Structure and regulation of the avian gene for fatty acid synthase

Goodridge, Alan G.; Carpenter, William R.; Goldman, Michael A.; Kameda, Kensuke; Stapleton, Susan R.

doi:10.1051/rnd:19890314

Cited by 10 publications

(14 citation statements)

References 28 publications

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“…It is regulated predominantly by the anabolic effects of insulin mostly through transcriptional effects [24,25], although other mechanisms are described and many other nutrients and hormones affect FAS expression [14]. Variations in FAS expression and enzyme activity have now been implicated in insulin resistance and obesity in humans [26-28].…”

Section: De Novo Lipogenesismentioning

confidence: 99%

Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter

Lodhi¹,

Wei²,

Semenkovich

2011

Trends in Endocrinology & Metabolism

124

109

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De novo lipogenesis, the production of fats from simple precursors, is often dismissed as irrelevant to the pathobiology of obesity caused by positive energy balance due to typical high fat diets. However, emerging data implicate de novo lipogenesis in the generation of metabolic signals that alter disease risk. Exploiting this signaling pathway represents lipoexpediency. Lipoexpediency is the concept of directing fats toward benefit even in the setting of lipid overload, and represents a strategy to complement efforts aimed at improving energy balance. Optimizing lipid signals initiated by key lipogenic enzymes such as fatty acid synthase might limit morbidity in people unlikely to abandon the lifestyle of the sedentary gourmand. The reality of lipid excess An epidemic with limited novel treatment approachesOver 40% of Americans have diabetes or prediabetes [1] and as many as a quarter of American adults have the metabolic syndrome, which predisposes to diabetes and cardiovascular disease [2]. Tobacco use increases health risks that have been decreased by public health measures targeted at smoking, but the adverse effects of obesity will probably negate the beneficial effects of declining tobacco use in the United States by 2020 [3]. The metabolic mayhem promoted by a Western lifestyle has been exported worldwide, and diabetes is now a major and accelerating public health problem in China [4]. Diabetes, obesity, and the metabolic syndrome also increase the risk of nonalcoholic fatty liver disease [5]. Lifestyle changes are difficult to institute given the pressures of Western culture, and other therapies are limited. For example, insulin therapy lowers hemoglobin A1c but may increase adiposity. Statins and reninangiotensin system (RAS) inhibitors decrease but do not eliminate cardiovascular risk, i.e. individuals with dyslipidemia, hypertension, and diabetes are still at considerable risk for heart attacks even when treated with statins and RAS inhibitors. PPAR agonists have a mixed record that is still evolving, and it is unknown if GLP-1 modulators will decrease complications of diabetes and obesity.

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Section: De Novo Lipogenesismentioning

confidence: 99%

Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter

Lodhi¹,

Wei²,

Semenkovich

2011

Trends in Endocrinology & Metabolism

124

109

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“…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).…”

mentioning

confidence: 99%

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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“…Hyperthyroidism in humans or T 3 injections in experimental conditions enhance hepatic lipogenesis (Diamant et al 1972, Laker & Mayes 1981, which is the limiting step in the conversion of acetyl-CoA into long-chain saturated FAs (Wakil et al 1983) and performed by the hepatic enzyme FAS using the coenzyme NADPH. Initially, the positive effects of thyroid hormones in lipogenesis were partially attributed to induction of FAS mRNA expression (Goodridge et al 1989), an observation supported when a TRE was identified on the FAS promoter (Radenne et al 2008). However, because PI3K and ERK1/2 or MAPK inhibitors attenuate the effect of T 3 on FAS mRNA, phosphorylation events are involved in the transcriptional regulation of FAS in response to thyroid hormones (Radenne et al 2008).…”

Section: Non-classic Pathways Of Thyroid Hormone Actions In Lipid Hommentioning

confidence: 93%

Non-classic thyroid hormone signalling involved in hepatic lipid metabolism

Cordeiro

Souza

Einicker‐Lamas

et al. 2013

Journal of Endocrinology

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Thyroid hormones are important modulators of lipid metabolism because the liver is a primary hormonal target. The hypolipidaemic effects of thyroid hormones result from the balance between direct and indirect actions resulting in stimulation of lipid synthesis and lipid oxidation, which favours degradation pathways. Originally, it was believed that thyroid hormone activity was only transduced by alteration of gene transcription mediated by the nuclear receptor thyroid hormone receptors, comprising the classic action of thyroid hormone. However, the discovery of other effects independent of this classic mechanism characterised a new model of thyroid hormone action, the non-classic mechanism that involves other signalling pathways. To date, this mechanism and its relevance have been intensively described. Considering the increasing evidence for non-classic signalling of thyroid hormones and the major influence of these hormones in the regulation of lipid metabolism, we reviewed the role of thyroid hormone in cytosolic signalling cascades, focusing on the regulation of second messengers, and the activity of effector proteins and the implication of these mechanisms on the control of hepatic lipid metabolism.

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Structure and regulation of the avian gene for fatty acid synthase

Cited by 10 publications

References 28 publications

Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter

Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter

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

Non-classic thyroid hormone signalling involved in hepatic lipid metabolism

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Structure and regulation of the avian gene for fatty acid synthase

Cited by 10 publications

References 28 publications

Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter

Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter

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

Non-classic thyroid hormone signalling involved in hepatic lipid metabolism

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