Information in this box is based on: Further reading

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1 Box 10.1 Dietary polyunsaturated fatty acids and the n-3:n-6 balance Dietary PUFAs are essential to health: indeed, specific FAs of the n-3 and n-6 families (α-linolenic acid, 18:3n-3 and linoleic acid, 18:2n-6) constitute the essential dietary FAs for mammals (Section 6.2.2). When PUFAs replace SFAs in the diet, some beneficial changes are observed: lowering of circulating lipid (cholesterol and/or TAG) concentrations, lowering risk of cardiovascular disease; potentially improvement in sensitivity to insulin, lowering diabetes risk. But how much of each of these families of PUFA should we consume? That is rather controversial. n-6 PUFA, when replacing SFA or carbohydrates: potentially increase inflammatory responses; potentially improve sensitivity to insulin (thus diabetes risk) n-3 PUFA, when replacing SFA or carbohydrates: reduce platelet aggregation and prolong bleeding time (in large amounts); stabilize the heart rhythm (shown in experimental animals, not clearly in humans); potentially reduce ( dampen down ) inflammatory responses (in each case, effects are listed in approximate order of the strength of the evidence in humans). (Note that effects on plasma lipid concentrations are covered elsewhere: see Box 10.4.) In addition, very long-chain n-3 PUFAs (or fish intake) have been shown to improve symptoms in rheumatoid and osteoarthritis (Section ), toreduceriskofbreastcancer(section10.2.1), andtobenefit someaspectsofcardiovasculardiseaserisk(section ). Inanimal models, very long-chain n-3 PUFAs have several additional benefits including protection against onset of Alzheimer s disease. The evidence for the latter in man is mixed, although a recent meta-analysis suggested that treatment periods have been too short to show benefit. Analysis of the diets of our palaeolithic hunter-gatherer ancestors by archaeologists suggests that they ate a dietary n-3:n-6 ratio of 1 : 1. The n-3 PUFA came mainly from plant sources (hence much of it was α-linolenic acid), although in some geographical locations sea-food (fish and shellfish) could have contributed quite large amounts of EPA, 20:5n-3, and DHA, 22:6n-3. There is an argument that this is the period when our genes evolved and therefore we would be healthy if we returned to this type of diet. Current diets in industrialized countries have a n-3:n-6 ratio more like 1 : 5 or 1 : 10 (the National Diet and Nutrition Survey in the UK found a ratio of 1 : 5.4 in adult men and women in 2000/2001; in the US, Kris-Etherton et al. (2000) reckoned the dietary n-3 : n-6 ratio to have changed from around 1 : 8 in the 1930s to 1 : 10 in the 1990s). Should we therefore try to change this ratio in favour of n-3 PUFA? One argument in favour of changing the ratio in favour of n-3 PUFA is that there is competition between n-3 and n-6 PUFA for desaturation via the 6-desaturase and elongation (see Section , Fig and Section ). Therefore, more n-6 PUFA in the diet will decrease the extent of conversion of α-linolenic acid to EPA and DHA. This can be shown in cellular systems, but is not clearly borne out in human feeding trials. Most nutritionists agree that it would be beneficial to increase intake of oily fish, and therefore EPA and DHA intake. This would, of course, change the n-3 : n-6 ratio in favour of n-3 PUFAs. But actually a number of expert reviews now consider that the n-3 : n-6 PUFA ratio is not, in itself, a valuable concept. A major reason is that this ratio assumes that all n-6 PUFAs are identical in their effects, and likewise for n-3 PUFA including α-linolenic acid, whereas this is manifestly not the case. Information in this box is based on: Kris-Etherton PM, Taylor DS, Yu-Poth S et al. (2000) Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr 71(Suppl):179S 188S. Food and Agriculture Organization (FAO) of the United Nations (2010) Fats and Fatty Acids in Human Nutrition. Report of an Expert Consultation. FAO Food and Nutrition Paper 91, FAO, Rome (Final report). Goyens PLL, Spilker ME, Zock PI, Katan MB& Mensink RP (2006) Conversion of α-linolenic acid in humans is influenced by the absolute amounts of α-linolenic acid and linoleic acid in the diet and not by their ratio. Am J Clin Nutr 84: Further reading Cunnane SC (2003). Problems with essential fatty acids: time for a new paradigm? Prog Lipid Res 42: Stanley JC, Elsom RL, Calder PC et al (2007). UK Food Standards Agency Workshop Report: the effects of the dietary n-6:n-3 fatty acid ratio on cardiovascular health. Br J Nutr 98: Griffin BA (2008) How relevant is the ratio of dietary n-6 to n-3 polyunsaturated fatty acids to cardiovascular disease risk? Evidence from the OPTILIP study. Curr Opin Lipidol 19: Kuipers RS, Luxwolda MF, Janneke Dijck-Brouwer DA et al (2010) Estimated macronutrient and fatty acid intakes from an East African Paleolithic diet. Br J Nutr 104:

2 Box 10.2 Lipid-related drug targets in obesity There has been much interest in a pharmaceutical treatment for obesity. In the 1930s, 2,4-dinitrophenol, a mitochondrial uncoupler (so mimicking the action of the uncoupling protein of brown adipose tissue: see Section 9.2.2), was used to increase metabolic rate, but proved fatal in many cases. According to the UK s National Health Service website ( Treatment.aspx), more than 120 different drug treatments for obesity have been tried over the years. There have been a number of attempts to activate brown adipose tissue to burn off excess calories. These have not as yet led to useful drug treatments (discussed also in Section 9.2.1). At present only two drugs are in clinical use. Phentermine is a drug of the phenethylamine class, similar to amphetamine. Like most of the drugs that have been used in obesity, it targets hypothalamic pathways regulating appetite, in recognition of the role that increased energy intake plays in obesity. The other drug in use at present targets a different pathway: fatty acid absorption from the small intestine. A bacterial metabolite known as tetrahydrolipstatin (orlistat is the generic drug name) is a potent irreversible inhibitor of pancreatic lipase in the small intestine, and so reduces the absorption of dietary fat. It is taken as a pill. At its most effective, it reduces fat absorption by about 30%. Patients taking this medication have to keep to a relatively low-fat diet as an unpleasant side-effect is leak of unabsorbed fatty material. Orlistat has been shown, in a randomized clinical trial, to reduce the incidence of type 2 diabetes in obese people. 2

3 Box 10.3 Lipid-related drug targets for hyperlipidaemias Many drug treatments are available for different types of hyperlipidaemias. The statin drugs (inhibitors of HMG-CoA reductase; Fig & Section 7.3.1) are effective at lowering elevated serum cholesterol concentrations in many patients and confer benefits in reduced risk of cardiovascular disease (Section ). They also somewhat reduce elevated serum TAG concentrations, probably because lower availability of hepatocyte cholesterol reduces VLDL-TAGs secretion. Other steps in the process of cellular uptake of cholesterol from the circulation are being investigated as drug targets. One is the protein proprotein convertase subtilisin/kexin type 9 (PCSK9, gene PCSK9). As mentioned in Section , PCSK9 is involved in intracellular degradation of the LDL receptor. Inhibitors of PCSK9 have the potential to increase removal of cholesterol from the circulation and hence reduce circulating concentrations, and are in clinical trials. Elevated serum TAG concentrations are targeted more effectively by the fibrate drugs, also called fibric acid derivatives. These act as activators of PPAR-α (Sections & ). Probably through their action in regulating apolipoprotein expression, they also raise serum HDL-cholesterol concentrations. Niacin, also called nicotinic acid or vitamin B3, also lowers serum TAG concentrations and raises HDL-cholesterol. For these purposes it is given in large doses (typically 1 2 g/day; compare with its recommended intake as a vitamin for prevention of pellagra, which is < 20 mg/day). Niacin is a ligand for the G protein-coupled receptor GPR109A (Table 7.5), whose endogenous ligand is thought to be 3-hydroxybutyrate, a ketone body: i.e. a product of hepatic fatty acid oxidation. The only known metabolic action of niacin is to suppress adipocyte lipolysis, thus potentially reducing supply of nonesterified fatty acids to the liver and consequently hepatic TAG secretion. However, it is thought to have additional effects leading to substantial elevation of HDL-cholesterol concentration, reduction in Lp(a) concentration (see Section 7.2.3), and anti-inflammatory effects. Agents that inhibit the action of CETP have marked effects in raising serum HDL-cholesterol concentrations but have, as yet, not proved useful in reducing CHD risk. Their use is described more in the main text. Before the introduction of the statins, many patients with elevated cholesterol concentrations were managed with so-called resins, substances that make a gel with water and bind cholesterol in the intestinal tract. This targets the entero-hepatic circulation of cholesterol (Section 7.1.2). Nowadays, patients who do not benefit sufficiently from statin treatment often receive the drug ezetimibe. Ezetimibe is an inhibitor of the Niemann-Pick C1-like protein-1 involved in cholesterol absorption in the small intestine (Section & Box 7.2). Note that dietary cholesterol itself is not a major regulator of plasma cholesterol concentrations (Section & Box 10.4): but because these treatments interrupt the entero-hepatic circulation of cholesterol they may have greater effects than reduction in dietary cholesterol. Certain plant sterols and stanols (phytosterols) can also interfere with the absorption of cholesterol of both dietary and biliary origin, and may have a useful cholesterol-lowering effect. They are marketed as components of spreads. It has long been believed that these phytosterols compete with cholesterol for incorporation into mixed micelles (Section 7.1.1), and tend to exclude cholesterol, hence reducing its absorption. However, more recent evidence suggests that they may increase the rate of cholesterol efflux from enterocytes back into the intestinal lumen. 3

4 Box 10.4 Effects of dietary fatty acids on serum cholesterol concentrations In many experiments in healthy subjects, the FA composition of the diet has been manipulated to assess the effect on the serum cholesterol concentration. These studies have been summarized by a number of investigators to produce predictive equations. Two examples are given here. Hegsted et al. (1965) produced the equation: Δserum cholesterol 0:026 2:16ΔSFA 1:65ΔPUFA 6:66ΔChol 0:53 where Δserum cholesterol represents the change in serum cholesterol concentration (mmol/l), ΔSFA and ΔPUFA are changes in the percentage of dietary energy derived from saturated and polyunsaturated fatty acids respectively, and ΔChol is the change in dietary cholesterol in 100 mg/day. Note that the term for ΔS is positive (an increase in SFA intake raises serum cholesterol) whereas that for ΔPis negative (an increase in PUFA intake reduces serum cholesterol). (The factor converts from mg/dl to mmol/l.) Yu et al. (1995) collated data from 18 studies in the literature that gave information on individual FAs in the diet. Their predictive equation was: Δserum cholesterol 0:0522Δ 12: 0 to 16:0 0:0008Δ18:0 0:0124ΔMUFA 0:0248ΔPUFA where ΔMUFA is the change in the percentage of dietary energy derived from monounsaturated fatty acids (other terminology as above). Note that most SFAs are shown as raising serum cholesterol, but stearic acid (18:0) as slightly lowering it. References Hegsted DM, McGandy RB, Myers ML & Stare FJ. (1965) Quantitative effects of dietary fat on serum cholesterol in man. Am J Clin Nutr 17: Yu S, Derr J, Etherton TD & Kris-Etherton PM (1995) Plasma cholesterol-predictive equations demonstrate that stearic acid is neutral and monounsaturated fatty acids are hypocholesterolemic. Am J Clin Nutr 61:

5 Box 10.5 Unusual isomers of dietary fatty acids may have particular health effects The double bonds in dietary UFAs are mostly of the cis geometrical configuration. However, some foods contain isomeric fatty acids in which the double bonds are in the trans configuration (Section & Box 11.4). These are produced naturally in ruminant animals and so enter the food chain in small amounts, but larger amounts enter the food chain from industrial hydrogenation of vegetable oils (discussed further in Box 11.4). A number of epidemiological studies have shown a relationship between trans-fa intake and cardiovascular disease: in the Nurses Health Study in the US, trans-fa intake was more strongly related to CHD risk than was SFA intake. Controlled feeding studies suggest that dietary trans-fas raise serum cholesterol and reduce HDL-cholesterol concentrations to a similar extent to SFAs. Given the similarity of their molecular configurations, this is perhaps not surprising. (Vaccenic acid, a product of rumen fermentation, seems to be an exception, and some studies suggest that it may have beneficial effects on health.) Trans-FAs can be replaced in food products with other fats, and moves are afoot worldwide to do so, discussed further in Box In most naturally occurring cis-pufas, the double bonds are separated by a methylene bridge; e.g. the most common form of linoleic acid in nature is c9,c12-18:2 (Section ). However, a large number of isomers of linoleic acid is found. Some of these have the double bonds between consecutive pairs of carbon atoms (the most common is c9,t11-18:2, also known as rumenic acid). This arrangement of double bonds is known as conjugated. The group of isomers of linoleic acid with this configuration is known collectively as conjugated linoleic acid (CLA). CLA is formed in the rumen of ruminant animals, and is found in milk fat, cheese and beef. CLA has come to prominence because of claims from animal studies that CLA can protect against some forms of cancer. Dietary CLA has also been shown to alter body composition in mice, with a loss of body fat, and in cultured adipocytes to reduce the activity of lipoprotein lipase. More recently, it has been claimed that dietary CLA may protect against atherosclerosis. However, the evidence in this respect is not clear-cut: there have also been demonstrations that high levels of CLA fed to rodents can predispose to the formation of fatty streaks in the aorta. Various mechanisms for the potential beneficial effects have been proposed, and may differ for the different isomers. For instance, some isomers are potent agonists of PPAR-α (Section 7.3.2). A quick internet search will show the availability many commercial preparations of CLA with claims such as helps promote fat loss and increases energy (!). As yet, however, there are no convincing studies showing beneficial effects of CLA on human health. 5