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1.
Coordinate control of rat liver lipogenic enzymes by insulin   总被引:4,自引:0,他引:4  
Recent evidence has established that insulin is required for the dietary induction of rat liver fatty acid synthetase [Proc. Nat. Acad. Sci. USA69, 3516 (1972)]. Since other hepatic lipogenic enzymes as well as fatty acid synthetase exhibit coordinate adaptation to nutritional changes [Advan. Enzyme Regul.10, 187(1972)], the role of insulin in the dietary induction of these enzymes has been investigated. When a high-carbohydrate, fat-free diet was fed to diabetic rats previously fasted for 48 hr, insulin was shown to be required for the dietary induction of acetyl-CoA carboxylase, citrate cleavage enzyme, malic enzyme, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, fatty acid synthetase, and glucokinase. Activity of serine dehydrase, selected as a model gluconeogenic enzyme, was increased in diabetic rats, whereas insulin treatment reduced the activity of this enzyme during the course of refeeding. The behavior of serine dehydrase was consistent with its gluconeogenic role. The activity of the cytosol isocitrate dehydrogenase did not change during refeeding in the diabetic or insulin-treated diabetic rat. Glucagon, the physiological antagonist of insulin, inhibited the increase in activity of each of the lipogenic enzymes requiring insulin for induction. Our results indicate that insulin is required for the coordinate regulation of the lipogenic enzymes of mammalian liver.  相似文献   

2.
Abstract— C6 glial cells in culture were utilized to study the regulation of the important lipogenic enzymes, fatty acid synthetase and acetyl-CoA carboxylase, and the synthesis of fatty acids and sterols. Regulation of these phenomena by lipid was demonstrated by the following observations. First, removal of serum from the culture medium was accompanied over the next five days by 2–3-fold increases in the lipogenic enzymatic activities and in 5–15-fold increases in rates of incorporation of acetate into fatty acids and sterols. Second, cells grown in delipidated serum exhibited approx 2-fold higher levels of activity of the lipogenic enzymes and 5–10-fold higher rates of synthesis of fatty acids and sterols than cells grown in normal calf serum. Third, cells grown in serum-free medium supplemented with concentrations of fatty acid comparable to those present in medium supplemented with serum exhibited activities of fatty acid synthetase comparable to those exhibited by cells grown in the serum-supplemented medium. The mechanism of these effects on fatty acid synthetase was shown by immunochemical techniques to involve alterations in content rather than in catalytic efficiency of the enzyme. The changes in content of the synthetase were caused by alterations in enzyme synthesis. In view of morphological and biochemical data suggesting that C6 cells are related to differentiating cells with properties of both astrocytes and oligodendroglia, the present data may indicate that regulation of palmitic acid synthesis by fatty acid or a product thereof occurs in brain during development.  相似文献   

3.
Fatty acid synthesis by subcellular fractions of heart and liver of chick embryos at varying stages of development has been studied. Fatty acid synthetase activity is associated with the embryonic heart at early stages of development, as suggested by substrate requirement, Schmidt decarboxylation of synthesized fatty acids and gas liquid chromatographic identification of the products as palmitic and stearic acids. The fatty acid synthetase activity decreases in heart cytosol with age of the embryo and is absent in the newly hatched chick and in older chicken. The acetyl CoA carboxylase activity is negligible in embryonic and adult chicken heart. The fatty acid synthetase activity in liver is low, but measurable during the entire embryonic development. The activity increases by about three-fold on hatching and thereafter in fed, newly hatched chicks by about 35-fold, over the basal embryonic activity. The acetyl and malonyl transacylase activities in the heart and liver cytosols during development followed closely the fatty acid synthetase activities in heart and liver, respectively. A non-coordinate induction of fatty acid synthetase and acetyl CoA carboxylase activities in liver was observed during development. The microsomal chain elongation in liver and heart followed the pattern of fatty acid synthetase activity in liver and heart, respectively. The mitochondrial chain elongation in embryonic heart is initially low and increases with age; while this activity in liver is higher in early stages of embryonic development than in the older embryos and the chicks. Measurement of lipogenesis from acetate-1-14C by liver and heart slices from chick embryos and newly hatched chicks support the conclusions reached in the studies with the subcellular fractions. The results obtained indicate that the major system of fatty acid synthesis in embryonic and adult heart is the mitochondrial chain elongation. In embryonic liver, fatty acid synthesis proceeds by chain elongation, while the de novo system is the major contributor to the lipogenic capacity of the liver after hatching.  相似文献   

4.
The major objectives of this study were to define the roles of adrenal glucocorticoids and glucagon in the long-term regulation of fatty acid synthetase and acetyl-CoA carboxylase of mammalian adipose tissue and liver. Particular emphasis was given to elucidation of the mechanisms whereby these hormones produce their regulatory effects on enzymatic activity. To dissociate mental manipulation, nutritional conditions were ridgidly controlled in the experiments described. Administration of glucocorticoids to adult rats led to a marked reductionin activities of fatty acid synthetase and carboxylase in adipose in adipose tissue but no change occurred in liver. Adrenalectomy produced an increase in activities of these lipogenic enzymes in adipose tissure, but, again, no change was noted in liver. The decrease in enzymatic activities in adipose tissue with glucocorticoid administration correlated well with a decrease in fatty acid synthesis, determined in vivo by the 3-H2O method. The mechanisms whereby glucocorticoids led to a decrease in fatty acid synthetase activity were elucidated by the use of immunochemical techniques. Thus, the decrease in fatty acid synthetase activity observed in adipose tissue was shown to reflect a decrease in content of enzyme, and not a change in catalytic efficiency. The mechanism underlying the decrease in enzyme content is a decrease in synthesis of the enzyme. The relation of the effects of glucocorticoids to the effects of certain other hormones involved in regulation of lipogenesis was investigated in hypophysectomized and in diabetic animals. Thus, the observation that the glucocorticoid effect on synthetase and carboxylase occurred in adipose tissue of hypophysectomized rats indicated that alterations in levels of other pituitary-regulated hormones were not necessary for the effect. That glucocorticoids play some role in regulation of synthetase and carboxylase in liver, at lease in the diabetic state, was shown by the observation that the low activities of these enzymes in diabetic animals could be restored to normal by adrenalectomy. An even more pronounced restorative effect was apparent in adipose tissue of adrenalectomized, diabetic animals. Administration of glucagon during the refeeding of starved rats resulted in a marked reduction in the induction of fatty acid synthetase, acetyl-CoA carboxylase and in the rate of incorporation of 3-H from 3-H2O into fatty acids in liver, but no change in these parameters occurred in adipose tissue. Administration of theophylline resulted in intermediate reduction in liver. The mechanisms whereby glucagon led tto a decrease in fatty acid synthetase activity were elucidated by the use of immunochemical techniques. Thus, the changes in fatty acid synthetase activity were shown to reflect reductions in content of enzyme. The mechanism underlying these reductions in content is reduced synthesis of enzyme.  相似文献   

5.
Abstract— C-6 glial cells in culture were utilized to define the role of glucocorticoid in the regulation of palmitic acid synthesis and the important lipogenic enzymes, fatty acid synthetase and acetyl-CoA carboxylase. Particular emphasis was given to fatty acid synthetase which exhibited more than a 50% reduction in specific activity when cells were exposed to hydrocortisone (10 μg/ml) for 1 week. Coordinate changes in acetyl-CoA carboxylase activity and in palmitic acid (and sterol) synthesis from acetate accompanied the alterations in fatty acid synthetase. Immunochemical techniques were utilized to show that the decrease in synthetase activity involved an alteration in enzyme content, not in catalytic efficiency. The changes in content of fatty acid synthetase were caused by alterations in enzyme synthesis. Glucocorticoids may regulate fatty acid synthetase in C-6 glial cells by a mechanism similar to that suggested for adipose tissue. The inhibition of palmitic acid synthesis may be relevant to other effects of glucocorticoids on developing brain.  相似文献   

6.
The activities of lipogenic enzymes, such as acetyl-CoA carboxylase, fatty acid synthetase and glucose-6-phosphate dehydrogenase, and glycerolipid synthesis increased significantly in mammary explants of 11-day-pseudopregnant rabbits in response to prolactin, in the presence of near-physiological concentrations of insulin and corticosterone in culture. Increasing the concentration of progesterone in culture resulted in suppression of glycerolipid synthesis and activities of acetyl-CoA carboxylase and fatty acid synthetase, but not the pentose phosphate dehydrogenases. However, at near-physiological concentration of progesterone, only acetyl-CoA carboxylase activity was decreased. Injection of prolactin intraductally into 11-day-pseudopregnant rabbits stimulated glycerolipid synthesis, fatty acid synthesis and enzymes involved in fatty acid synthesis, after 3 days. Intraductal injection of progesterone separately or together with prolactin had no significant effect on basal or stimulated lipogenesis in mammary glands. Intramuscular injection of progesterone at 10 mg/day did not suppress fatty acid synthesis stimulated when prolactin was injected intraductally, but a significant inhibition was observed at a higher dose (80 mg/day).  相似文献   

7.
After in vivo administration of lead nitrate, functional changes of the mitochondrial tricarboxylate carrier and of the cytosolic lipogenic enzymes acetyl-CoA carboxylase and fatty acid synthetase have been detected in rat liver. The rate of citrate transport was greatly reduced in rats during both the proliferative phase (3 days after the lead nitrate administration) and the involutive phase (5 days after the metal injection), which follows hepatic hyperplasia and corresponds to the peak of hepatocyte apoptosis. In both phases, a decrease of the lipogenic enzyme activities has been detected. In treated animals, an alteration of mitochondrial lipid composition has also been found. The modified lipid microenvironment could be responsible for the decreased carrier activity which, in turn, may account for the reduced activities of the lipogenic enzymes.  相似文献   

8.
The development of the lipogenic capacity in brown adipose tissue was studied in suckling lean (Fa/fa) and obese (fa/fa) Zucker pups aged from 7 to 22 days. In both lean and obese pups, activities of the two key lipogenic enzymes, fatty acid synthetase and acetyl-CoA carboxylase, and of citrate cleavage enzyme rose from the early to the late suckling period. Compared with lean pups, 7-day-old fa/fa pups showed a 35% increase in fat accumulation in interscapular brown adipose tissue and a 25% increase in fatty acid synthetase activity. By 10 days of age, fat deposition, lipogenesis in vivo (assessed by the incorporation of 3H from 3H2O into fatty acids) and fatty acid synthetase activity were 1.5-2-fold higher in pre-obese than in lean pups. Compared with lean pups, the increased lipogenesis in vivo observed in brown adipose tissue of 10-day-old pre-obese pups could not entirely account for the difference in fat deposition observed in this tissue, suggesting that additional mechanisms are at play to explain the increased fat content of this tissue.  相似文献   

9.
Diets supplemented 5% with L-histidine produce hypercholesterolemia and increase cholesterol biosynthesis in rat liver. We now report an inhibitory effect of L-histidine on lipogenic enzymes in the liver. In this study, L-histidine was added to chow and fat-free diets and fed to rats for 18 days. After two days of fasting, the rats were refed the same diet for three days prior to sacrifice. L-histidine decreased fatty acid synthetase activity by 51% when it was added to the chow diet and by 26% when it was added to the fat-free diet. Isocitrate dehydrogenase activity was not altered significantly in rats fed diets supplemented with L-histidine.  相似文献   

10.
Administration of triamcinolone or dexamethasone to rats led to a prompt, marked and persistent rise in liver acetyl-CoA carboxylase activity. The activity of fatty acid synthetase increased to a lesser extent and after a more prolonged glucocorticoid treatment, whereas the changes in that of NADP-malate dehydrogenase and ATP-citrate lyase were not appreciable. The overall channeling of [1-14-C]acetyl-CoA to fatty acids was enhanced. The triamcinolone effect on acetyl-CoA carboxylase activity appeared to be dependent on the coincident hyperinsulinemia since it was not obtained in alloxan-diabetic rats, whereas the alanine-aminotransferase-inducing effect of this hormone was additive to that of insulin deficiency. In adipose tissue triamcinolone treatment caused a reduction in the activity of all lipogenesis enzymes and blunted their response to insulin administration. The antagonism of glucocorticoids toward insulin, selectively modulating the responses of the insulin-sensitive enzymes in liver and adipose tissue is discussed. The rise in hepatic lipogenic capacity, through the retention of the ability of insulin to induce acetyl-CoA carboxylase, may be physiologically important in restraining the ketogenesis from acetyl-CoA despite the increased fat utilization during glucocorticoid excess.  相似文献   

11.
Induction of lipogenesis during differentiation in a "preadipocyte" cell line.   总被引:30,自引:0,他引:30  
3T3-L1 fibroblasts differentiate in culture into cells having adipocyte character. This transition is accompanied by a 40- to 50-fold rise in the incorporation of [14C]acetate into triglyceride. The increase in lipogenic rate is exactly parallel to a coordinate rise in the activities of the key enzymes of the fatty acid biosynthetic pathway (ATP-citrate lyase, acetyl-CoA carboxylase, and fatty acid synthetase). Immunological studies indicate that the elevated acetyl-CoA carboxylase activity is the product of an increased cellular enzyme level.  相似文献   

12.
A human breast cell line has been identified which contains prodigious levels of fatty acid synthetase but has a very low capacity for lipogenesis from glucose, lactate or acetate. The fatty acid synthetase from this cell line appears to be structurally and functionally normal, and the low lipogenic capacity of the cells appears to be due to the low activities of other lipogenic enzymes, notably acetyl-CoA carboxylase. Thus, the SKBr3 cell line appears to lack the long-term coordinated control of acetyl-CoA carboxylase and fatty acid synthetase commonly observed in normal lipogenic tissues.  相似文献   

13.
The BHE strain of rat is characterized by early hyperinsulinemia and maturity onset hyperlipemia and hyperglycemia. Since we have previously shown that insulin is required for the coordinate regulation of a number of lipogenic enzymes in rat liver, a comparative study of the hepatic activities of the rate-limiting enzymes of lipid synthesis and the in vivo rates of fatty acid and cholesterol synthesis in the liver and the adipose tissue has been conducted in BHE and Wistar rats. In the liver, BHE rats had 25–28% higher acetyl-CoA carboxylase and fatty acid synthetase activities as measured in vitro but a 100% greater rate of fatty acid synthesis in vivo as compared to Wistar animals. These results strongly suggest that factors other than the amount of acetyl-CoA carboxylase, such as allosteric effectors, must be operating in vivo, thereby facilitating the carboxylase to function at its maximal capacity in BHE rats. Such a regulation of fatty acid biosynthesis by allosteric modifiers of acetyl-CoA carboxylase is already known, although the mechanism of this regulation is not fully understood. BHE rats also exhibited a twofold greater rate of fatty acid synthesis in the adipose tissue compared to the Wistar rats. Thus, increased lipogenic capacity and increased lipogenesis in BHE rats are consistent with early hyperinsulinemia in this strain. Furthermore, BHE rats had 71% more 3-hydroxy-3-methylglutaryl CoA reductase activity with a 97% greater rate of cholesterol synthesis as compared to Wistar rats. In contrast, cholesterol 7α-hydroxylase activity was only 20% greater in BHE rats compared to Wistar rats, suggesting that the BHE rat does not have the capacity to degrade cholesterol to bile acids at a rate commensurate with the increased rate of cholesterol synthesis. This difference in synthesis versus degradation might account for the hypercholesterolemia which occurs in BHE rats, but not in Wistar rats.  相似文献   

14.
The polysome fractions involved in the synthesis of the rat-liver inducible lipogenic enzymes, ATP citrate lyase and fatty acid synthetase, were identified by their binding of radioiodinated specific antibodies to enzyme. Both of these populations of specific polysomes were shown to be markedly heavier than specific polysomes involved in albumin synthesis. The quanity of antibody bound to the lipogenic enzyme-related polysomes was markedly affected by the dietary status of the animal. A dietary regimen which induced ipogenesis resulted in a tenfold increase in the hepatic activities of these enzymes found in normally fed animals. The radioactivity bound to hepatic polysomes of induced rats was likewise greater than tenfole higher, presumably reflecting an increase in the number of polysomes active in enzyme synthesis. The fasting state resulted in lower hepatic enzyme activity than normal and correspondingly less binding of ATP citrate lyase and fatty acid synthetase antibodies to the heavy polysomes of the sucrose gradient.  相似文献   

15.
The induction of rat liver malic enzyme by restriction of protein intake has been studied in conjunction with the biosynthesis of fatty acids, fatty acid synthetase, glutathione reductase, and other “lipogenic” enzymes in the various experimental animals. No correlation has been detected between malic enzyme activity and lipogenesis under these conditions. Conversely, a positive correlation between malic enzyme and glutathione reductase has been noted. Possible functions of malic enzyme which appear consistent with these observations are postulated.  相似文献   

16.
B M Spiegelman  H Green 《Cell》1981,24(2):503-510
During the adipose differentiation of 3T3-F442A cells, there is an increase in the synthesis of numerous proteins, including the lipogenic enzymes glycerophosphate dehydrogenase, fatty acid synthetase and malic enzyme. Agents that increase cAMP content (Dibutyryl cAMP, theophylline, and isoproterenol) are known to induce lipolysis in fat cells; but the same agents are shown here to reduce the synthesis of the lipogenic enzymes during adipose differentiation. The extent of reduction depends on the agent used and differs for the three enzymes; fatty acid synthetase is most sensitive and its synthesis can be suppressed completely. In contrast to their effects on lipogenic enzyme synthesis, these agents do not affect morphological changes or the synthesis of several other proteins, of which some increase and others (such as actin) decrease during the differentiation. The effects of the agents on the synthesis of lipogenic enzymes are not dependent on lipolysis, since they take place to the same degree in cells not permitted to accumulate triglyceride. Translation in vitro of mRNA isolated from cells treated with the agents promoting cAMP accumulation indicates that the levels of functional mRNA for lipogenic enzymes are reduced. We conclude that, in addition to its activation of lipolysis, cAMP reduces specifically mRNA accumulation for lipogenic enzymes. These results also demonstrate the independent control of morphological change and enzyme synthesis during adipose differentiation.  相似文献   

17.
1. The rate of mammary-gland lipogenesis measured in vivo from 3H2O was suppressed after decreasing the milk demand by decreasing the number of pups from ten to two or three, as well as by giving diets containing lipid [Grigor & Warren (1980) Biochem. J. 188, 61-65]. 2. The specific activities of the lipogenic enzymes fatty acid synthase, glucose 6-phosphate dehydrogenase and 'malic' enzyme increased between 6- and 10-fold in the mammary gland and between 2- and 3-fold in the livers during the first 10 days of lactation. The increases in specific activity coupled with the doubling of liver mass which occurred during pregnancy and lactation resulted in considerable differences in total liver activities when compared with virgin animals. 3. Although consumption of a diet containing 20% peanut oil suppressed the activities of the three lipogenic enzymes in the livers, only the 'malic' enzyme was affected in the mammary glands. 4. In contrast, decreased milk demand did not affect the specific activities of any of the liver enzymes, whereas it resulted in suppression of all three lipogenic enzymes of the mammary glands. There was no effect on either the cytoplasmic malate dehydrogenase or the lactate dehydrogenase of the mammary gland. 5. In all the experiments performed, the activity of the fatty acid synthase correlated with the amount of material precipitated by the rabbit antibody raised against rat fatty acid synthase.  相似文献   

18.
1. The inclusion of sucrose in the diet of rats led to an increase in hepatic fatty acid synthetase activity compared with that of rats fed with starch as the sole carbohydrate. The higher activity occurred within 18h of the introduction of sucrose and persisted with fluctuations for the 30 days of the experiment. Reversal of the diets in some rats after 21 days led to changes in the enzyme activity to values appropriate to the second diet. The plasma triglyceride concentration followed a similar pattern. 2. A comparison of the effects of diets with starch, glucose, maltose, sucrose or fructose showed that fructose gave the highest values of triglyceride content and of fatty acid synthetase activity in liver, but the lowest values of the synthetase activity in adipose tissue and the lowest values of plasma insulin concentration. These effects may perhaps be attributed to the low insulin response to fructose and to the high affinity of the liver for this sugar. 3. When the diet contained fructose or sucrose there was a correlation between hepatic synthetase activity and plasma triglyceride concentration. Neither of these, however, was related to plasma insulin concentration. On the other hand, there was a correlation between plasma insulin concentration and fatty acid synthetase activity in adipose tissue. 4. When rats were starved and then re-fed the differences in enzyme activities induced by fructose or glucose were minimized. This, together with the varying degree of difference during the course of the experiments, may explain why other workers, using the starvation-re-feeding technique and making measurements on one day only, have failed to observe differences in the activities of lipogenic enzymes in animals fed with either fructose or glucose.  相似文献   

19.
The activity and mRNA concentrations of two lipogenic enzymes, fatty-acid synthase and acetyl-CoA carboxylase were measured in the liver and white adipose tissue of rats weaned to a carbohydrate-rich diet containing either long-chain or medium-chain fatty acids, and compared to those of rats weaned on a diet containing less than 1% (total energy) fat (high-carbohydrate diet). In the liver, the diet containing long-chain fatty acids inhibited the increase of both lipogenic-enzyme mRNA concentrations and activities seen at weaning on the high-carbohydrate diet but did not prevent the decrease in phosphoenolpyruvate carboxykinase mRNA and activity. In contrast, the diet containing medium-chain fatty acids induced a slower but finally similar increase in lipogenic-enzyme mRNA concentrations and activities. In adipose tissue, a similar trend was observed, although the inhibitory effect of the diet containing long-chain fatty acids was considerably less marked than in liver. It is concluded that medium-chain and long-chain fatty acids have not the same inhibitory potency of the gene expression of lipogenic enzymes, and that long-chain fatty acids have a more marked effect in the liver.  相似文献   

20.
Male chicks were fed a commercial ration and were given drinking water which contained 0, 50, 100, 150, 200 or 300 mug of mercury/ml as mercuric chloride from hatching to 3 weeks of age. In one experiment, the mercuric chloride was administered by injection into the abdominal cavity rather than in the drinking water. At 3 weeks the chicks were killed, and the livers were removed and weighed. The activity of fatty acid synthetase in the 800 X gav supernatant fractions of the liver homogenates and in vivo incorporation of [14C]acetate into liver and carcass fatty acids and respiratory 14CO2 was determined as indicated. Administration of mercury at a treatment level of 300 mug/ml of drinking water depressed growth, feed and water consumption, liver weight, hepatic fatty acid synthetase activity, and in vivo incorporation of [14C]acetate into liver and carcass fatty acids, and increased the production of respiratory 14CO2 as compared with controls. In experiments in which graded doses of mercury were administered, body weights, liver weights, and feed and water intakes of the chicks receiving 0, 50 and 100 mug of mercury/ml of drinking water were similar to each other, but these parameters were severely depressed by 200 mug of mercury/ml of drinking water. Mercury caused a dose-related decrease of fatty acid synthetase activity. Incorporation of [14C]acetate into carcass fatty acid was depressed by 50 and 200 mug of mercury/ml of drinking water; incorporation into liver fatty acids and production of respiratory 14CO2 was not affected by mercury. Intra-abdominal injection of 6 mg of mercury/100 g body weight (as mercuric chloride) into well alimented chicks depressed hepatic fatty acid synthetase activity at 1 h post-injection. The data are consistent with the hypothesis that a portion of the effects of mercury on fatty acid synthesis are direct rather than a secondary effect of inanition.  相似文献   

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