Rate-limiting function of 3-hydroxy-3-methylglutaryl-coenzyme A synthase in ketogenesis

Dashti, Nassrin; Ontko, Joseph A.

doi:10.1016/0006-2944(79)90024-3

Cited by 61 publications

(30 citation statements)

References 24 publications

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“…In liver, this reaction occurs in 2 essentially different pathways: (1) the production of mevalonate from HMG-CoA before the synthesis of sterols and isoprenoids of various functions; and (2) the conversion of HMG-CoA into acetoacetate and then into other related compounds by means of the ketogenetic pathway that occurs in mitochondria. 43 Mitochondrial HMG-CoA synthase has been assumed to be the rate-limiting enzyme of ketogenesis. 43 The elongation, incorporation into complex lipids, or degradation of very long chain fatty acids requires the activation of these compounds to their CoA thioesters by enzymes including mitochondrial 3-oxoacyl-CoA thiolase and long chain acyl-CoA synthetase (an enzyme that converts the free long-chain fatty acids into fatty acid CoA esters), which are key intermediates in the synthesis of complex lipids such as triglycerides, phospholipids, and cholesterol esters.…”

Section: Discussionmentioning

confidence: 99%

“…43 Mitochondrial HMG-CoA synthase has been assumed to be the rate-limiting enzyme of ketogenesis. 43 The elongation, incorporation into complex lipids, or degradation of very long chain fatty acids requires the activation of these compounds to their CoA thioesters by enzymes including mitochondrial 3-oxoacyl-CoA thiolase and long chain acyl-CoA synthetase (an enzyme that converts the free long-chain fatty acids into fatty acid CoA esters), which are key intermediates in the synthesis of complex lipids such as triglycerides, phospholipids, and cholesterol esters. The relative abundance of mRNA transcripts for these genes were 4.8-to 2.1-fold less in subjects with cirrhosis secondary to NASH when compared with controls.…”

Section: Discussionmentioning

confidence: 99%

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Hepatic Gene Expression in Histologically Progressive Nonalcoholic Steatohepatitis

et al. 2003

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Although the molecular basis for the pathophysiology of nonalcoholic steatohepatitis (NASH) is poorly understood, insulin resistance and mitochondrial dysfunction are physiologic hallmarks of this condition. We sought evidence of a transcriptional or pretranscriptional basis for insulin resistance and mitochondrial dysfunction through measurement of hepatic gene expression (messenger RNA [mRNA]) using high-density synthetic oligonucleotide microarray analysis (Hu6800 GeneChip, Affymetrix, CA). Global hepatic gene expression was determined in snap-frozen liver biopsy specimens from 4 groups: (1) patients with cirrhotic-stage NASH (n ‫؍‬ 6), (2) patients with cirrhosis caused by hepatitis C virus (HCV) (n ‫؍‬ 6), (3) patients with cirrhosis secondary to primary biliary cirrhosis (PBC) (n ‫؍‬ 6), and (4) healthy controls (n ‫؍‬ 6). Genes were considered to be expressed differentially in NASH only if there was a greater than 2-fold difference in abundance of mRNA when compared with each of the control groups. Sixteen genes were uniquely differentially expressed (4 overexpressed and 12 underexpressed) in patients with cirrhotic-stage NASH. Genes that were significantly underexpressed included genes important for maintaining mitochondrial function (copper/zinc superoxide dismutase, aldehyde oxidase, and catalase). Glucose 6-phospatase, alcohol dehydrogenase, elongation factor-TU, methylglutaryl coenzyme A (CoA), acyl CoA synthetase, oxoacyl CoA thiolase, and ubiquitin also were underexpressed in NASH. Genes that were overexpressed in NASH included complement component C3 and hepatocyte-derived fibrinogen-related protein, potentially contributing to impaired insulin sensitivity. In conclusion, these studies provide evidence for a transcriptional or pretranscriptional basis for impaired mitochondrial function (attenuated capacity for the dismutation of reactive oxygen species) and diminished insulin sensitivity (increased acute phase reactants) in patients with histologically progressive NASH. Further studies are required to determine the mechanism and the physiologic significance of these findings. (HEPATOLOGY 2003;38:244-251.)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hepatic Gene Expression in Histologically Progressive Nonalcoholic Steatohepatitis

et al. 2003

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“…Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase is a potential regulatory site in the pathway converting acetyl-CoA to ketone bodies [1][2][3]. In rats, hepatic ketogenic capacity increases rapidly during postnatal development [4] or fasting [5], when the liver mRNA, protein and activity of mitochondrial HMG-CoA synthase increase [6][7][8][9][10][11].…”

Section: Gene Expression Of Mitochondrial 3-hydroxy-3-methylglutaryl-mentioning

confidence: 99%

Gene expression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in a poorly ketogenic mammal: effect of starvation during the neonatal period of the piglet

Adams

Alho

Asins

et al. 1997

Biochemical Journal

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The low ketogenic capacity of pigs correlates with a low activity of mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase. To identify the molecular mechanism controlling such activity, we isolated the pig cDNA encoding this enzyme and analysed changes in mRNA levels and mitochondrial specific activity induced during development and starvation. Pig mitochondrial synthase showed a tissue-specific expression pattern. As with rat and human, the gene is expressed in liver and large intestine; however, the pig differs in that mRNA was not detected in testis, kidney or small intestine. During development, pig mitochondrial HMG-CoA synthase gene expression showed interesting differences from that in the rat: (1) there was a 2–3 week lag in the postnatal induction; (2) the mRNA levels remained relatively abundant through the suckling–weaning transition and at maturity, in contrast with the fall observed in rats at similar stages of development; and (3) the gene expression was highly induced by fasting during the suckling, whereas no such change in mitochondrial HMG-CoA synthase mRNA levels has been observed in rat. The enzyme activity of mitochondrial HMG-CoA synthase increased 27-fold during starvation in piglets, but remained one order of magnitude lower than rats. These results indicate that post-transcriptional mechanism(s) and/or intrinsic differences in the encoded enzyme are responsible for the low activity of pig HMG-CoA synthase observed throughout development or after fasting.

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“…The amount of [2,3-''C]succinyl-enzyme is expressed as mol succinyl group bound/mol synthase dimer (Mr approximately 100000) with the assumption that only protein displaying enzymic activity immediately before treatment would be succinylated. Values are means from two sets of experiments inactivate endogenous HMG-CoA synthase [29], to demonstrate that rat liver extracts do not prevent desuccinylation of the enzyme. The extracts were prepared from either control or glucagon-treated rats; no difference between these extracts was observed.…”

Section: Assays Of Hmc-coa Synthase Activity Succinyl-enzyme Succinmentioning

confidence: 99%

Glucagon activates mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase in vivo by decreasing the extent of succinylation of the enzyme

Quant

Tubbs

Brand

1990

European Journal of Biochemistry

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1. 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (EC 4.1.3.5) in extracts of rat liver mitochondria can be inactivated by succinyl-CoA and activated by incubation in a medium designed to cause desuccinylation ('desuccinylation medium'). 2. The enzyme is less active in extracts of whole liver from control rats than from rats treated with glucagon or mannoheptulose. Incubation in desuccinylation medium raises the activity in extracts from control rats to the same value as treated rats, suggesting that the extent of succinylation in vivo is greater in controls than in hormone-treated animals. 3. This result is also obtained in liver homogenates and in isolated mitochondria. 4. Increasing the succinyl-CoA content of mitochondria to the same high level lowers the enzyme activity to the same value in mitochondria isolated from control or treated rats. In each case subsequent incubation of the lysates in desuccinylation medium raises the enzyme activity by the same extent. 5. Measurement of the incorporation of radiolabel from 2-o~o[S-'~C]glutarate into protein is consistent with the proposal that all these changes in activity in isolated mitochondria may be explained by changes in the extent of succinylation of the enzyme. 6. From these data and our earlier work we conclude that, in vivo, mitochondrial HMG-CoA synthase in fed rats is normally substantially succinylated (about 40%) and inactivated, and that glucagon increases the activity of HMG-CoA synthase by lowering the concentration of succinyl-CoA and thus decreasing the extent of succinylation of the enzyme (to less than 30%). This may be an important control mechanism in ketogenesis.The control of ketogenesis in liver is not fully understood [I -31 but it is clear that the production of ketone bodies can be stimulated by treatment of animals with glucagon [4-91. Although there is good evidence that some control of ketogenic flux is exerted at carnitine palmitoyltransferase I [3, 9 -121, there is also strong evidence that under certain conditions control shifts to an unidentified intramitochondrial control site [13-201. On the basis of experiments in vitro with mitochondrial HMG-CoA synthase purified from ox liver, Lowe and Tubbs [21] proposed that glucagon might increase ketogenic flux through the HMG-CoA pathway by lowering the succinylCoA concentration and therefore the succinylation state of HMG-CoA synthase.In support of this hypothesis we have observed increased HMG-CoA synthase activity and decreased intramitochondrial succinyl-CoA levels in extracts prepared from rapidly frozen livers of rats after short-term treatment with glucagon or mannoheptulose. These effects persisted in isolated mitochondria, validating their use as a model system in which to examine the effects of hormones on HMG-CoA synthase. We also showed that succinyl-CoA inhibited HMG-CoA synthase activity in isolated mitochondria and that the differences in the activity of the enzyme in mitochondria isolated from glucagon-treated or mannoheptulose-treated rats and shamCorrespondence ...

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Rate-limiting function of 3-hydroxy-3-methylglutaryl-coenzyme A synthase in ketogenesis

Cited by 61 publications

References 24 publications

Hepatic Gene Expression in Histologically Progressive Nonalcoholic Steatohepatitis

Hepatic Gene Expression in Histologically Progressive Nonalcoholic Steatohepatitis

Gene expression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in a poorly ketogenic mammal: effect of starvation during the neonatal period of the piglet

Glucagon activates mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase in vivo by decreasing the extent of succinylation of the enzyme

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