Disease relevance of Me1

• We have identified and characterized lambda bacteriophage clones containing genomic DNA encoding rat malic enzyme [(S)-malate:NADP+ oxidoreductase (oxaloacetate-decarboxylating); EC 1.1.1.40] [1].
• Dehydroepiandrosterone (DHEA), a naturally occurring steroid secreted from the adrenal, has been reported to decrease the body weight gain in rodents without suppressing food intake and to stimulate malic enzyme activity in liver (Tepperman, H. M., de la Garza, S. A., and Tepperman, J. (1968) Am. J. Physiol. 214, 1126-1132) [2].
• In this report we have studied insulin regulation of malic enzyme (ME) gene transcription in rat H-35 hepatoma cells and localized the insulin-responsive region of the ME promoter between positions -177 and -102 [3].
• The hypersensitivity results confirm that thyroid hormone stimulation of malic enzyme synthesis occurs in part at the level of transcription, and localization of malic enzyme gene expression suggests this stimulation is accompanied by recruitment of hepatocytes [4].
• The relative level of incorporation of radiolabeled amino acid into malic enzyme was determined by immunoprecipitation with antibody to malic enzyme and formaldehyde-fixed Staphylococcus aureus (Cowens I strain) as an immunoadsorbent [5].

Psychiatry related information on Me1

• Our data suggest that during the initial critical period of brain maturation, malic enzyme is under the control of thyroid hormones [6].

High impact information on Me1

• Response of hepatic mitochondrial alpha-glycerophosphate dehydrogenase and malic enzyme to constant infusions of L-triiodothyronine in rats bearing the Walker 256 carcinoma. Evidence for divergent postreceptor regulation of the thyroid hormone response [7].
• Thyroid hormone-carbohydrate interaction in the rat: correlation between age-related reductions in the inducibility of hepatic malic enzyme by triiodo-L-thyronine and a high carbohydrate, fat-free diet [8].
• Glucose and triiodothyronine both induce malic enzyme in the rat hepatocyte culture: evidence that triiodothyronine multiplies a primary glucose-generated signal [9].
• Enzymes studied included malic enzyme (ME), fatty acid synthetase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase [10].
• Experiments were designed to analyze the relationship of a single i.v. dose of triiodothyronine (T3), the level of plasma and hepatic nuclear T3 attained, and the tissue response as reflected in increased activity of hepatic mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) and cytosol "malic enzyme" (ME) [11].

Chemical compound and disease context of Me1

• Mitochondrial malic enzymes. Mitochondrial NAD(P)+-dependent malic enzyme activity and malate-dependent pyruvate formation are progression-linked in Morris hepatomas [12].
• T3-dependent estrogen responses measured were antagonism of T3-evoked increases in pituitary GH, body weight, tibia length and hepatic malic enzyme, and increases in serum triglycerides [13].
• In both normal and diabetic rats, AR administration decreased food consumption, weight gain and blood glucose concentration, and increased liver weight, liver:body weight ratio, total liver lipid, liver protein and malic enzyme (ME) activity [14].
• 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 [15].
• 2. Phenotype effects (obese greater than lean) were present for weight gain, adiposity, serum glycemic and lipid parameters, and for liver glucokinase, glucose-6-phosphate dehydrogenase, and malic enzyme activity [16].

Biological context of Me1

• S1 nuclease and primer-extension assays showed that transcription of the malic enzyme gene initiates at multiple sites, the strongest one at position -31 relative to the ATG. "TATA and CCAAT box" homologies are not present in the proximal promoter region [1].
• Kinetics of induction by thyroid hormone of the two hepatic mRNAs coding for cytosolic malic enzyme in the hypothyroid and euthyroid states. Evidence against an obligatory role of S14 protein in malic enzyme gene expression [17].
• Coding nucleotide sequence of rat liver malic enzyme mRNA [18].
• The putative NADP-binding site for malic enzyme was identified by amino acid sequence homology with the NADP-binding site of the enoyl reductase domain of fatty acid synthetase [18].
• Stimulation of hepatic mitochondrial alpha-glycerophosphate dehydrogenase and malic enzyme by L-triiodothyronine. Characteristics of the response with specific nuclear thyroid hormone binding sites fully saturated [11].

Anatomical context of Me1

• We have stimulated in a cultured hepatocyte system the synergistic interaction between triiodothyronine (T3) and dietary carbohydrate in the induction of malic enzyme (ME) [9].
• CONCLUSIONS: Neoplastic cells acquire a growth advantage by their capacity to synthesize cholesterol and obtain reduced nicotinamide adenine dinucleotide phosphate by the malic enzyme pathway when G6PD activity is inhibited by peroxisome proliferators [19].
• Since thyroid hormones regulate liver malic enzyme synthesis predominantly at the nuclear level and carbohydrates at the cytoplasmic level, the additive effect of triiodothyronine and a high carbohydrate diet on the activity of malic enzyme is readily explicable [20].
• Regulation of malic enzyme by carbohydrates is liver-specific, since no response is observed in the following nonhepatic tissues: brain, heart, spleen, kidney, testis, and lung [20].
• These results indicate that the maintenance of pyridine nucleotides in their reduced form by malic enzyme is responsible for the lack of t-butyl hydroperoxide-induced Ca2+ efflux by tumor mitochondria respiring on succinate [21].

Associations of Me1 with chemical compounds

• In rat liver, triiodothyronine (T3) and dietary carbohydrate induce the expression of the genes coding for malic enzyme (ME) (EC 1.1.1.40) and S14 protein [17].
• When fed to rats it induces the thermogenic enzymes mitochondrial sn-glycerol-3-phosphate dehydrogenase and cytosolic malic enzyme in their livers [22].
• Here we show that cultured cerebellar granule neurons form releasable [(14)C]glutamate from H(14)CO(3)(-) and [1-(14)C]pyruvate via pyruvate carboxylation, probably mediated by malic enzyme [23].
• Underlying this change is a generalized induction of the enzymes involved in lipogenesis, including glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malic enzyme, which together serve to generate the additional NADPH required for increased fatty acid synthesis [24].
• This report presents evidence indicating that induction of the hexose-shunt dehydrogenases involves increased enzyme synthesis secondary to elevated enzyme specific mRNA levels, as has previously been shown for malic enzyme [24].

Regulatory relationships of Me1

• However, insulin but not IGF-I induced the expression of the lipogenic marker malic enzyme, suggesting that IGF-I but not insulin is involved in the thermogenic differentiation process of fetal brown adipocytes [25].
• We examined the effect of clofibrate (fibrate derivative) administration for 14 days to rats on malic enzyme (as an adequate control of fibrates action) and leptin mRNAs level in the white and brown adipose tissues (WAT and BAT, respectively) [26].

Other interactions of Me1

• As a control, we examined the effect of a high carbohydrate diet which is known to increase malic enzyme mRNA without affecting either transcriptional rate or nuclear RNA (Dozin, B., Rall, J. E., and Nikodem, V. M. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 4705-4709) [27].
• Insulin-induced early growth response gene (Egr-1) mediates a short term repression of rat malic enzyme gene transcription [3].
• In this study we investigated the effect of GH and IGF-I on the metabolic response of T3 in target tissues by evaluating the activity of two T3-dependent liver enzymes: mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) and cytosolic malic enzyme (ME) in rat hepatocytes in primary culture [28].
• A single low dose of triiodothyronine induces rapid increases in cytochrome-c1 and ANT2 mRNA species which parallel changes in the activity of the hormone-responsive malic enzyme, but are earlier than other mitochondrial biogenetic events [29].
• However, dietary levan did not affect the gene expression of hepatic malic enzyme, phosphatidate phosphohydrolase and HMG CoA reductase [30].

Analytical, diagnostic and therapeutic context of Me1

• A malic enzyme specific radioimmunoassay confirmed this [31].
• Slight additional purification of malic enzyme was achieved with preparative disc electrophoresis [32].
• Molecular cloning of a cDNA sequence for rat malic enzyme. Direct evidence for induction in vivo of rat liver malic enzyme mRNA by thyroid hormone [33].
• We further characterized expression of the malic enzyme gene as a function of thyroidal state by localizing malic enzyme mRNA in hepatocytes using in situ hybridization histochemistry [4].
• Crystallization of an NADP+-dependent malic enzyme from rat liver [34].

References