Lipid Metabolism, Metabolic Syndrome, and Cancer
In rodents, inhibition of ceramide de novo synthesis pathway by serine palmitoyltransferase inhibitor myriocin improves insulin sensitivity and prevents insulin resistance associated metabolic diseases [ 30 , 34 - 36 ]. In humans, it is well documented the association of ceramides accumulation in peripheral tissues, including muscle and fat, of obese subjects with insulin resistance [ 37 - 40 ].
Since the s, it has long been believed that consumption of foods containing high amounts of SFAs, including meat fats, milk fat, butter, lard, coconut oil, etc, is not only a risk factor for dyslipidemia and insulin resistance, but also a risk factor for cardiovascular diseases.
However, recent evidence from systematic reviews, meta-analyses and prospective cohort studies indicates that SFAs alone maybe not associated with an increased risk of cardiovascular disease. A randomized controlled dietary intervention trial that compared a carbohydrate restricted diet to a low fat diet over a week period in overweight subjects with atherogenic dyslipidemia found that carbohydrate restriction, rather than a low fat diet may improve features of MS and cardiovascular risk [ 41 ].
In a recent cross-sectional study conducted in Japanese to exam the relationship between dietary ratio of PUFA to SFA with cardiovascular risk factors and MS, the data showed that dietary polyunsaturated to saturated fatty acid ratio was significantly and inversely related to serum total and LDL cholesterol, but did not significantly relate to single metabolic risk factors or the prevalence of MS [ 42 ].
However, on the other hand, some SFAs such as stearic acid and fatty acids found in milk and milk products appear to be beneficial and may diminish the risk for cardiovascular disease. Palmitoleic acid cis, n-7 has been linked to both beneficial metabolic effects. It has been reported that adipose-produced cis-palmitoleate directly improved hepatic and skeletal muscle insulin resistance and related metabolic abnormalities, and suppressed hepatic fat synthesis as well [ 44 ].
A prospective cohort study showed that circulating trans-palmitoleate trans, n-7 is associated with lower insulin resistance, decreased presence of atherogenic dyslipidemia, and incidence of diabetes incidence [ 45 ] suggesting metabolic benefits of dairy consumption. There is also strong evidence collected by systematic review and meta-analysis of randomized controlled trials showing that consumption of polyunsaturated fat as a replacement for saturated fat alleviates coronary heart disease risk [ 46 ].
While many studies have found that replacement of saturated fats with polyunsaturated fats in the diet produces more beneficial outcomes on cardiovascular health [ 47 , 48 ], the effects of substituting monounsaturated fats or carbohydrates are still unclear. In human diets, ALA is usually derived from botanical sources such as perilla, flaxseed, canola, rapeseed, soybean, linseed and walnut. Recent researches have shown that, while diets rich in saturated fatty acids SFAs are associated with an increased prevalence of obesity and type 2 diabetes, supplement of omega-3 PUFAs rich in eicosapentaenoic acid EPA and docosahexaenoic acid DHA has anti-inflammatory and anti-obesity effects and protect against metabolic abnormalities [ 50 ].
Earlier epidemiologic observations showed the beneficial properties of n-3 PUFAs in populations consuming large amounts of fatty fish and marine mammal oils [ 51 ]. Later studies showed that a 3-wk supplement with fish oil rich in n-3 PUFA in healthy humans resulted in improved sensitivity to insulin, higher fat oxidation, and increased glycogen storage [ 52 ]. Most subsequent studies confirmed these effects and observed that supplementation with n-3 PUFAs, either EPA or DHA alone, or with their combination in fish oil, has favorably effects on many adverse serum and tissue lipid alterations related to the metabolic syndrome by reducing levels of fasting and postprandial serum triacylglycerols and free fatty acids [ 53 , 54 ].
Some of the effects of n-3 PUFAs on lipid and lipoprotein metabolism could remain in subjects who become overtly diabetic. In addition, other recognized benefits of n-3 PUFAs include a reduction in inflammatory status, decreased platelet activation, mild reduction in blood pressure, improved endothelial function, and increased cellular antioxidant defense, all of which may prove particularly favorable in overweight, hypertensive patients [ 55 ].
Adipose tissue depots compromise heart health
Furthermore, supplementation with fish oil also blunted the sympathetic activity elicited by mental stress in healthy volunteers [ 56 ]. However, the beneficiary effects of n-3 PUFA supplementation on cardiovascular risk prevention are association with other components of lifestyle, ie, weight control, regular physical activity, and consumption of other dietary ingredients contributing to risk reduction [ 57 ].
Studies in animal and humans have demonstrated that, in addition to be used as fuels and structural components of the cell, the dietary intake of marine fish oil is also effective in lowering both triglyceride Tg and VLDL-Tg concentration in experimental animals and normal and hyper- triglyceridemic men [ 58 , 59 ], which might be related to decreased mRNA encoding several proteins involved in hepatic lipogenesis including SREBP1, and enhanced fatty acid oxidation throughout a peroxisome proliferator- activated receptors PPARs —stimulated process [ 60 , 61 ].
Moreover, n-3 PUFAs elevate the fatty acid composition of membrane phospholipids that modify membrane-mediated processes such as insulin transduction signals, activities of lipases and biosynthesis of eicosanoids [ 62 ]. Furthermore, dietary fish oil consumption normalizes the function of many tissues or cells involved in insulin sensitivity in the sucrose-rich diet SRD fed rats.
It reverses dyslipidemia and improves insulin action and adiposity by reducing adipocytes cell size, increasing insulin sensitive and decreasing the release of fatty acids. Both oxidative and non-oxidative glucose pathways are improved in muscle. In isolated beta cells, lipid contents and glucose oxidation return to normal [ 63 ]. All these effects lead to the improvement of glucose- stimulated insulin secretion and muscle insulin insensitivity.
Adipose tissue plays a key role in the development of MetS and improvement of adipose tissue function is specifically linked to the beneficial effects of n-3 PUFA [ 64 ].
Lipid metabolism - Wikipedia
Case—control and cohort studies have found positive associations between several cancers such as prostate cancer[ 67 ], ovarian cancer[ 68 ], breast cancer[ 69 ], colon cancer[ 70 ] etc, and an intake of foods with high levels of saturated fats, such as red meat, eggs, and dairy products. However, controversial results have also been reported about the role of high fat diet in carcinogenicity [ 71 , 72 ].
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This is largely due to the complexity of the diet, not only the fat components such as SFA, MUFA, and PUFA may vary among people in different regions, but also other non-fat nutrients may also alter the function of fat. Therefore only preclinical animal studies with clearly-defined fat composition may help elucidate the causal relationship between dietary fat and cancer. Interested readers are advised to read recent review articles about the association of dietary lipids with prostate [ 75 ] and breast cancer [ 76 ], and potential mechanisms for the association of dietary lipids with cancer [ 77 - 79 ].
Recent studies have shown that high fat diet with saturated animal fat as major fat in the diet is associated with several cancer such as prostate cancer[ 67 ], colon cancer[ 80 ], ovarian cancer[ 68 ] and breast cancer[ 81 ]etc, whereas high fat diet with plant oils is not associated with cancer risk, however this may not be true, plant oils high in omega-6 fatty acids may be risk factors for cancer, which will be discussed in the polyunsaturated fatty acid section.
It has been found that cancer incidence in the Mediterranean countries, where the main source of fat is olive oil, is lower than in other areas of the world.
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Such effects may be due to the main MUFA in olive oil, oleic acid, and to certain minor compounds such as squalene and phenolic compounds [ 82 ]. Recent studies have also shown that canola oil, with high MUFA, oleic acid, can decrease colon and breast cancer incidence significantly [ 83 , 84 ].
So far, no epidemiological studies or animal studies can clearly demonstrate the preventive effect of MUFA on cancer, However, in vivo analysis of the fatty acid composition of the adipose tissue of breast cancer and healthy women showed that elevated adipose MUFA, oleic acid, are associated with reduced odds of breast cancer[ 85 ]. Increasing evidences from animal and in vitro studies indicate that populations who ingest high amounts of omega-3 fatty acids in their diets have lower incidences of breast, colon, and, perhaps, prostate cancers.
Paola et al. Berquin et al.
Although it has been generally accepted that dietary lipids are associated with carcinogenesis and the development of cancer, the detailed mechanism is still far from clear. They can also be used for membrane lipid biosynthesis. Upon environmental stimulus, these lipids may be hydrolyzed and free fatty acidsare released. Omega-6 PUFAs such as ARA released from membrane lipids will be converted to normal eicosanoids, and regulate cellular physiology; however elevated levels of these eicosanoids may accelerate cell proliferation and lead to inflammation and carcinogenesis, etc[ 92 ].
Whereas omega-3 PUFAs such as EPA, when released from membrane lipids, may be converted to eicosanoids with opposite activity to the product of omega-6 fatty acids, which inhibit cell proliferation and COX-2 activity, thus providing cancer preventive function[ 93 ]. Another mechanism of regulation of cancer initiation and development may be elucidated by fatty acid signaling pathway through its receptors. In particular, two transcription factors, sterol regulatory element binding protein-1c SREBP-1c and peroxisome proliferator activated receptor alpha PPAR alpha , have emerged as key mediators of gene regulation by FA [ 94 , 95 ].
SREBP-1c induces a set of lipogenic enzymes in liver. Thus inhibits the de novo lipogenesis of fatty acids, which is of particular importance for cancer cells [ 96 ]. PPAR alpha plays an essential role in metabolic adaptation to fasting by inducing the genes for mitochondrial and peroxisomal FA oxidation as well as those for ketogenesis in mitochondria. PPAR alpha is also required for regulating the synthesis of highly unsaturated FA, indicating pleiotropic functions of PPAR alpha in the regulation of lipid metabolic pathways.
Thus, in addition to its inhibition of fatty acid biosynthesis through SREBP, omega-3 fatty acids induce fatty acid degradation through PPAR alpha, in so doing, they regulate fatty acid metabolism and metabolic diseases. Multiple mechanisms of omega-3 fatty acids mediated inhibition of cancer may include suppression of neoplastic transformation and cell growth,and enhanced apoptosis and antiangiogenicity etc[ 97 ].
De novo fatty acid biosynthesis occurs in essentially all cells, but adipose tissue and liver are the major sites. The first committed step in fatty acid synthesis is catalyzed by fatty acid synthase FAS , a multifunctional cytosolic protein that primarily synthesizes palmitate. Variations in FAS expression and enzyme activity have been implicated in insulin resistance and obesity in humans [ 98 ]. A circulating form of FAS has been reported as a biomarker of metabolic stress and insulin sensitivity. In humans it changes with weight loss and may reflect improved insulin sensitivity [ 99 ].
Fatty acid elongation is catalyzed by Elovl elongation of very long-chain fatty acid proteins. Elovl6 is thought to be involved in de novo lipogenesis and is regulated by dietary, hormonal and developmental factors. Mice with Elov6 deficiency are obese but protected from insulin resistance [ , ]. Malonyl-CoA is a potent inhibitor of carnitine- palmitoyl transferase 1 CPT1 , which transports FAs into the mitochondria for oxidation, thus plays a key role in the regulation of both mitochondrial fatty acid oxidation and fat synthesis.
ACC catalyzes a key rate-controlling step in both de novo lipogenesis and fatty acid oxidation. Lipogenesis and FA oxidation are highly integrated processes. Studies in genetically modified mice have demonstrated that inhibition of FA synthesis and storage is associated with upregulation of FA oxidation [ ].
For examples, knockout the diacylglycerol acyltransferase DGAT , an enzyme that catalyses the final acylation step of TAG synthesis, reduced fat deposition and protected mice against diet- induced obesity and, in the meanwhile, elevated mice energy expenditure and increased activity, suggesting a correlation of disrupted FA storage and increased FA oxidation [ , ]. As a major component of the metabolic syndrome, NAFLD characterizes with the accumulation of TAGs in hepatocytes, and development of steatohepatitis, cirrhosis, and hepatocellular carcinoma.
FAs stored in adipose tissue and newly made through liver de novo lipogenesis are the major sources of TAGs in the liver [ ]. Lipogenesis is also an insulin- and glucose-dependent process that is under the control of specific transcription factors.
SREBP1 gene expression is decreased in adipose tissue of obese subjects and the aberrant activation of SREBPs may contribute to obesity-related pathophysiology in various organs, including cardiac arrhythmogenesis and hepatic insulin resistance. Lipogenesis is also regulated by glucose activated carbohydrate response element-binding protein ChREBP , which induces gene expression of liver-type pyruvate kinase, a key regulatory enzyme in glycolysis; this enzyme in turn provides the precursors for lipogenesis [ ].
ChREBP knockout mice show decreased liver triglyceride but increased liver glycogen content indicating that ChREBP may regulate metabolic gene expression to convert excess carbohydrate into triglyceride rather than glycogen [ ]. Enhanced flux of glucose derivatives through glycolysis, which sustain the redirection of mitochondrial ATP to glucose phosphorylation, and de novo FA synthesis is a hallmark of aggressive cancers. Lipogenic enzymes such as, FAS, ACC, and ACL involved in FA biosynthesis, glycerolphosphate dehydrogenase involved in lipid biosynthesiss, and SREBP1, the master regulator oflipogenicgene expression, are found to be overexpressed in a number of cancer or cancer cells, such as prostate cancer[ ], ovarian cancer[ ], breast cancer[ ], lung cancer[ ], colon cancer[ ], and etc.
Some research has been carried out to provide insights into the molecular mechanism of the association of lipogenesis and cancer.