Regulation Of Lipogenic Enzymes Research Articles

Antitumor effects of curcumin: A lipid perspective.

Lipid metabolism plays an important role in cancer development due to the necessities of rapidly dividing cells to increase structural, energetic, and biosynthetic demands for cell proliferation. Basically, obesity, type 2 diabetes, and other related diseases, and cancer are associated with a common hyperactivated "lipogenic state." Recent evidence suggests that metabolic reprogramming and overproduction of enzymes involved in the synthesis of fatty acids are the new hallmarks of cancer, which occur in an early phase of tumorigenesis. As the first evidence to confirm dysregulated lipid metabolism in cancer cells, the overexpression of fatty acid synthase (FAS) was observed in breast cancer patients and demonstrated the role of FAS in cancer. Other enzymes of fatty acid synthesis have recently been found to be dysregulated in cancer, including ATP-dependent citrate lyase and acetyl-CoA carboxylase, which further underscores the connection of these metabolic pathways with cancer cell survival and proliferation. The degree of overexpression of lipogenic enzymes and elevated lipid utilization in tumors is closely associated with cancer progression. The question that arises is whether the progression of cancer can be suppressed, or at least decelerated, by modulating gene expression related to fatty acid metabolism. Curcumin, due to its effects on the regulation of lipogenic enzymes, might be able to suppress, or even cause regression of tumor growth. This review discusses recent evidence concerning the important role of lipogenic enzymes in the metabolism of cancer cells and whether the inhibitory effects of curcumin on lipogenic enzymes is therapeutically efficacious.

Fenugreek Seed Extract Prevents Fat Deposition in Monosodium Glutamate (MSG)-Obese Rats

To evaluate the preventive effects of an aqueous extract of Trigonella foenum-graecum seeds (AqE-TFG) on fat deposition and dyslipidemia in monosodium glutamate (MSG)-obese rats. Neonatal male Wistar rats were injected with MSG (4 g/kg b. w., subcutaneously) from day 2 to 14 after birth, on alternate days. From day 43 to 70, MSG treated rats were administered orally with AqE-TFG (0.5 and 1.0 g/kg b. w.). The anthropometric and biochemical parameters were analyzed on day 71. Treatment with AqE-TFG produced significant (P < 0.05 or P < 0.01) reduction in body weight gain, Lee's index, white adipose tissue (WAT) weights, adiposity index, blood glucose, serum insulin, leptin, lipids (low density lipoprotein cholesterol and very low density lipoprotein cholesterol), cardiac risk indexes (atherogenic index and coronary risk index), and homeostatic model assessment index. AqE-TFG treatment restored the activities of liver and epididymal WAT lipogenic enzymes (fatty acid synthetase and glucose-6-phosphate dehydrogenase) towards normal levels. Histological studies of liver also supported the experimental findings. These findings demonstrated the preventive effect of AqE-TFG on fat deposition and dyslipidemia possibly by improvement in glucose and lipid metabolism, enhancement of insulin sensitivity and down regulation of lipogenic enzymes.

Expression, purification and preliminary crystallographic analysis of human thyroid hormone responsive protein

Thyroid hormone responsive protein (Thrsp, also known as Spot 14 and S14) is a carbohydrate-inducible and thyroid-hormone-inducible nuclear protein specific to liver, adipose and lactating mammary tissues. Thrsp functions to activate genes encoding fatty-acid synthesis enzymes. Recent studies have shown that in some cancers human Thrsp (hS14) localizes to the nucleus and is amplified, suggesting that it plays a role in the regulation of lipogenic enzymes during tumourigenesis. Thrsp, a member of the Spot 14 superfamily, is an acidic homodimeric protein with no sequence similarity to other mammalian gene products and its biochemical function is elusive. To shed light on the structure-function relationship of this protein, human Thrsp was crystallized. Recombinant human Thrsp (hThrsp), the N-terminally truncated human Thrsp(10-146) (hThrsp9) and their selenomethionyl (SeMet) derivatives were expressed in Escherichia coli, purified and crystallized using the hanging-drop vapour-diffusion method. Diffraction-quality crystals were grown at 293 K using Li(2)SO(4) as a precipitant. Using synchrotron radiation, data for the hThrsp SeMet derivative, hThrsp9 and its SeMet derivative were collected to 4.0, 3.0 and 3.6 Å resolution, respectively, at 100 K. The crystals of full-length hThrsp and its SeMet derivative belonged to space group P4(1)2(1)2, with approximate unit-cell parameters a = b = 123.9, c = 242.1 Å, α = β = γ = 90.0°. In contrast, the crystals of the truncated hThrsp9 and its SeMet derivative belonged to space group P2(1)2(1)2(1), with approximate unit-cell parameters a = 91.6, b = 100.8, c = 193.7 Å, α = β = γ = 90.0°. A molecular-replacement solution calculated using a murine Spot 14 structure as a search model indicated the presence of six molecules per asymmetric unit, comprising three hThrsp homodimers.

SAFB1, an RBMX-binding protein, is a newly identified regulator of hepatic SREBP-1c gene

Sterol regulatory element-binding protein (SREBP)-1c plays a crucial role in the regulation of lipogenic enzymes in the liver. We previously reported that an X-chromosome-linked RNA binding motif (RBMX) regulates the promoter activity of Srebp-1c. However, still unknown was how it regulates the gene expression. To elucidate this mechanism, we screened the cDNA library from mouse liver by yeast two-hybrid assay using RBMX as bait and identified scaffold attachment factor B1 (SAFB1). Immunoprecipitation assay demonstrated binding of SAFB1 to RBMX. Chromatin immunoprecipitation assay showed binding of both SAFB1 and RBMX to the upstream region of Srebp-1c gene. RNA interference of Safb1 reduced the basal and RBMX-induced Srebp-1c promoter activities, resulting in reduced Srebp-1c gene expression. The effect of SAFB1 overexpression on Srebp-1c promoter was found only in the presence of RBMX. These results indicate a major role for SAFB1 in the activation of Srebp-1c through its interaction with RBMX.

Human spot 14 protein interacts physically and functionally with the thyroid receptor

Spot 14 (S14) is a small acidic protein with no sequence similarity to other mammalian gene products. Its biochemical function is elusive. Recent studies have shown that, in some cancers, human S14 (hS14) localizes to the nucleus and is amplified, suggesting that it plays a role in the regulation of lipogenic enzymes during tumorigenesis. In this study, we purified untagged hS14 protein and then demonstrated, using various biochemical methods, including analytic ultracentrifugation, that hS14 might form a homodimer. We also found several lines of evidence to suggest physical and functional interactions between hS14 and the thyroid hormone receptor (TR). The ubiquitous expression of hS14 in various cell lines and its cell-type-dependent functions demonstrated in this study suggest that it acts as a positive or negative cofactor of the TR to regulate malic enzyme gene expression. These findings provide a molecular rationale for the role of hS14 in TR-dependent transcriptional activation of the expression of specific genes.

Androgens and the control of lipid metabolism in human prostate cancer cells

Since the development of endocrine therapy for the treatment of prostate cancer, now more than 50 years ago, androgens have been known to play a major role in the regulation of various aspects of the biology of prostate cancer cells. Recently, using the human prostate cancer cell line LNCaP as an experimental paradigm of androgen-sensitive prostate cancer cells, we demonstrated that, apart from their effects on cell proliferation and protein secretion, androgens also induce a marked accumulation of cytoplasmic lipid droplets. The accumulating lipids (triacylglycerols and cholesteryl esters) are at least in part synthesized de novo, suggesting that androgens modulate the expression and/or activity of enzymes involved in lipogenesis. One key lipogenic enzyme that we have shown to be affected by androgens is fatty acid synthase (FAS), a complex multifunctional enzyme that plays a central role in the synthesis of fatty acids and that recently has been shown to be overexpressed in a variety of cancers, including prostate cancer. Interestingly, the influence of androgens on lipogenic enzymes is not restricted to FAS alone. Several other enzymes involved in the same metabolic pathway of fatty acid synthesis are affected as well, as are several key enzymes leading to the synthesis of cholesterol. These findings are reminiscent of the coordinate control of lipogenic enzymes by the recently characterized sterol regulatory element binding proteins (SREBPs) and suggest that androgens might not (only) act directly on the expression of all these genes individually, but rather affect the expression and/or activity of these or other transcription factors involved in the regulation of lipogenic enzymes. Ongoing studies in our laboratory support this concept and provide evidence for the existence of a novel cascade mechanism of androgen action. In view of the recent interest in the prognostic significance of lipogenic enzymes and their potential role as targets for antineoplastic therapy, our findings on the regulation of lipogenic enzymes by androgens not only provide novel insights into the complex mechanisms by which androgens affect prostate cancer cells, but may also open new avenues for diagnosis and therapy.

Diet differentially regulates glucokinase and L-type pyruvate kinase gene expression in rat liver.

The regulation of gene expression of glucokinase (GK) and L-type pyruvate kinase (L-PK) in rat liver was investigated and compared with the previously reported regulation of lipogenic enzymes. Experiments were conducted in which the time courses and responses to diet quantity of mRNA concentrations and enzyme activities after refeeding a carbohydrate/protein diet (CP) to food-deprived rats were measured. The effects of dietary nutrients on the gene expression were investigated in rats refed either the CP diet, a carbohydrate diet without protein (C), a protein diet without carbohydrate (P), or a carbohydrate/protein/corn oil diet (CPF). The effects of the CPF diet on the gene expression after insulin treatment to diabetic rats were also investigated. After refeeding the CP diet, GK mRNA concentration and enzyme activity reached maximum levels in 2 h and 16-24 h, respectively, whereas those of L-PK peaked in 16 h and 48 h, respectively, similar timecourse to lipogenic enzymes. Moreover, GK mRNA concentrations were maximal in rats fed 20% of the ad libitum diet intake, and L-PK mRNA concentrations, like lipogenic enzyme mRNA, were maximal in rats fed approximately 50% of ad libitum intake. GK mRNA concentrations were significantly increased in parallel with an increase in plasma insulin and glucose concentrations. GK and L-PK mRNA and enzyme levels in rats fed the C diet were comparably induced to the levels in those fed the CP diet. L-PK mRNA induction by the CP diet was significantly reduced by dietary polyunsaturated fatty acids (CPF diet), whereas the GK mRNA induction was not significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of diet on the development and regulation of lipogenic enzymes in adipose tissue.

Influence of diet on the development and regulation of lipogenic enzymes in adipose tissue.

Regulation of lipogenic enzymes in human diploid fibroblasts by hormones

The hormonal regulation of two regulatory enzymes of fatty acid synthesis acetyl-CoA carboxylase (EC 6.4.1.2) and glucose-6-phosphate dehydrogenase (EC 1.1.1.49), has been investigated in human diploid fibroblasts. There was a 35% increase in acetyl-CoA carboxylase activity, 72 h following addition of 10 mU/ml insulin to the culture medium. Addition of 1 μ/ml of 3,3′5-triiodthyronine for 72 h resulted in an increase in acetyl-CoA carboxylase activity to 166% of the controls. The simultaneous addition of 1 μg/ml triidothyronine and 10 mU/ml insulin caused the enzyme activity to rise to 240% of the controls. A dose-dependent reduction in acetyl-CoA carboxylase activity was brought about by 1·10 −4 to 1·10 −3 M dibutyryul cyclic AMP. The earliest effect of dibutyryl cyclic AMP was observed within 24 h. Glucose-6-phosphate dehydrogenase followed qualitatively the same pattern of response, whereas the constitutive enzyme, lactate dehydrogenase (EC 1.1.127), did not show significant changes in these experiments. The data demonstrate common features of hormonal regulation of lipogenesis in human fibroblasts with liver and adipose tissue and substantiate the growing evidence that thyroid hormones are of major importance for the regulation of this process.

62] Cultured avian liver explants for studies of lipogenic enzymes

Publisher Summary This chapter describes the cultured avian liver explants for the studies of lipogenic enzymes. Most primary liver cell culture systems for the study of lipid metabolism involve disassociated hepatocytes and utilize serum that contains many hormones, unknown growth factors, and lipids, and thus makes it difficult to evaluate the role of hormones and lipids in the regulation of lipogenic enzymes. The characterization of an embryonic avian liver explant culture system maintained in a chemically defined culture medium, not containing serum, has made it possible to probe into the mechanism of hormonal induction of lipogenic enzymes, such as fatty acid synthase, stearoyl-CoA desaturase, and malic enzyme. The explants cultured in control medium lacking hormones maintained their initial specific activities of [U- 14 C]glucose oxidation to CO 2 , [ 3 H]uridine incorporation into RNA, and [ 3 H]leucine incorporation into cellular proteins. These results indicate that the functional viability of the liver can be maintained in explant culture for at least 120 h. The liver explant culture system is well suited for the investigation of mechanism by which insulin induces lipogenic enzymes.

Regulation of lipogenic enzymes by dietary unsaturated fatty acids in Ceratitis capitata larvae

1. 1. Enzyme activities of acetyl-CoA carboxylase, fatty acid synthetase, fatty acid chain desaturation and elongation activities as well as the fatty acid incorporation activities into acylglycerols and phosphoglycerides, have been investigated after feeding diets high in either oleic acid or linoleic acid to larvae of the Dipterous Ceratitis capitata. 2. 2. Acetyl-CoA carboxylase and fatty acid synthetase activities were depressed in the larvae fed on the unsaturated fatty acid-rich diets; these enzyme activities were mostly influenced by either linoleic acid or oleic acid, respectively. 3. 3. Both unsaturated fatty acids, mainly linoleic acid, influenced both the desaturation and the elongation of palmitoyl-CoA. Microsomal and mitochondrial desaturation decreased markedly in both nutritional status; microsomal elongation was also decreased in both dietary conditions. 4. 4. The fatty acid incorporation into acylglycerols and phosphoglycerides was mainly modified in the microsomal fraction by the unsaturated fatty acids. The diminution of the incorporation was mainly carried out by the linoleic acid-rich diet.