-hydroxy-3-methylglutaryl-CoA cycle in central nervous system of suckling rat

Cullingford, E. Tim; Dolphin, T. Colin; Bhakoo, Kishore; Peuchen, S; Canevari, Laura; Clark, Benjamin R.

doi:10.1042/bj3290373

Cited by 49 publications

(32 citation statements)

References 44 publications

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“…Similar to the short-term infusion conditions reported in Table 1, only small amounts of 3 H dpm were found, 97 Ϯ 1 dpm in the etomoxir infused group and 122 Ϯ 1 dpm in the control group as compared with 1.7 ϫ 10 6 dpm and 1.2 ϫ 10 6 dpm in the chloroform phase of the extract, respectively. These data suggest either that the products of FA metabolism are rapidly removed from the enterocyte or FA is poorly metabolized in enterocytes (41,42).…”

Section: Resultsmentioning

confidence: 91%

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

Washington

Cook

Mansbach

2003

Journal of Lipid Research

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Following digestion of dietary triacylglycerol (TAG), intestinal epithelial cells absorb fatty acids and monoacylglycerols that are resynthesized into TAG by enzymes located on the endoplasmic reticulum (ER).The intestinal epithelial absorptive cell has little control over the rate of entry of the absorbed products of lipid digestion, fatty acids (FAs) and monoacylglycerols (MAGs). These must be disposed of rapidly, otherwise the cells risk destruction of their cellular membranes. The enterocytes are able to store some of the FA (and MAG) bound to liver FA binding protein (L-FABP), which is expressed in the intestine (1). Most of the remainder is rapidly resynthesized into triacylglycerol (TAG) (2). The synthetic steps take place on the membrane of the endoplasmic reticulum (ER), which is the site of the neutral lipid acyl transferases. Exactly on which face of the ER membrane the last enzyme in this pathway, diacylglycerol acyltransferase (DGAT) [which acylates diacylglycerol (DAG) to TAG], exists is controversial.A pathway for the synthesis of TAG within the lumen of the ER of liver cells, presumably leading to the synthesis of VLDL particles, has been identified that utilizes cytosolic TAG and acyl-CoA to produce TAG within the ER lumen. The ER lumenal TAG was found to consist of two acyl groups from the cytosolic TAG and one acyl group from cytosolic FA-CoA (3). This pathway of intralumenal ER synthesis of TAG was shown to be carnitine dependent and was inhibited by glybenclamide, a potent inhibitor of carnitine acyltransferase (3). These investigators predicted the existence of a lipase outside the ER and a second DGAT within the hepatic ER lumen. A lipase is known to exist in intestinal cytosol (4), and two DGATs have recently been identified in the intestine by Farese's laboratory (5, 6).Studies in liver by Coleman and Bell (7,8) showed that DGAT was on the cytosolic face of the ER, as suggested by protease digestion experiments with and without ER membrane permeation. These studies were later challenged by Saggerson and by Zammit, who found that only on liver ER membrane disruption could the full activity of DGAT be expressed (9-11), suggesting that DGAT was in part a latent enzyme; that is, in order for full activity to be

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Section: Resultsmentioning

confidence: 91%

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

Washington

Cook

Mansbach

2003

Journal of Lipid Research

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“…The HMGCS2 gene is also expressed in extrahepatic tissues. In rats, HMGCS2 is expressed in testis, ovary, intestine, kidney, brain, colon, and lymphocytes (6,7,(17)(18)(19). In humans, expression has been reported in liver, skeletal muscle, heart, pancreas, testis, and colon (20).…”

Section: Introductionmentioning

confidence: 99%

Ketogenic HMGCS2 Is a c-Myc Target Gene Expressed in Differentiated Cells of Human Colonic Epithelium and Down-Regulated in Colon Cancer

Camarero

Mascaró

Mayordomo

et al. 2006

Molecular Cancer Research

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HMGCS2, the gene that regulates ketone body production, is expressed in liver and several extrahepatic tissues, such as the colon. In CaCo-2 colonic epithelial cells, the expression of this gene increases with cell differentiation. Accordingly, immunohistochemistry with specific antibodies shows that HMGCS2 is expressed mainly in differentiated cells of human colonic epithelium. Here, we used a chromatin immunoprecipitation assay to study the molecular mechanism responsible for this expression pattern. The assay revealed that HMGCS2 is a direct target of c-Myc, which represses HMGCS2 transcriptional activity. c-Myc transrepression is mediated by blockade of the transactivating activity of Miz-1, which occurs mainly through a Sp1-binding site in the proximal promoter of the gene. Accordingly, the expression of human HMGCS2 is down-regulated in 90% of Myc-dependent colon and rectum tumors. HMGCS2 protein expression is down-regulated preferentially in moderately and poorly differentiated carcinomas. In addition, it is also down-regulated in 80% of small intestine Myc-independent tumors. Based on these findings, we propose that ketogenesis is an undesirable metabolic characteristic of the proliferating cell, which is down-regulated through c-Myc-mediated repression of the key metabolic gene HMGCS2.

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“…thermo.) [47] ; ACC human [117] ; ACC S. cerevisiae [118] ; ACC E. coli [119] ; CPS E. coli [120], CPS S. cerevisiae [121] ; transcarboxylase (TC), 5 S subunit [122] and 1.3 S subunit [123] of P. shermanii ; ODCα (oxaloacetate decarboxylase α-subunit) Klebsiella pneumoniae [124] ; ODCα Salmonella typhimurium [125] ; PCCα (PCC α-subunit) human [126] ; 3-hydroxyl-3-methylglutaryl-CoA lyase (HMG-lyase) rat (Rattus norvegicus) [127] ; HMG-lyase chicken (Gallus gallus) [128].…”

Section: Figure 1 Multiple Sequence Alignment Of Pc With Other Biotinmentioning

confidence: 99%

Structure, function and regulation of pyruvate carboxylase

Jitrapakdee

Wallace

1999

Biochemical Journal

183

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Pyruvate carboxylase (PC; EC 6.4.1.1), a member of the biotin-dependent enzyme family, catalyses the ATP-dependent carboxylation of pyruvate to oxaloacetate. PC has been found in a wide variety of prokaryotes and eukaryotes. In mammals, PC plays a crucial role in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitter substances, and in glucose-induced insulin secretion by pancreatic islets. The reaction catalysed by PC and the physical properties of the enzyme have been studied extensively. Although no high-resolution three-dimensional structure has yet been determined by X-ray crystallography, structural studies of PC have been conducted by electron microscopy, by limited proteolysis, and by cloning and sequencing of genes and cDNA encoding the enzyme. Most well characterized forms of active PC consist of four identical subunits arranged in a tetrahedron-like structure. Each subunit contains three functional domains: the biotin carboxylation domain, the transcarboxylation domain and the biotin carboxyl carrier domain. Different physiological conditions, including diabetes, hyperthyroidism, genetic obesity and postnatal development, increase the level of PC expression through transcriptional and translational mechanisms, whereas insulin inhibits PC expression. Glucocorticoids, glucagon and catecholamines cause an increase in PC activity or in the rate of pyruvate carboxylation in the short term. Molecular defects of PC in humans have recently been associated with four point mutations within the structural region of the PC gene, namely Val145 → Ala, Arg451 → Cys, Ala610 → Thr and Met743 → Thr.

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Molecular cloning of rat mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase and detection of the corresponding mRNA and of those encoding the remaining enzymes comprising the ketogenic 3-hydroxy-3-methylglutaryl-CoA cycle in central nervous system of suckling rat

Cited by 49 publications

References 44 publications

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

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

Ketogenic HMGCS2 Is a c-Myc Target Gene Expressed in Differentiated Cells of Human Colonic Epithelium and Down-Regulated in Colon Cancer

Structure, function and regulation of pyruvate carboxylase

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