All Journals Journal. Biochemistry and Cell Biology. Sorry, you do not have access to this content. You have requested the following content: Biochemistry and Cell Biology, , Vol. Metabolism and control of lipid structure modification. Abstract The lipid composition characteristic of a particular cellular membrane can become significantly altered, sometimes quite suddenly, when the cell is placed under environmental stress.
Cited by View all 11 citing articles. Online access to the content you have requested requires one of the following:. Trans fats also reduce HDL-C, an important lipoprotein for mediating the reverse cholesterol transport. On the other hand, phytosterols, plant proteins, isoflavones, and soluble fiber are protective diet factors against cardiovascular diseases by modulating plasma lipoprotein levels.
Therefore, diet is an important tool for the prevention and control of cardiovascular diseases, and should be taken into account as a whole, i. Keywords: cholesterol; lipoproteins; vegetable protein; fiber; fat; phytosterols. Cardiovascular diseases are caused by atherosclerosis, a process characterized by the endothelial dysfunction and deposit of cholesterol into macrophages and smooth muscle cells in the endothelial wall due to high levels of LDL-C, lipoprotein a , remnant lipoprotein, and low levels of HDL-C SCHAEFER, Hypercholesterolemia is critical to the formation of atherosclerosis.
The presence of heart disease in populations with average total cholesterol less than mg. This document recognizes that the dietary therapy is an important tool to reduce and control cholesterol levels. A small reduction, estimated in 1. The purpose of this review is to present objectively the main food components that are involved in the modulation of blood cholesterol and lipoproteins and the consequent prevention or control of cardiovascular disease by dietary means.
Fatty acids are saponifiable organic substances, which can be classified as saturated or unsaturated depending on the absence or presence of double bond in the carbon chain, respectively. Unsaturated fatty acids are classified as monounsaturated or polyunsaturated depending on the number of unsaturations in the molecule. Most fats contain different proportions of each of these fatty acids, but they are usually classified according to the predominant type.
Unsaturated fatty acids are predominantly of plant origin, whose oils are extracted from cereals, legumes, and fruits while the saturated fatty acids are predominantly of animal origin. However, coconut, cocoa, and palm oils are predominantly constituted of saturated fatty acids, whereas fish oil is rich in unsaturated fatty acids. Polyunsaturated fatty acids PUFA , precursors of n-3 and n-6 families, linoleic, and linolenic acid, respectively, are defined as essential fatty acids because they are not synthesized endogenously by humans due to lack of desaturase enzymes, which are capable of inserting double bonds between carbon and , as well as hydrogenase enzymes capable of removing such unsaturation.
Alfa linoleic acid ALA is found in green tissues of plants, soybean oil, flaxseed, and canola. The n-6 fatty acids are found in vegetable oils, except for coconut, cocoa, and palm oil. Several studies have shown that the consumption of EPA and DHA is inversely related to the incidence of cardiovascular diseases.
After two years of study, it was observed that consumption of EPA increased by four times 2. The GISSI prevention study was designed to investigate the effect of fish oil on morbidity and mortality after a heart attack. These cardioprotective benefits have been largely attributed to the anti-arrhythmic effect of EPA and DHA, but are also related to the improvement of other cardiovascular risk factors. The Institute of Medicine of the National Academies recommends that 0. Saturated fatty acids are found predominantly in animal products like butter, lard, and beef fat, but can also be obtained by the hydrogenation process of vegetable oils.
Another important source of saturated fatty acids is coconut, cocoa and palm oils. It is estimated that the relative ability of the saturated fatty acids to promote the increase of serum cholesterol is twice greater than lowering the cholesterol promoted by PUFA JAMA, Therefore, the dietary recommendations aimed at reducing the consumption of saturated fatty acids arise out of these observations.
Note that not all saturated fatty acids alter serum lipids in the same way. The main sources of trans fatty acids TFA are partially hydrogenated fats and products made with these fats, such as bakery products and fried foods. A small proportion of trans fatty acids TFA of the diet originates from fat of ruminant animals found mainly in meat and whole milk; vaccenic acid trans n-7 and elaidic acid trans n-9 represent most of the TFAS originated from the partial hydrogenation of vegetable oils.
In an observational study, it was found that the consumption of 2. It has been observed that the increase of one unit 1.hedowetalyny.ml/3645-outcall-massage.php
Biochemistry: Lipid Metabolism
According to the IV Brazilian Guidelines on Dyslipidemia and Prevention of Atherosclerosis, there is no consensus on the maximum allowed amount of trans fat in the diet. Sterols are unsaponifiable lipids containing a perhi-dropenteno-phenanthrene core. Sterols can be of animal or vegetable origin, being cholesterol and phytosterol their major components, respectively Figure 1.
The difference between cholesterol and phytosterols is that phytosterols have an ethyl group attached to carbon Cholesterol is a sterol found in animal products such as eggs, organ meats, whole milk and its derivatives, sausages, cold cuts, skinless poultry and seafood shrimp, oysters, shellfish, octopus, lobster , and pig meats. However, a review study of McNamara shows that the additional consumption of mg per day of cholesterol increases the total cholesterol by approximately 2. Among the mechanisms by which dietary cholesterol changes the plasma lipid concentrations, it is featured the inhibition of the activity of LDL receptors on the membrane.
This is a dietary strategy indicated for patients at high risk, who are seeking significant reduction in total cholesterol and LDL-C. Phytosterols, sterols, and stanols are structurally similar to cholesterol. Stanols are saturated sterols and less abundant in nature than sterols Figure 1.
Phytosterols are present in small amounts in nuts, seeds, and vegetable oils and perform analogous structural functions to cholesterol in animal tissues. More than 40 phytosterols have been identified, but sitosterol, campesterol, and stigmasterol are the most abundant. Studies have shown that phytosterols reduce LDL-C in a dose-dependent way. When they are consumed in quantities above 2. The mechanism of action by which phytosterols reduce plasma cholesterol is by competing in the absorption of cholesterol in the intestine.
After the hydrolysis of phytosterol esters in the small intestine, free sterols replace cholesterol in the micelles and thus reduce the absorption of cholesterol, but the exact mechanism is still unknown. The potential of soy protein to reduce cholesterol has been studied extensively in animals and humans. This change in total cholesterol and LDL-C was dependent on the concentration of cholesterol at baseline, and it is greater the hypocholesterolemic effect in individuals with higher cholesterol levels at baseline.
A more recent meta-analysis of 10 studies published between and , including individuals whose cholesterol levels at baseline were between and mg. Thus, it seems that the hypocholesterolemic effect of soy is relatively modest on subjects with mild hypercholesterolemia. With regard to HDL-C, a significant increase of 5. Since there was no difference in the lipoprotein concentration of the 2 groups that received soy protein, this can be interpreted in two ways: either the isoflavone is not involved in the effect on humans, or the isoflavone has reached a plateau with respect to the ability to influence the blood lipid profile.
The mechanism of action of soy protein in reducing blood cholesterol has not been fully elucidated. So far, only soy protein health claim has been approved, both nationally and internationally. The two bodies, respectively, also recommended that soy consumption should be associated with a balanced diet and a healthy lifestyle, and a diet low in saturated fatty acids. The main sources of soy in the diet are soybean oil, soy bean curd tofu , soy sauce, soy flour, soy milk, and soy protein concentrate.
Other legume seed proteins are being studied in order to evaluate their hypocholesterolemic effect.
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Another grain that had been recently studied is amaranth, a pseudoceral, whose protein isolate IPA proved quite effective in reducing cholesterol in hypercholesterolemized hamsters. These results illustrated how plant proteins often show a protective effect against hypercholesterolemia. However, this effect should not be considered alone. Isoflavones are a class of phytoestrogens, a group of phytochemical from plant with non-steroidal estrogen-like activity.
The presence of the phenol ring and the distance between the hydroxyl group, which are identical in estradiol and isoflavones, are considered prerequisites for estrogen action SETCHELL, It is this chemical and structural similarity of endogenous estrogen that leads to the hypothesis that isoflavones may be responsible for the hypocholesterolemic effect of soy SETCHELL, Isoflavones are widespread in legumes and are present in greater amounts in soy.
Genistein, daidzein and glycitein are the major soy isoflavones. Genistein and daidzein are conjugated to sugar as glycosides. It has been shown that equol has a higher affinity for estrogen receptors than daidzein. They can be released from the original protein during gastrointestinal digestion or during food processing. They can be absorbed, and thus exert a systemic effect. Since isolated soy protein appears to be the bioactive component in soy responsible for the beneficial effect on lipid metabolism, a new line of research was developed recently, in which the soy peptides are studied.
Furthermore, the more aggressive cancer cell lines and high grade primary tumors contain increased free fatty acid levels, which could be reduced by the MAGL inhibitor JZL and short hairpin RNAs, suggesting MAGL-dependent lipolysis is a major source of intracellular free fatty acids. The MAGL-regulated lipid hydrolysis appears to be important for the transformed properties of tumor cells. Inhibition of MAGL inhibits migration, invasion and survival of cancer cells in vitro and xenograft tumor growth in mice.
Strikingly, the functional defects of MAGL inhibition were reversed by exogenous addition of saturated fatty acids in vitro or feeding mice a high-fat diet. The question raised from this study is why both lipogenesis and lipolysis are increased in cancer cells. Further studies need to be performed to test whether fatty acids derived from de novo synthesis versus lipolytic release differ in both compositions and functions. In addition to their recognized roles in regulating cell proliferation and survival, these oncogenic signals also promote the expression and activity of enzymes involved in fatty acid synthesis.
It has been reported that oncogenic signaling pathways regulate lipid metabolism at multiple steps, including transcriptional, translational and post-translational levels. FASN and ACC are used here as two examples to depict the complexity of oncogenic signal regulation of lipid metabolizing enzymes. Recent reports show that FASN expression is also modulated by other transcription factors, such as the members of p53 family and the lipogenesis-related nuclear protein SPOT14[ 39 , 40 ]. Furthermore, posttranslational regulation also contributes to the regulation of FASN expression in cancer cells.
Functional inactivation of USP2a results in reduced FASN protein expression and decreased cell proliferation and enhanced apoptosis[ 41 ]. In prostate adenocarcinoma, the significant gain in FASN gene copy number is supposed to cause the resultant increase in FASN protein expression[ 42 ]. In addition to the intracellular signaling pathways, FASN expression is also affected by extracellular microenvironmental stresses. The hostile microenvironment of solid tumors, such as hypoxia, low pH, and nutrient starvation could activate several intracellular signaling pathways to promote FASN expression[ 36 ].
In addition, extracellular acidosis can upregulate the transcriptional expression of FASN gene in breast cancer cells via an epigenetic fashion[ 44 ]. De novo lipid biosynthesis is directly supported by the generation of acetyl-CoA and NADPH from glucose and glutamine metabolism, which is regulated by a number of oncoproteins and tumor suppressors.
Glycolysis provides the carbon source, acetyl-CoA, for the de novo fatty acid synthesis. During aerobic glycolysis, glucose is broken down to pyruvate. A series of enzymes are involved in the glycolytic reaction and considered to be highly relevant to tumorigenesis, such as glucose transporter 1 GLUT1 , hexokinase HK , pyruvate kinase PK [ 51 , 52 ]. Glucose-derived pyruvate sequentially enters the mitochondria and is decarboxylated to acetyl-CoA by pyruvate dehydrogenase PDH , an enzyme located in the inner mitochondrial membrane. A part of citrate generated from the TCA cycle exits mitochondria and is catalyzed by ACL to cytosolic acetyl-CoA, as the precursor of fatty acids biosynthesis[ 53 ].
To maintain TCA cycle, the citrate exported to cytosol from mitochondria must be replenished. The recurrence of citrate is through glutaminolysis. Myc also plays critical role in glutamine metabolism. It promotes glutaminolysis and triggers cellular addiction to glutamine by direct and indirect transcriptional regulation of genes involved in glutamine metabolism. On one hand, Myc binds to the promoters and induces the expression of SLC38A5 and SLC1A5, two high affinity glutamine transporters, to promote cellular glutaminolysis[ 57 , 58 ].
Suppression of Myc expression using small hairpin RNAs in human SF glioma cells leads to a significant reduction in glutaminolysis, indicated by glutamine consumption and ammonia production[ 58 ]. On the other hand, Myc represses the transcription of miRa and miRb, leading to greater expression of their target protein, mitochondrial glutaminase, in human P B lymphoma cells and PC3 prostate cancer cells[ 59 ], therefore, enhancing cancer cell glutaminolysis indirectly.
Moreover, Myc-stimulated mitochondrial glutamine metabolism results in a decreased contribution of glucose to the mitochondrial-dependent synthesis of phospholipids[ 57 ]. NADPH is another essential component required for fatty acid biosynthesis. Enhanced lipogenesis in cancer cells has also been proposed to be required to balance the redox potential through the use of NADP oxidase[ 60 ]. The predominant one is through the pentose phosphate pathway PPP.
The inhibition effect of p53 is independent of its transcriptional activity and is through directly controlling the enzymatic activity of G6PDH[ 63 ]. In addition, PPP is regulated by pyruvate kinase isoform M2 PKM2 , which is predominantly expressed in self-renewing cells such as embryonic and adult stem cells and tumor cells[ 65 ]. PKM2 controls the conversion of phosphoenolpyruvate PEP to pyruvate, the rate-limiting step of glycolysis. Knockdown of PKM2 expression in human cancer cell lines and replacing it with PKM1 reduced tumor formation in nude mouse xenografts, correlated with the decreased lactate production and increased oxygen consumption[ 66 ].
OAA derived from cytosolic citrate is catalyzed to malate, which is converted to pyruvate by malic enzyme concurrently generating NADPH. Therefore, malic enzyme is considered to be a lipogenic enzyme whose activity correlates with de novo fatty acid synthesis[ 67 ] and is found to be highly expressed in tumor cells[ 68 ]. Many enzymes involved in lipid metabolism are selectively overexpressed in cancer cells, making them good targets for cancer therapy.
Indeed, a variety of agents have been developed to target lipogenic enzymes and the key regulators involved in lipid metabolism in cancer cell for therapeutic purpose. One of the most attractive targets for inhibition in cancer chemotherapy is FASN, due to its high degree of overexpression in cancer cells. When used in in vitro , xenograft and genetically induced mouse model studies, these inhibitors have supported FASN as an excellent target[ 1 , 69 ]. They killed cancer directly or sensitized them to other therapies such as 5-fluorouracil and trastuzumab[ 70 - 73 ].
A potential negative aspect of FASN inhibition might be its effect on food intake and body weight. Mice treated with cerulenin and C75 exhibited decreasing eating and consequent rapid weight loss, which may be caused by the inhibition of carnitine palmitoyltransferase 1 CPT-1 in the hypothalamus[ 74 - 76 ]. In addition to FASN, other lipogenic enzymes are also promising targets for cancer therapy. Stable knockdown of ACL by RNAi significantly impairs glucose-dependent lipid synthesis and decreases cytokine-stimulated cell proliferation in vitro and prevents Akt-mediated tumorigenesis in vivo [ 53 ].
Selective inhibition of ACL by chemical inhibitor SB limits proliferation and survival of tumor cells in vitro and in vivo [ 21 , 22 ]. In preclinical studies, 6-amino-nicotinamide 6-An that inhibits G6PDH, have demonstrated anti-tumorigenic effects in leukemia, glioblastoma and lung cancer cell lines[ 78 ]. Furthermore, targeting fatty acid oxidation also appears to be promising. Additionally, MAGL inhibitors suppress the pathogenesis of aggressive cancer cells[ 34 ].
There are increasing evidences to support that oncoproteins directly reprogram the metabolism of cancer cells, and make them addict to certain metabolic pathways. Therefore, the signaling pathways controlling the altered metabolism in cancer cells are attractive targets for cancer therapy. Like the Warburg effect, alteration of lipid metabolism is another nearly ubiquitous change in tumor cells. However, there is a lack of clear understanding of lipid metabolism in cancer cells.
The increased de novo lipogenesis in cancer cells has been well described. Interestingly, recent studies also reported that lipolysis and lipid oxidation are upregulated in cancer cells[ 18 , 31 , 34 ]. In fact, fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer cells[ 18 ]. It is still unclear why both lipid biosynthetic and mobilizing activities are upregulated in cancer cells. Further investigation on the regulation of these pathways will offer new therapeutic opportunities for the development of anticancer agents.
Meanwhile, these tumor-associated lipid metabolism features may be used in the diagnosis and prognosis of human cancers. Peer reviewers: Ming Zhang, Dr. Advanced Search. This Article. Citation of this article. Zhang F, Du G. Dysregulated lipid metabolism in cancer. Corresponding Author of This Article. Article-Type of This Article. Open-Access Policy of This Article.
Biochemistry and Cell Biology
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Total Article Views All Articles published online. Times Cited of This Article. Journal Information of This Article. All rights reserved. World J Biol Chem. Author contributions : All authors made the equal contributions. Citation: Zhang F, Du G. This scheme represents the main regulation of lipogenesis in cancer cells.
Lipid metabolizing enzymes are regulated by oncogenic signals. Growth factor-activated PI3K-AKT or hypoxia-induced HIF stimulates glucose transporters and hexokinases to promote glycolysis, providing more synthetic precursors for fatty acid synthesis.