الفهرس 
Introduction
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Abstract
FAS is a complex multifunctional enzyme consisting of two identical monomers. The FAS monomer (270 kDa) contains seven catalytic activities. Only the dimer form of FAS is functional. The monomers are arranged in a head-to-tail manner generating two centers for palmitate synthesis. The component activities of the monomer are organized in three domains.
Every tissue in the body has some level of FAS however FAS is rich in liver, brain, breast, and lung. in adult human tissues FAS is distributed mainly in cells with high lipid metabolism (adipocytes, corpus luteum, hepatocytes, sebaceous glands, and Type II alveolar cells), in hormone-sensitive cells (anterior pituitary, apocrine gland, breast, endometrium, prostate, seminal vesicle, and adrenal cortex), and in a subset of epithelial cells of duodenum and stomach, colon absorptive cells, cerebral neurons, basket cells of cerebellum, decidua, uroepithelium, and epidymis.
FAS is the central enzyme in de novo lipogenesis, catalyzing all of the enzymatic steps in the conversion of acetyl-CoA and malonyl-CoA to palmitate. FAS activity measurements and FAS mRNA levels are frequently used as markers of de novo lipogenesis. FAS plays an important role in intracellular processes, such as apoptosis and proliferation, as well as a role in energy homeostasis. Circulating FAS is a biomarker of metabolically demanding human diseases.
FAS catalyzed endogenous fatty acid biogenesis appears to be necessary to integrate a number of signaling pathways that regulate lipid metabolism, proliferation, and survival in human epithelial cells. FAS-catalyzed de novo lipogenesis in the hypothalamus has an important impact on food intake and body weight homeostasis. FAS is believed to be a major determinant of the maximal hepatic capacity to generate fatty acids by de novo lipogenesis. Brain FAS plays a critical role in the regulation of not only feeding, but also physical activity. FAS plays an important role during embryonic development.
Based on the organization of their catalytic units, FAS systems are divided into two types. Type I FASs contain all catalytic activities of the cyclic reaction as discrete domains on a single polypeptide chain (α) or on two different polypeptides (α and β). Type I FASs are further divided into two subgroups. The first subgroup is the animal FAS. The second subgroup is the microbial FAS and it comprises some bacterial type I FASs and fungal FASs. Bacterial, plant, and mitochondrial FASs belong to the type II FAS systems.
Based on the intracellular localization of FAS two kinds of this lipogenic enzyme are classically recognized in eukaryotic cells: cytosolic (FAS I) and mitochondrial FAS (FAS II). While “cytosolic FAS” is the major responsible for the de novo biosynthesis of fatty acids, “mitochondrial FAS” provides the octanoyl precursor required for the essential lipoylation pathway.
Under normal physiological conditions any increase in FAS expression in human tissues is tightly regulated by a number of environmental, hormomal and nutritional signals. FAS activity is not known to be regulated by allosteric effectors or covalent modification.
Lipogenesis occurs in human adipose tissue and can be induced by insulin, further enhanced by glucocorticoids, and suppressed by polyunsaturated fatty acids (PUFA) in a hormone-dependent manner.
The gene for FAS is located on chromosome 17 near the q25 band, which is close to the telomere and could serve as an important marker in analysis of this chromosome. FAS gene contains three transcription initiation (Ti) sites and two promoters.
Both SREBP1 and an USF are major transcription factors regulating FAS gene transcription. FAS expression has been found to be controlled by tumor suppressors and oncogenes, including p53, p63, p73, and H-ras.
The modulation of FAS activity is a novel target for the regulation of food intake. FAS is an attractive potential target for obesity therapies because it is regulated by major mediators of energy balance and controls steady-state levels of substrates affecting food intake. Inhibition of FAS reduces food intake, incurs profound and reversible weight loss and prevents preadipocyte differentiation.
FAS is over-transcripted and over-expressed in human diabetes. Deregulation of FAS-catalyzed fatty acid synthesis is associated with the pathogenesis of obesity and type 2 diabetes that share the hallmark of insulin resistance. The quantitative determination of FAS molecules in blood might be considered a non invasive and objective method to easily and rapidly identify FAS-related metabolic altered states of insulin sensitivity in human subjects.
Circulating FAS is a biomarker of overnutrition-induced insulin resistance. Insulin-resistant conditions such as obesity, type 2 diabetes and cancer arise from a common FAS-driven ”lipogenic state”. So, the use of insulin sensitizers in parallel with forthcoming FAS inhibitors should be a valuable therapeutic approach would improve energy-flux status and ameliorate insulin sensitivity.
FAS protein, also called oncogenic antigen-519 (OA-519), is overexpressed in the majority of human malignancies and their pre-neoplastic lesions, including cancer of the prostate, breast, colorectum, ovary, bladder, oesophagus, stomach, lung, oral tongue, thyroid, skin, endometrium, and pancreas. Increased FAS protein expression is also found in nephroblastoma, mesothelioma, meningioma, glioma, melanoma and soft tissue sarcomas.
Human FAS is an attractive target as both a diagnostic and a prognostic marker for cancer cells. FAS overexpression is considered to be one of the most common molecular changes in cancer cells.
The need of malignant cells for high expression of FAS has been attributed to maintenance of the lipid supply required by highly proliferative cells, regulation of stimulatory signaling pathways through palmitoylation of proteins and stabilizing membrane domains, as well as restoration of oxidation potential through consumption of NADPH under hypoxic conditions.
FAS localizes in cancer cell culture supernatants and in the blood of cancer patients. Significant elevations of “extracellular FAS” are detected in the circulation of patients with breast, prostate, colon, pancreatic and ovarian cancer.
The extracellular form of FAS should be considered a tumor marker able to assess cancer virulence as its up-regulation is more pronounced in the late (metastatic) stages of human malignancies.
Treatment of tumor cells with pharmacologic inhibitors of FAS leads to cell cycle arrest, followed by apoptosis of the tumor cells. As FAS plays an important role in obesity and cancer initiation and progression, natural inhibitors of FAS are emerging as potential therapeutic agents to treat cancer and obesity.
Serum FAS concentrations are increased in patients with chronic liver impairment, and are associated with specific histological alterations and biochemical markers of portal inflammation. FAS measurement may contribute significantly to the evaluation of these patients. FAS may serve as a new diagnostic marker or therapeutic target for the progression of NAFLD.
High levels of extracellular FAS have recently been found in supernatants from Hepatitis C Virus-infected liver cells. There is a causal relationship between HCV infection and FAS abundance level. Induction of FAS in HCV-infected cells could also contribute to the tumorigenesis.
Estrogen modulates FAS gene expression in human perisoteum. Estrogen deficiency is one of the major causes for postmenopausal osteoporosis. FAS expression increased with absence of estrogen suggests a possible inhibitory effect of estrogen on FAS expression in periosteum.
FAS is over expressed significantly in pathologic and normal mucosa of patients with ulcerative colitis, mainly in the acute phase. FAS could be a useful signal for early detection of this condition. In patients with Celiac disease, FAS offers a measure of metabolic necessities and proliferation of small bowel epithelial cells and can be considered a marker of mucosal damage.
Human epithelial tongue cells infected with EBV express much more FAS than uninfected cells. Using FAS inhibitors may be a completely novel approach for blocking the lytic form of EBV replication.
cerulenin is a chemically unstable inhibitor of FAS. The synthetic FAS inhibitor C75 as an analog of cerulenin has both anti-obesity and anti-tumor properties. The first generation of FAS inhibitors including C75 and Orlistat, The second generation FAS inhibitor include C93. Orlistat is a novel inhibitor of the thioesterase domain of FAS. Ursolic acid, a pentacyclic triterpenoid acid, widely exists in berries, leaves, flowers, and fruits. Ursolic acid potently inhibited the activity of FAS.
Hoechst 33342 is inhibitor of FAS and this is attributed to the degradation of FAS protein by activated caspases rather than by inhibition of FAS enzyme activity or FAS mRNA synthesis. Osthole is effective in suppressing FAS expression in HER2-overexpressing breast cells. Coix seed extract could significantly inhibit FAS activity in liver.
The flavones luteolin and apigenin along with the flavonol quercetin, having the most potent inhibitory activity toward FAS. Polygonum Multiflorum Thunb., Ginkgo Biloba L. and green tea are plants that have inhibitory effect on FAS.
The phenolic constituents containing the conjugated system of phenyl and carbonyl, especially xanthones and benzophenones could be considered as a promising class of FAS inhibitors. The green tea polyphenol epigallocatechin 3-gallate (EGCG) is an inhibitor of FAS with antitumoral activity. UCM-Gi028 is a new polyphenolic compound that inhibits FAS with greater efficacy than EGCG.
Acyl-CoA Hexanoate (C6) specifically inhibits the insulin and T3 effect on FAS enzymatic activity and protein expression. C6 inhibits FAS at a transcriptional level by targeting the T3 response element on the FAS promoter.