**2. Dietary lipids and metabolic diseases**

### **2.1. Dietary lipids and metabolic syndrome**

MS, also known as syndrome X, or the insulin resistance syndrome, is a combination of medical disorders comprising an array of metabolic risk factors including central obesity, dyslipidemia, hypertension, glucose intolerance, and insulin resistance[7]. The worldwide prevalence of MS causes lots of health problems not only in the developed countries, but also in the developing countries as well. Individuals with MS are at high risk for diabetes and cardiovascular disease. Increasingly accumulated evidence shows that aberrations in lipid metabolism are the central to the etiology of MS.

As one of the most abundant lipid species and major components of very-low-density lipoprotein (VLDL) and chylomicrons, triacylglycerols (TAG) play an important role in metabolism as energy sources. It can be acquired from de novo synthesis in liver or dietary lipids. Depending on the oil source, TAGs are either the main constituents of vegetable oils (typically more unsaturated) or animal fats (typically more saturated). Animal fat comprises about 40% of the energy intake in the human diet in Western countries, and a high proportion of this is TAG. Fat tissue, liver and intestine are the major places where TAG is synthesized and stored. There is also some intracellular storage of TAG e.g. in the muscle and brain cells. The storage of TAG can be replenished from dietary fat, or by endogenous synthesis of fat from carbohydrates or proteins, which mainly takes place in the liver.

The overabundance of nutrients such as lipids in obesity and caloric surplus leads to aberrant lipid management and ectopic fat accumulation (i.e., ''lipotoxicity''), which is a fundamental component of metabolic disease and insulin resistance [8, 9].

#### *2.1.1. Fatty acids and insulin resistance*

186 Lipid Metabolism

and cardiovascular diseases [6].

proliferation. Disruption of phospholipid homeostasis may lead to carcinogenesis and MS [4, 5]. Triacylglycerol, as an important energy storage form, is closely related to glucose homeostasis and its disregulation is associated with onset of MS such as diabetes, obesity,

In this chapter, we focused on the metabolism of phospholipid and triacylglycerol (including fatty acids) and discussed the association of lipid metabolism disorders with pathogenesis of MS and cancer as shown in Figure1. We also discussed the emerging role of omega-3 polyunsaturated fatty acids in preventing lipid disorder associated MS and cancer.

Dietary Lipids

De novo synthesis

**Figure 1.** Inter-relationship between lipid metabolism, metabolic syndrome and cancer

Metabolic syndrome cancer

Metabolic signaling Mitogenic signaling

Lipid metabolism

Insulin resistance

MS, also known as syndrome X, or the insulin resistance syndrome, is a combination of medical disorders comprising an array of metabolic risk factors including central obesity, dyslipidemia, hypertension, glucose intolerance, and insulin resistance[7]. The worldwide prevalence of MS causes lots of health problems not only in the developed countries, but also in the developing countries as well. Individuals with MS are at high risk for diabetes and cardiovascular disease. Increasingly accumulated evidence shows that aberrations in

**2. Dietary lipids and metabolic diseases** 

Beta oxidation

**2.1. Dietary lipids and metabolic syndrome** 

lipid metabolism are the central to the etiology of MS.

Insulin resistance is the center underlying the different metabolic abnormalities in the metabolic syndrome, in which pathophysiological conditions insulin becomes less effective in lowering blood glucose. Insulin resistance can be induced by various environmental factors, including dietary habits. Muscle, liver and fat are the three major tissues for maintaining blood glucose levels. In the presence of insulin, fat and muscle cells absorb glucose, and the liver regulates glucose levels by reducing its secretion and increasing its storage in the form of glycogen. However, in the condition of insulin resistance, glucose uptake by muscle and fat cells is disrupted, and glycogen synthesis and storage are also reduced in liver cells, resulting in failure of suppressing glucose production and releasing into the blood. Impaired glucose metabolism is associated with molecular alterations of insulin signaling, which is particularly well characterized in muscle [10].

Insulin also facilitates the uptake and storage of amino acids and fatty acids by converting them to protein and lipid, respectively. Besides the diminished glucose- lowering effects, insulin resistance also causes reduced actions of insulin on lipids and results in decreased uptake of circulating lipids and increased hydrolysis of stored triglycerides and, as a consequence, elevates free fatty acids in the blood plasma. Elevated levels of free fatty acids and triglycerides in the blood and tissues have been reported to contribute to impaired insulin sensitivity in many studies [11, 12]. Increased contents of fatty acids and their metabolites cause phosphorylation of insulin receptor substrate 1 (IRS-1) at serine, which blocks IRS-1 tyrosine phosphorylation and the associated activation of phosphatidylinositol-3' kinase (PI3K) activity, and results in a decreased translocation of the glucose transporter GLUT4 to membrane of muscle and liver cells [13, 14].

The conversion of fatty acids to acetyl-CoA, the process known as β-oxidation, mainly occurs in the mitochondria. Defects in mitochondrial fatty acid oxidation and in adipocyte fat metabolism may increase fatty acid content in muscle and liver, which, in turn, cause impaired transport of glucose and defective glycogen synthesis in muscle, and sustained output of glucose from the liver, which finally lead to hyperinsulinemia and insulin resistance. In addition, oxidative stress and cytokine induction in liver may lead to the development of nonalcoholic fatty liver (NAFLD). Considerable experimental evidence suggests that increased hepatic fat synthesis contributes to nonalcoholic steatohepatitis and associated insulin resistance [15].

Lipid Metabolism, Metabolic Syndrome, and Cancer 189

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

Since the 1950s, 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 12-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. In a systematic review, after comparing with those of trans, other saturated, and unsaturated fatty acids (USFAs), Hunter et al [43] found that stearic acid raised LDL cholesterol, and compared with USFA, stearic acid lowered HDL cholesterol and increased

Palmitoleic acid (cis-16:1, 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 transpalmitoleate (trans-16:1, 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.

Omega-3 PUFAs (also called ω−3 fatty acids or n−3 fatty acids are commonly found in marine and plant oils, which contain a double bond at the third carbon atom from the

resistance [37-40].

*2.1.2. Fatty acids and cardiovascular diseases* 

the total cholesterol/HDL cholesterol ratio [43].

*2.1.3. Omega-3 PUFAs and metabolic syndrome* 

Dietary fat composition is the major sources of free fatty acids in the blood and tissue. Consumption of high fat diets is strongly and positively associated with overweight that, in turn, deteriorates insulin sensitivity, particularly when the excess of body fat is located in abdominal region. Epidemiological evidence and experimental animal studies clearly show that saturated fat significantly worsen insulin resistance, while monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) improve it through modifications in the composition of cell membranes, and an elevated ratio of saturated fats to unsaturated fats is a risk factor for MS [16, 17].

A multicenter study has shown that shifting from a diet rich in saturated fatty acids (SFAs) to one rich in monounsaturated fat improves insulin sensitivity in healthy people [18]. Substitution of unsaturated fat for saturated fat reduces both LDL cholesterol and plasma triglycerides in insulin resistant individuals [16]. Several early cross- sectional studies have found a positive association between saturated fat intake and hyperinsulinaemia, and insulin resistance [19, 20], while polyunsaturated fat intake was inversely associated with plasma insulin levels whereas linoleic acid intake was positively associated with fasting plasma insulin concentrations, and increased unsaturated fat intake is associated with improved insulin sensitivity [16, 21].

In addition, numerous observations in rodent and cell culture models as well as obese and diabetic humans have shown that chronic lipid exposure is associated with insulin resistance [22-24], and fatty acid composition in body tissues is related to the incidence of diabetes [25]. Particular, intramuscular or hepatic content of TAG, diacylglycerol (DAG), or ceramide is negatively correlated with insulin sensitivity [26-28], which may be caused by disrupted insulin-stimulated translocation of the GLUT4 by ectopic accumulation of TAG and other lipid molecules in liver and muscle.

More and more evidence suggests that ceramide, composition of sphingosine and fatty acid and found in high concentrations within the cell membrane, plays a critical role in insulin resistance [29]. Both *in vitro* and *in vivo* studies have produced a large body of data implicating that accumulation of ceramide and its metabolites is associated with nutrientinduced pathogenesis of insulin resistance and metabolic diseases, including diabetes, cardiomyopathy, and atherosclerosis [28-30]. In cultured cells, ceramide inhibits insulinstimulated glucose uptake by blocking translocation of the glucose transporter GLUT4, and glycogen synthesis [31, 32]. These effects are due to the ability of ceramide to block activation of Akt/PKB, a serine/threonine kinase that is activated by insulin and growthfactors. It is also found that accumulation of ceramide may impair mitochondrial function by altering mitochondrial membrane permeability, inhibiting electron transport chain intermediates, and promoting oxidative stress [33].

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].

#### *2.1.2. Fatty acids and cardiovascular diseases*

188 Lipid Metabolism

associated insulin resistance [15].

a risk factor for MS [16, 17].

improved insulin sensitivity [16, 21].

and other lipid molecules in liver and muscle.

intermediates, and promoting oxidative stress [33].

output of glucose from the liver, which finally lead to hyperinsulinemia and insulin resistance. In addition, oxidative stress and cytokine induction in liver may lead to the development of nonalcoholic fatty liver (NAFLD). Considerable experimental evidence suggests that increased hepatic fat synthesis contributes to nonalcoholic steatohepatitis and

Dietary fat composition is the major sources of free fatty acids in the blood and tissue. Consumption of high fat diets is strongly and positively associated with overweight that, in turn, deteriorates insulin sensitivity, particularly when the excess of body fat is located in abdominal region. Epidemiological evidence and experimental animal studies clearly show that saturated fat significantly worsen insulin resistance, while monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) improve it through modifications in the composition of cell membranes, and an elevated ratio of saturated fats to unsaturated fats is

A multicenter study has shown that shifting from a diet rich in saturated fatty acids (SFAs) to one rich in monounsaturated fat improves insulin sensitivity in healthy people [18]. Substitution of unsaturated fat for saturated fat reduces both LDL cholesterol and plasma triglycerides in insulin resistant individuals [16]. Several early cross- sectional studies have found a positive association between saturated fat intake and hyperinsulinaemia, and insulin resistance [19, 20], while polyunsaturated fat intake was inversely associated with plasma insulin levels whereas linoleic acid intake was positively associated with fasting plasma insulin concentrations, and increased unsaturated fat intake is associated with

In addition, numerous observations in rodent and cell culture models as well as obese and diabetic humans have shown that chronic lipid exposure is associated with insulin resistance [22-24], and fatty acid composition in body tissues is related to the incidence of diabetes [25]. Particular, intramuscular or hepatic content of TAG, diacylglycerol (DAG), or ceramide is negatively correlated with insulin sensitivity [26-28], which may be caused by disrupted insulin-stimulated translocation of the GLUT4 by ectopic accumulation of TAG

More and more evidence suggests that ceramide, composition of sphingosine and fatty acid and found in high concentrations within the cell membrane, plays a critical role in insulin resistance [29]. Both *in vitro* and *in vivo* studies have produced a large body of data implicating that accumulation of ceramide and its metabolites is associated with nutrientinduced pathogenesis of insulin resistance and metabolic diseases, including diabetes, cardiomyopathy, and atherosclerosis [28-30]. In cultured cells, ceramide inhibits insulinstimulated glucose uptake by blocking translocation of the glucose transporter GLUT4, and glycogen synthesis [31, 32]. These effects are due to the ability of ceramide to block activation of Akt/PKB, a serine/threonine kinase that is activated by insulin and growthfactors. It is also found that accumulation of ceramide may impair mitochondrial function by altering mitochondrial membrane permeability, inhibiting electron transport chain Since the 1950s, 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 12-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. In a systematic review, after comparing with those of trans, other saturated, and unsaturated fatty acids (USFAs), Hunter et al [43] found that stearic acid raised LDL cholesterol, and compared with USFA, stearic acid lowered HDL cholesterol and increased the total cholesterol/HDL cholesterol ratio [43].

Palmitoleic acid (cis-16:1, 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 transpalmitoleate (trans-16:1, 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.

#### *2.1.3. Omega-3 PUFAs and metabolic syndrome*

Omega-3 PUFAs (also called ω−3 fatty acids or n−3 fatty acids are commonly found in marine and plant oils, which contain a double bond at the third carbon atom from the

#### 190 Lipid Metabolism

methyl-end of the carbon chain. These PUFAs, including α-linolenic acid (ALA, 18:3, n-3), eicosapentaenoic acid (EPA, 20:5, n−3) and docosahexaenoic acid (DHA, 22:6, n−3), are considered as essential fatty acids because they can not be de novo synthesized by the human body. In human diets, ALA is usually derived from botanical sources such as perilla, flaxseed, canola, rapeseed, soybean, linseed and walnut. EPA and DHA are found in fish and some other sea foods [49]. 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].

Lipid Metabolism, Metabolic Syndrome, and Cancer 191

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]. In accordance with the general anti-inammatory action, n-3 PUFA supplementation induces production and secretion of adiponectin [65], the major adipokine exerting an insulin-sensitizing effect, and prevents adipose tissue hyperplasia and hypertrophy, and induces mitochondrial biogenesis in adipocytes [66], which effects maybe mediated by n-3 PUFA induced AMP-activated protein

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]. 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. Up to now, it is generally accepted that cis-MUFA and omega-3 PUFAs are inversely associated with the increased risk of cancer, while SFA and omega-6 PUFAs are associated with the development of cancer [73]. However, physiologically, the metabolism of fatty acids are connected, any results based on a single fatty acids may be incomprehensive, therefore a fat containing diet with elevated MUFA and low ratio of omega-6/omega-3 fatty acid is suggested to be associated with cancer prevention and protection [74]. Interested readers are advised to read recent review articles about the association of dietary lipids with prostate [75] and breast cancer [76], and

kinase (AMPK), a metabolic sensor controlling intracellular metabolic uxes [64].

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. Such effects may be due to

**2.2. Dietary lipids and cancer** 

*2.2.1. Saturated fatty acids* 

*2.2.2. Monounsaturated fatty acids* 

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]. 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].

The mechanisms underlying beneficiary effects of use n-3 PUFAs/fish oils or a combination of EPA and DHA have been extensively analyzed. 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]. In accordance with the general anti-inammatory action, n-3 PUFA supplementation induces production and secretion of adiponectin [65], the major adipokine exerting an insulin-sensitizing effect, and prevents adipose tissue hyperplasia and hypertrophy, and induces mitochondrial biogenesis in adipocytes [66], which effects maybe mediated by n-3 PUFA induced AMP-activated protein kinase (AMPK), a metabolic sensor controlling intracellular metabolic uxes [64].

#### **2.2. Dietary lipids and cancer**

190 Lipid Metabolism

against metabolic abnormalities [50].

methyl-end of the carbon chain. These PUFAs, including α-linolenic acid (ALA, 18:3, n-3), eicosapentaenoic acid (EPA, 20:5, n−3) and docosahexaenoic acid (DHA, 22:6, n−3), are considered as essential fatty acids because they can not be de novo synthesized by the human body. In human diets, ALA is usually derived from botanical sources such as perilla, flaxseed, canola, rapeseed, soybean, linseed and walnut. EPA and DHA are found in fish and some other sea foods [49]. 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

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

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]. 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

The mechanisms underlying beneficiary effects of use n-3 PUFAs/fish oils or a combination of EPA and DHA have been extensively analyzed. 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

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,

lipoprotein metabolism could remain in subjects who become overtly diabetic.

consumption of other dietary ingredients contributing to risk reduction [57].

lipases and biosynthesis of eicosanoids [62].

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]. 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. Up to now, it is generally accepted that cis-MUFA and omega-3 PUFAs are inversely associated with the increased risk of cancer, while SFA and omega-6 PUFAs are associated with the development of cancer [73]. However, physiologically, the metabolism of fatty acids are connected, any results based on a single fatty acids may be incomprehensive, therefore a fat containing diet with elevated MUFA and low ratio of omega-6/omega-3 fatty acid is suggested to be associated with cancer prevention and protection [74]. 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].

#### *2.2.1. Saturated fatty acids*

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.

#### *2.2.2. Monounsaturated fatty acids*

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. Such effects may be due to

#### 192 Lipid Metabolism

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]. Although the authors suggested that such effect may be caused by omega-3 fatty acids, ALA, as high as 10% in canola oil, however, the role of oleic acid, as high as 61% in canola oil, cannot be excluded. 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]. Although the mechanism underling the protective function of oleic acid on cancer is, so far, not clear, it has been found that oleic acid, when complexed with the molten globule form of alpha-lactalbumin (α-LA), acquires tumoricidal activity [86]. Carrillo et al found that oleic acid can inhibit store-operated Ca(2+) entry (SOCE), a Ca(2+) influx pathway, involved in the control of multiple cellular and physiological processes including cell proliferation, thus regulating the growth of colon carcinoma cells [87].

Lipid Metabolism, Metabolic Syndrome, and Cancer 193

through fatty acid β-oxidation. They can also be used for membrane lipid biosynthesis. Upon environmental stimulus, these lipids may be hydrolyzed and free fatty acids are 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. PUFA, but not SFA or MUFA, suppressES the induction of lipogenic genes by inhibiting the expression and processing of SREBP-1c. Thus inhibits the de novo lipogenesis

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. FAs released from adipose tissue during fasting are considered as ligands of PPAR alpha. Dietary PUFA, except for 18:2 n-6, are likely to induce FA oxidation enzymes via PPAR alpha as a "feed-forward " mechanism. 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

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

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,

of fatty acids, which is of particular importance for cancer cells [96].

**3. De novo lipogenesis in metabolic disease** 

**3.1. De novo lipogenesis in metabolic syndrome** 

reflect improved insulin sensitivity [99].

antiangiogenicity etc [97].

#### *2.2.3. Polyunsaturated fatty acids*

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. [88] used MTT viability test and expression of apoptotic markers to evaluate the effect of PUFAs on cancer growth, and their results indicated that EPA and DHA might induce modifications of tumor cell membrane structure leading to an obviously decreased induction rate of breast cancer. Menéndez et al. [89] also reported that omega-3 PUFAs ALA suppresses the overexpression of HER2, which plays an important role in aetiology, progression and chemosensitivity of various types of human cancers, suggesting that ALA is a potential anticancer agent. However, the clinical roles of omega-3 PUFAs may rely not only on the absolute content but also on the proportion of omega-3 PUFAs to omega-6 PUFAs in the cells due to the inverse biological functions of these two series of PUFAs. A higher omega-6/omega-3 PUFAs ratio contributes to many diseases including cancer, cardiovascular and inflammation. Reducing the omega-6/omega-3 PUFAs ratio can help lower the risk of initiation and development of cancer. Berquin et al. established a prostate-specific phosphatase and tension homolog (PTEN) knockout mouse model, and the result demonstrated that a dietary ratio of omega-6/omega-3 PUFA lower than 5 was effective in suppressing tumor growth, and extending animal lifespan [90] The recent research suggested that a balanced ratio of omega-6/omega-3 PUFAs (1:1) exerts a beneficial effects on cell function and physiology [91].

#### *2.2.4. Potential mechanisms of the association of dietary lipids with cancer*

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. When lipids are digested and absorbed by small intestine mucosa cells, they can be transported to adipocytes for storage, or used for energy production by peripheral cells through fatty acid β-oxidation. They can also be used for membrane lipid biosynthesis. Upon environmental stimulus, these lipids may be hydrolyzed and free fatty acids are 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. PUFA, but not SFA or MUFA, suppressES the induction of lipogenic genes by inhibiting the expression and processing of SREBP-1c. 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. FAs released from adipose tissue during fasting are considered as ligands of PPAR alpha. Dietary PUFA, except for 18:2 n-6, are likely to induce FA oxidation enzymes via PPAR alpha as a "feed-forward " mechanism. 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].
