Rates of acetate turnover and lipid synthesis in normal, hypothyroid and hyperthyroid rats

Dayton, Seymour; Dayton, Joan; Drimmer, Fred; Kendall, Forrest E.

doi:10.1152/ajplegacy.1960.199.1.71

Cited by 61 publications

(18 citation statements)

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“…Indeed, it is well known that insulin stimulates hepatic triacylglycerol secretion through the general activation of de novo lipid synthesis [57]. It is also well established that T 3 stimulates de novo lipid synthesis in the liver, increasing synthesis of TG [58,59]. However, the use of betulinic acid, an inhibitor of DGAT, a rate limiting step in the esterification pathway (Fig.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Akpa

Point

Sawadogo

et al. 2010

Lipids

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Fatty acid synthase (FAS) is responsible for the de novo synthesis of palmitate and stearate. This enzyme is activated by insulin and T(3), and inhibited by fatty acids. In this study, we show that insulin and T(3) have an inducing effect on FAS enzymatic activity, which is synergetic when both hormones are present. Octanoate and hexanoate specifically inhibit this hormonal effect. A similar inhibitory effect is observed at the level of protein expression. Transient transfections in HepG2 cells revealed that hexanoate inhibits, at least in part, FAS at a transcriptional level targeting the T(3) response element (TRE) on the FAS promoter. The effect of C6 on FAS expression cannot be attributed to a modification of insulin receptor activation or to a decrease in T(3) entry in the cells. Using bromo-hexanoate, we determined that hexanoate needs to undergo a transformation in order to have an effect. When incubating cells with triglyceride-hexanoate or carnitine-hexanoate, no effect on the enzymatic activity induced by insulin and T(3) is observed. A similar result was obtained when cells were incubated with betulinic acid, an inhibitor of the diacylglycerol acyltransferase. However, the incubation of cells with Triacsin C, a general inhibitor of acyl-CoA synthetases, completely reversed the inhibitory effect of hexanoate. Our results suggest that in hepatic cells, hexanoate needs to be activated into a CoA derivative in order to inhibit the insulin and T(3)-induced FAS expression. This effect is partially transcriptional, targeting the TRE on the FAS promoter.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Akpa

Point

Sawadogo

et al. 2010

Lipids

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“…High plasma concentrations of both FFA and glycerol, on the other hand, are effective stimulators of hepatic VLDL-triglyceride synthesis and release. A second factor acting in the same direction is enhancement of hepatic fatty acid synthesis by thyroid hormones (32)(33)(34). It has been shown that the release of triglycerides by an isolated perfused rat liver is closely related to the rate of de novo fatty acid synthesis (35).…”

Section: Discussionmentioning

confidence: 99%

Plasma triglyceride metabolism in thyroid disease

Nikkilä¹,

Kekki²

1972

J. Clin. Invest.

216

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A B S T R A C T Plasma endogenous triglyceride transport kinetics were determined in 16 hyperthyroid and in 12 hypothyroid patients and the results compared with those of euthyroid control subjects. In addition, the removal of exogenous particulate fat (Intralipid; Vitrum, Sweden) from the circulation and the postheparin plasma lipolytic activity (PHLA) were studied in these patients for further characterization of the alterations of plasma triglyceride metabolism in thyroid disease.In thyrotoxicosis the average plasma triglyceride level was slightly but significantly increased above that of control subjects. This change was associated with augmented production of triglycerides whereas the mean fractional removal rate was not different from normal. There was a significant linear correlation between the concentration and turnover rate of plasma triglycerides in both hyperthyroid and euthyroid subjects but the concentration/turnover rate ratio was less in the former group suggesting that the efficiency of removal of triglycerides from the circulation was improved in thyroid hyperfunction. The elimination of intravenously administered particulate fat occurred more rapidly in untreated hyperthyroid patients than in euthyroid control subjects. The mean PHLA was also above normal in thyrotoxicosis. Upon adequate treatment of the hyperthyroid state the fasting plasma triglyceride concentration was further increased.Hypothyroid patients showed another pattern of alteration of triglyceride kinetics. The synthesis of plasma triglycerides was normal but the fractional removal of both endogenous and exogenous triglycerides was markedly reduced and this change seems to account for the hypertriglyceridemia associated with thyroid hypofunction. The plasma PHLA was also clearly decreased in the hypothyroid state.Plasma FFA and glycerol levels were increased in hyperthyroidism and plasma FFA was slightly deReceived for publication 17 January 1972 and in revised form 3 April 1972. creased in hypothyroid patients, but these variables were not significantly correlated with any parameter of triglyceride metabolism.Endogenous triglyceride turnover rate was significantly correlated with serum protein-bound iodine (PBI) and T3 uptake in thyrotoxicosis but not in hypothyroidism. Removal of exogenous fat was not related to postheparin plasma lipolytic activity but the fractional endogenous triglyceride transport showed a highly significant relationship to this lipase activity in a mixed group of hyper-and hypothyroid patients.The results suggest that thyroid hormones control both production and removal of plasma triglycerides.

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“…Insulin and triiodothyronine (T 3 ) are involved in mediating the effects of diet on lipogenesis in vivo (34). Hepatic lipogenesis is increased in hyperthyroid states or in response to T 3 injection (10,15,19,24,25,28,62,71,76,83) as well as in hyperinsulinemic subjects (80). In vivo, these two hormones are also involved in the long-term regulation of lipogenic enzymes activities such as fatty acid synthase (37).…”

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Hepatic regulation of fatty acid synthase by insulin and T₃: evidence for T₃genomic and nongenomic actions

Radenne¹,

Akpa²,

Martel³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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is a key enzyme of hepatic lipogenesis responsible for the synthesis of long-chain saturated fatty acids. This enzyme is mainly regulated at the transcriptional level by nutrients and hormones. In particular, glucose, insulin, and T 3 increase FAS activity, whereas glucagon and saturated and polyunsaturated fatty acids decrease it. In the present study we show that, in liver, T 3 and insulin were able to activate FAS enzymatic activity, mRNA expression, and gene transcription. We localized the T 3 response element (TRE) that mediates the T3 genomic effect, on the FAS promoter between Ϫ741 and Ϫ696 bp that mediates the T 3 genomic effect. We show that both T3 and insulin regulate FAS transcription via this sequence. The TRE binds a TR/RXR heterodimer even in the absence of hormone, and this binding is increased in response to T 3 and/or insulin treatment. The use of H7, a serine/threonine kinase inhibitor, reveals that a phosphorylation mechanism is implicated in the transcriptional regulation of FAS in response to both hormones. Specifically, we show that T 3 is able to modulate FAS transcription via a nongenomic action targeting the TRE through the activation of a PI 3-kinase-ERK1/2-MAPK-dependent pathway. Insulin also targets the TRE sequence, probably via the activation of two parallel pathways: Ras/ERK1/2 MAPK and PI 3-kinase/Akt. Finally, our data suggest that the nongenomic actions of T 3 and insulin are probably common to several TREs, as we observed similar effects on a classical DR4 consensus sequence. fatty acid synthase; triiodothyronine; insulin; triiodothyronine response element; phosphoinositide 3-kinase; extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase LIPOGENESIS CONVERTS DIETARY CARBOHYDRATES to fatty acids primarily in liver (28). Insulin and triiodothyronine (T 3 ) are involved in mediating the effects of diet on lipogenesis in vivo (34). Hepatic lipogenesis is increased in hyperthyroid states or in response to T 3 injection (10,15,19,24,25,28,62,71,76,83) as well as in hyperinsulinemic subjects (80). In vivo, these two hormones are also involved in the long-term regulation of lipogenic enzymes activities such as fatty acid synthase (37).Fatty acid synthase (FAS; EC.2.3.1.85) is a key enzyme in hepatic lipogenesis. In the presence of NADPH, this multifunctional enzyme catalyzes the conversion of acetyl-CoA and malonyl-CoA into long-chain saturated fatty acids such as palmitate and stearate (92). The de novo synthesis of fatty acids in human and chicken takes place mainly in the liver (30, 58), whereas in rodents the adipose tissue is also lipogenic (30). In vertebrates, FAS is a homodimer made of two identical peptide chains of ϳ260 kDa (85, 91), located in the cytoplasm of the cell (31). FAS is encoded by a unique gene that generates only one mRNA in mouse (73) and two in chicken and rat, as a result of alternative splicing (3). In the liver, the activity of FAS, like most lipogenic enzymes (95), is regulated through nutrients and hormones. Starvation causes a decrea...

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Rates of acetate turnover and lipid synthesis in normal, hypothyroid and hyperthyroid rats

Cited by 61 publications

References 0 publications

Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Plasma triglyceride metabolism in thyroid disease

Hepatic regulation of fatty acid synthase by insulin and T₃: evidence for T₃genomic and nongenomic actions

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Rates of acetate turnover and lipid synthesis in normal, hypothyroid and hyperthyroid rats

Cited by 61 publications

References 0 publications

Inhibition of Insulin and T3‐Induced Fatty Acid Synthase by Hexanoate

Inhibition of Insulin and T3‐Induced Fatty Acid Synthase by Hexanoate

Plasma triglyceride metabolism in thyroid disease

Hepatic regulation of fatty acid synthase by insulin and T3: evidence for T3genomic and nongenomic actions

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Product

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Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Hepatic regulation of fatty acid synthase by insulin and T₃: evidence for T₃genomic and nongenomic actions