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PubMed1981

The role of dietary protein in hepatic lipogenesis in the young rat.

1. The effect of varying dietary levels of casein (40-140 g/kg) on hepatic lipogenesis and the levels of hepatic fatty acid synthetase (FAS), glucose-6-phosphate dehydrogenase (EC 1.1.1.49; G6PD), malic enzyme (EC 1.1.1.40; ME), citrate cleavage enzyme (EC 4.1.3.8; CCE), acetyl CoA carboxylase (EC 6.4.1.2; AcCx), glucokinase (EC 2.7.1.2; GK), and pyruvate dehydrogenase (PDH) was examined in young, growing rats. 2. The activities of AcCx, FAS, G6PD and in vivo fatty acid synthesis were generally found to increase with increased dietary protein. 3. The levels of GK and PDH were not related to dietary protein. 4. ME decreased with increasing dietary protein. 5. The results demonstrate a dissociation between hepatic fatty acid synthesis and ME and suggest that when rats consume low-protein diets the NADPH needed for fatty acid synthesis is generated primarily by ME but that as the level of dietary protein is increased the contribution of ME is reduced while that of the phosphogluconate pathway becomes more important.

ATP Citrate (pro-S)-Lyase↗

PubMed1984

Hepatic lipogenesis in young rats given proteins of different quality.

The effect of feeding casein, lactalbumin, soya-bean protein, gluten or gelatin on hepatic lipogenesis and the levels of hepatic fatty acid synthetase (FAS), glucose-6-phosphate dehydrogenase (EC 1.1.1.49; G6PD), malic enzyme (EC 1.1.1.40; ME) ATP-citrate lyase (EC 4.1.3.8; CL), acetyl CoA carboxylase (EC 6.4.1.2; ACCx) and glucokinase (EC 2.7.1.2; GK) was examined in young growing rats. The total activities of ACCx, FAS, CL, GK, G6PD, GK, ME and fatty acid synthesis in vivo were positively correlated with protein quality. The specific activities of ACCx, FAS, CL, G6PD and fatty acid synthesis in vivo were positively correlated with protein quality. The specific activities of GK and ME were unrelated to protein quality. The results demonstrate a dissociation between ME and hepatic lipogenesis and suggest a role for the NADPH generated by ME which is not related to the needs of fatty acid synthesis.

Animals↗

PubMed2005

Cloning and characterization of a gene encoding a malic enzyme involved in anaerobic growth in Mucor circinelloides.

A 3193 bp contiguous sequence has been cloned from the oleaginous fungus Mucor circinelloides, that contains a full-length gene encoding a putative NADP+: dependent malic enzyme (EC. 1.1.1.40). The cloned DNA contains a 2154 bp putative open reading frame containing five introns and encoding a protein of 616 amino acids. The gene encoded what appeared to be an anaerobic isoform of malic enzyme (isoform II); this conclusion is supported by transcript analysis and by the fact that the ORF contains an N-terminal mitochondrial target sequence (a similar cellular location was identified for the anaerobic malic enzyme in Saccharomyces cerevisiae; Boles et al. 1998). The cloned gene did not encode either isoform III (the isoform associated with active growth) or isoform IV (associated with lipid accumulation) previously identified. M. circinelloides therefore must possess (at least) two structural genes for malic enzyme.

Anaerobiosis↗

PubMed1994

Plant mitochondrial NAD+-dependent malic enzyme. cDNA cloning, deduced primary structure of the 59- and 62-kDa subunits, import, gene complexity and expression analysis.

The 59- and 62-kDa subunits of the mitochondrial NAD+-dependent malic enzyme (EC 1.1.1.39) were purified from Solanum tuberosum L. (potato). NH2-terminal and internal amino acid sequence information was used to identify cDNAs encoding the two subunits. Comparison of the nucleotide sequences revealed that the subunits have 60% identity at the DNA level and 65% identity at the deduced amino acid level, implying that they are derived from a common ancestral gene. The plant NAD+-dependent malic enzymes belong to a family of related enzymes, including cytosolic and chloroplastic NADP+-dependent malic enzymes (EC 1.1.1.40) and bacterial NAD+-dependent malic enzymes (EC 1.1.1.38). The cDNAs were transcribed and translated in vitro and the resultant polypeptides imported into isolated mitochondria and shown to be processed. Southern blot analysis of potato genomic DNA revealed a simple pattern of hybridization for both subunits, indicating a simple gene structure or small number of genes encoding the two subunits. Northern blot analysis of RNA from a range of potato tissues has shown that the steady state levels for the two subunits are equivalent, suggesting that they are coordinately expressed.

Amino Acid Sequence↗

PubMed1980

Regulation of hepatic lipogenesis by dietary maize oil or tripalmitin in the meal-fed mouse.

1. The effect of varying dietary levels of maize oil and tripalmitin (0--250 g fat/kg) on hepatic lipogenesis and the levels of hepatic fatty acid synthetase (FAS), glucose-6-phosphate dehydrogenase (EC 1.1.1.49; G6PD), malic enzyme (EC 1.1.1.38, 1.1.1.39, 1.1.1.40; ME) and glucokinase (EC 2.7.1.2; GK) was examined in meal-fed mice. 2. Meal-fed mice compared to mice fed ad lib. show enhanced hepatic lipogenesis as demonstrated by an increased rate of in vivo fatty acid synthesis and increased levels of FAS, ME and G6PD. The level of GK in meal-fed mice was unchanged by meal feeding. 3. Maize oil more effectively reduced in vivo hepatic lipogenesis than tripalmitin in meal-fed mice. 4. Maize oil more effectively reduced the hepatic levels of FAS, G6PD, ME and GK than tripalmitin in meal-fed mice. 5. The increased inhibition by maize oil observed at all levels of fat in the diet investigated and has been shown not to be due to decreased carbohydrate intake nor to differences between the absorption of maize oil and tripalmitin.

Animals↗

PubMed1998

Effect of the source of dietary fat on postweaning lipogenesis in lean and fat pigs.

Twenty-four male piglets weaned after 21 days, 12 of the Large White lean breed (LW) and 12 of the Alentejano fat breed (AL), have been used to compare the effects of genotype and source of dietary fat on the activities of enzymes involved in lipogenesis and on the composition of selected fatty tissues. During 4 weeks the piglets were fed isoenergetic and isonitrogenous experimental diets, containing 5 % of either olive oil or tallow. In AL piglets the acetylcoenzyme A carboxylase activity was three- and ninefold higher, the malic enzyme activity six- and fivefold, and the glucose-6-phosphate dehydrogenase activity was four- and fivefold higher in the dorsal subcutaneous and in the perirenal fat, respectively, than in LW piglets. In general, fatty tissues of the AL piglets contained a higher proportion of saturated fatty acids. Olive oil induced a significant increase in the activities of malic enzyme and glucose-6-phosphate dehydrogenase in both tissues, but only slightly increased the acetylcoenzyme A carboxylase activity in perirenal fatty tissues (p < 0.05). The fatty acid profile of the subcutaneous and of the perirenal fat was strongly affected by the composition of dietary fat. These observations showed that the source of dietary fat influenced markedly lipid metabolism and body composition since a very early age.

Acetyl-CoA Carboxylase↗

PubMed2002

Metabolic flux responses to pyruvate kinase knockout in Escherichia coli.

The intracellular carbon flux distribution in wild-type and pyruvate kinase-deficient Escherichia coli was estimated using biosynthetically directed fractional 13C labeling experiments with [U-13C6]glucose in glucose- or ammonia-limited chemostats, two-dimensional nuclear magnetic resonance (NMR) spectroscopy of cellular amino acids, and a comprehensive isotopomer model. The general response to disruption of both pyruvate kinase isoenzymes in E. coli was a local flux rerouting via the combined reactions of phosphoenolpyruvate (PEP) carboxylase and malic enzyme. Responses in the pentose phosphate pathway and the tricarboxylic acid cycle were strongly dependent on the environmental conditions. In addition, high futile cycling activity via the gluconeogenic PEP carboxykinase was identified at a low dilution rate in glucose-limited chemostat culture of pyruvate kinase-deficient E. coli, with a turnover that is comparable to the specific glucose uptake rate. Furthermore, flux analysis in mutant cultures indicates that glucose uptake in E. coli is not catalyzed exclusively by the phosphotransferase system in glucose-limited cultures at a low dilution rate. Reliability of the flux estimates thus obtained was verified by statistical error analysis and by comparison to intracellular carbon flux ratios that were independently calculated from the same NMR data by metabolic flux ratio analysis.

Allosteric Regulation↗

PubMed1978

Light modulation of the activity of carbon metabolism enzymes in the crassulacean Acid metabolism plant kalanchoë.

When intact Kalanchoë plants are illuminated NADP-linked malic dehydrogenase and three enzymes of the reductive pentose phosphate pathway, ribulose-5-phosphate kinase, NADP-linked glyceraldehyde-3-phosphate dehydrogenase, and sedoheptulose-1,7-diphosphate phosphatase, are activated. In crude extracts these enzymes are activated by dithiothreitol treatment. Light or dithiothreitol treatment does not inactivate the oxidative pentose phosphate pathway enzyme glucose-6-phosphate dehydrogenase. Likewise, neither light, in vivo, nor dithiothreitol, in vitro, affects fructose-1,6-diphosphate phosphatase. Apparently the potential for modulation of enzyme activity by the reductively activated light effect mediator system exists in Crassulacean acid metabolism plants, but some enzymes which are light-dark-modulated in the pea plant are not in Kalanchoë.

Journal Article↗

PubMed2006

Glycoprotein isolated from Acanthopanax senticosus protects against hepatotoxicity induced by acute and chronic alcohol treatment.

The protective effect of a 30 kDa glycoprotein (GF-AS) isolated from the stem bark of Acanthopanax senticosus against acute and chronic alcohol-induced hepatotoxicity were studied. N-terminal amino acid sequence of GF-AS showed NH(2)-Val-Ala-Tyr-Pro-Trp-Ala-Gly-Phe-Ala-Leu-Ser-Leu-Glx-Pro-Pro-Ala-Gly-Tyr-. GF-AS significantly increases the activities of alcohol-metabolizing enzymes, including alcohol dehydrogenase, microsomal ethanol metabolizing system, and acetaldehyde dehydrogenase in rats acutely treated with alcohol, resulting in decreased plasma alcohol levels. GF-AS also increases the activities of antioxidant enzymes and glutathione level. Markers of liver injury induced by alcohol: elevated serum levels of aspartate aminotransferase, alanine aminotransferase, triglyceride and cholesterol, are reduced by GF-AS in both acutely and chronically treated rats. The activities of lipogenic enzymes including malic enzyme, glucose-6-phosphate dehydrogenase, and 6-phosphoglucuronic acid dehydrogenase in chronic alcohol-treated rats are significantly decreased by GF-AS. Furthemore, GF-AS improves histological change in fatty liver and hepatic lesions induced by alcohol. Collectively, GF-AS may alleviate alcohol-induced hepatotoxicity through increasing ethanol and lipid metabolism, as well as antioxidant defense systems in livers injured by acute- and chronic-alcohol treatment.

Acute Disease↗

PubMed1986

Effect of the peroxisomal proliferator di(2-ethylhexyl)phthalate on component reactions of the rat hepatic microsomal fatty acid chain elongation system and on other hepatic lipogenic enzymes.

The feeding of 2% di(2-ethylhexyl)phthalate (DEHP) to rats increased the hepatic microsomal elongation of palmitoyl-CoA by about twofold, while those of palmitoleoyl-CoA and gamma-linolenoyl-CoA decreased to 83 and 63%, respectively, of the control values. When component reactions of the elongation pathway were measured, it was observed that only the activity of condensing enzyme was increased by twofold, while those of beta-ketostearoyl-CoA reductase, beta-hydroxypalmitoyl-CoA dehydrase, and trans-2-hexadecenoyl-CoA reductases were not affected. Furthermore, the time course for induction of both condensation and elongation of palmitoyl-CoA was similar. In vitro addition of DEHP had no effect on either condensation or elongation. Thus, these results indicate that the peroxisomal proliferator induces only the condensing enzyme which is the regulatory and rate-limiting step of elongation sequence. The DEHP treatment also markedly enhanced the cytosolic NADPH-generating activities of glucose-6-PO4 dehydrogenase (2.2-fold) and malic enzyme (7.3-fold). Unexpectedly, the activities of fatty acid synthetase and citrate cleavage enzyme were unaffected. These results are discussed in light of the fact that these lipogenic enzymes are coordinately induced by diet or hormones.

Acyl Coenzyme A↗

PubMed1993

Tumor-induced alterations in hepatic malic enzyme and carnitine palmitoyltransferase activity.

To better understand the role of the liver in the hypertriglyceridemia observed in a tumor-bearing state, we have examined tumor-induced alterations in hepatic lipogenesis and fatty acid oxidation. The effects of differing tumor burden as well as tumor excision on the activity and mRNA levels of malic enzyme and carnitine palmitoyltransferase were studied in Fisher 344 rats bearing a methylcholanthrene-induced sarcoma. Serum triacylglycerols and plasma nonesterified fatty acids (NEFA) levels were both elevated with increasing tumor burden (P < 0.05 vs control). The elevation disappeared with tumor removal. Malic enzyme activity of tumor bearers, compared with control rats, declined with an increase in tumor burden. These two variables were negatively correlated (r = -0.90, P < 0.01). The changes in activity were accompanied by positively correlated changes in mRNA levels (r = 0.73, P < 0.01). Carnitine palmitoyltransferase activity was not altered, even in the presence of a large tumor burden. Hepatic lipogenesis, reflected by malic enzyme activity, was tumor-dependent and was significantly reduced during the period of circulating hypertriglyceridemia. Fatty acid oxidation, reflected by carnitine palmitoyltransferase activity, was not enhanced in spite of an ample supply of NEFAs to the liver from the peripheral tissues. The data suggest that neither hepatic lipogenesis nor fatty acid oxidation contribute to hypertriglyceridemia in the tumor-bearing state.

Animals↗

PubMed1993

Cytosolic lipogenic enzymes: effect of fibric acid derivatives in vitro.

The effect of fibric acid derivatives, clofibric acid (CFB), bezafibrate (BFB), and gemfibrozil (GFB) on hepatic cytosolic enzymatic activities involved in saturated fatty acid synthesis has been estudied in vitro. From all the activities tested (fatty acid synthetase, acetyl-CoA carboxylase, ATP-citrate lyase, malic enzyme, malic dehydrogenase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase), only acetyl-CoA carboxylase and glucose-6-phosphate dehydrogenase were significantly inhibited by fibrates, with the following order of potency: GFB > BFB > > CFB. The characteristics of the inhibition phenomena (IC50, kinetic analysis, time and protein dependence, etc) and their transcendence to the effects of fibric acid derivatives in vivo are discussed.

Animals↗

PubMed1991

Genetic regulation of malic enzyme activity in the mouse.

Cytosolic malic enzyme catalyzes the NADP(+)-dependent oxidative decarboxylation of malate to pyruvate and CO2. Additionally, this enzyme produces large amounts of reducing equivalents (NADPH) required for de novo fatty acid synthesis and provides a precursor for oxaloacetate replacement in the mitochondria. Malic enzyme is considered a key lipogenic enzyme and changes in enzyme activity parallel changes in the lipogenic rate. As would be expected, the activity of malic enzyme responds to a variety of dietary and hormonal factors acting mainly on the rate of enzyme synthesis. In the mouse, the structural locus for malic enzyme (Mod-1) is located on chromosome 9. Two alleles reflecting differences in electrophoretic mobility have been identified. This report demonstrates that the amount of hepatic malic enzyme activity is strain-dependent and is regulated by a malic enzyme regulator locus (Mod1r) located on the proximal end of chromosome 12. Two alleles have been identified: Mod1ra, conferring high enzyme activity (C57BL/6J), and Mod1rb, conferring low enzyme activity (C57BL/KsJ). Biochemical studies have demonstrated differences in the apparent Km and Vmax and in specific activity on purification and immunoprecipitation, features that suggest changes in enzyme structure even though no differences were observed by electrophoresis and isoelectric focusing. These combined data suggest that differences in both enzyme quantity and structure may be involved in the genetic regulation of malic enzyme activity in mice.

Animals↗

PubMed2000

Effect of stationary phase hydrophobicity and mobile phase composition on the separation of carboxylic acids in ion chromatography.

In a previous work, we studied the retention behavior of monovalent and divalent carboxylic acids on a highly cross-linked polystryene-divinylbenzene anion-exchange column (IonPac AS4A-SC) using a carbonate-based buffer, and a retention model was applied to the chromatographic data obtained. In this work we characterized the retention of carboxylates (formic, acetic, propionic, lactic, pyruvic, oxalic, malonic, succinic, fumaric, maleic, tartaric, glutaric, adipic, malic, mucic, trans-beta-hydromuconic, trans,trans-muconic acids) on a column with higher hydrophilicity (IonPac AS11) according to analyte and stationary phase properties, using previously investigated eluent compositions and comparing the retention data obtained. Moreover, the effect of organic modifiers (CH3OH and CH3CN) in the eluent on the retention factors was also evaluated. The chromatographic data obtained on the IonPac AS11 column were fitted by the retention model and allowed one to obtain and to compare ion-specific selectivity constants (parameters of the model) with the ones obtained with the previous column.

Carboxylic Acids↗

PubMed1997

Effects of dietary fructose or glucose on triglyceride production and lipogenic enzyme activities in the liver of Wistar fatty rats, an animal model of NIDDM.

Effects of dietary carbohydrates on triglyceride production and hepatic lipogenic enzyme activities were examined in Wistar fatty rats, an animal model of noninsulin dependent diabetes mellitus, fed fructose or glucose and were compared with those of Wistar lean rats. Carbohydrates were supplied in 10% drinking solutions for 21 days. As compared with lean rats, Wistar fatty rats were characterized by hyperglycemia, hyperinsulinemia and hypertriglyceridemia, the last of which was associated with an increased hepatic activity of fatty acid synthetase and an increased rate of triglyceride secretion from the liver to the circulation. Feeding fructose to genetically obese diabetic rats produced a threefold increase in the hepatic activity of fatty acid synthetase, a twofold increase in NADPH-generating enzymes (malic enzyme and glucose-6-phosphate dehydrogenase) and a 56% increase in the rate of triglyceride secretion, with a resultant 86% increase in plasma triglyceride concentrations. Feeding glucose produced a similar increase in the activity of NADPH-generating enzymes and triglyceride production in the fatty liver but it differed in producing no change in plasma triglyceride concentrations or hepatic fatty acid synthetase activity. Neither dietary fructose nor glucose changed glycemia or insulinemia. These results show that in genetically obese, diabetic rats feeding fructose and glucose is associated with an increase in hepatic lipogenic enzyme activities and triglyceride production, and suggest that fructose stimulates triglyceride production but impairs triglyceride removal, whereas glucose stimulates both of them.

Animals↗

PubMed1994

Metabolism of malate in bovine adrenocortical mitochondria studied by 13C-NMR spectroscopy.

13C-NMR spectroscopy was used to study the metabolism of [13C]malate in bovine coupled adrenocortical mitochondria. The most apparent difference between the mitochondria from steroidogenic tissues and mitochondria from other tissues is the presence, in addition to the normal respiratory chain, of a second electron-transport system responsible for steroid hydroxylation. [13C]malate was synthesized from [13C]succinate by isolated adrenocortical mitochondria. The basic functional suspension consisted of oxygenated mitochondria to which were added ADP, inorganic phosphate (Pi) and [13C]malate, both in the absence or presence of the steroid substrate, deoxycorticosterone. These mitochondria synthesized [13C]citrate and [13C]pyruvate from [13C]malate. The 13C labeling of these two metabolites demonstrated an important role of the malic enzyme and the kinetics depended on the presence of the steroid substrate; the citric acid cycle was stopped during the hydroxylation pathway. The addition of cyanide, a strong inhibitor of the respiratory chain, confirmed an increased malic enzyme activity when hydroxylation occurred, since pyruvate was trapped by formation of a cyanohydrin. The relative enzymic activities of malic enzyme and isocitrate dehydrogenase were compared, both in the absence or presence of the steroid substrate, by supplementing the basic suspension with unlabeled exogenous metabolites, such as pyruvate or oxaloacetate.

Adrenal Cortex↗

PubMedDate not supplied

[Lipogenesis, aging and hormonal regulation].

Thyroid hormones stimulate hepatic synthesis of fatty acids as well as activities of lipogenic enzymes. According to the present study, there also partially exists an age dependency. In livers of 3- and 18-month-old rats of the Wistar strain both the velocity of fatty acid synthesis and the activities of lipogenic enzymes were measured in dependence on thyroid function. An impaired stimulation of malic enzyme activity under hyperthyreosis conditions was found in the older animals. The velocity of fatty acid synthesis was diminished in the group of 18-month-old rats, but there was no age dependence with respect of the effect of a variation in thyroid status. In the adipose tissue of the older animals, the activities of lipogenic enzymes were lowered. In this tissue no effects of thyreohormones in either young or old rats were observed.

ATP Citrate (pro-S)-Lyase↗

PubMed1985

Effects of growth hormone on lipogenic enzyme activities in cultured rat hepatocytes.

The presence of cloned methionyl human growth hormone at 1 microgram/ml medium for the final 5 days of a 6-day culture period decreased the activity of malic enzyme (EC 1.1.1.40) 45% from 202 to 112, fatty acid synthetase 52% from 26 to 12, and ATP citrate lyase (EC 4.1.3.8) 20% from 192 to 154 nmol NADPH.min-1.mg-1 supernatant protein in rat hepatocytes maintained in serum-free primary culture. Also, the activity of mitochondrial glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) decreased 52% from 20 to 9 nmol.min-1.mg-1 mitochondrial protein. In the same cells, no changes were observed in the activity of 6-phosphogluconate dehydrogenase (EC 1.1.1.44) and lactate dehydrogenase (EC 1.1.1.27). Glucose-6-phosphate dehydrogenase (EC 1.1.1.49) was increased 2.4-fold from 70 to 183 nmol.min-1.mg-1 protein, indicating the activity of this enzyme was paradoxically increased, whereas other enzymes involved in lipogenesis were decreased. Half-maximal decrease of malic enzyme activity and increase of glucose-6-phosphate dehydrogenase activity occurred at 10 and 3 ng methionyl human growth hormone per milliliter medium, respectively. These values are within the range of normal circulating growth hormone concentrations in the rat. The effects on malic enzyme and glucose-6-phosphate dehydrogenase appeared after 3-day exposure to growth hormone. These findings are consistent with the hypothesis that growth hormone antagonizes the action of agents that stimulate the activity of malic enzyme while concomitantly increasing the extractable activity of glucose-6-phosphate dehydrogenase.

ATP Citrate (pro-S)-Lyase↗