Fats, fatty acids and cholesterol
Fats and oils are the most energy dense of the three main macronutrients, providing 37 kg/g. They are often referred to as lipids and serve both structural and metabolic functions. Triglycerides are the main constituents of both dietary and stored fat. Triglycerides are formed by combining glycerol with three fatty acid molecules (Fig. 6.1). During digestion, triglycerides are broken down into these constituent parts, with glycerol able to be converted to glucose via the process of gluconeogenesis, and this can be an important source of glucose for red blood cells in states of reduced carbohydrate intake.
Figure 6.1.Example of an unsaturated fat triglyceride (C55H98O6)
Source: Wikipedia WITHOUT PERMISSION https://upload.wikimedia.org/wikipedia/commons/b/be/Fat_triglyceride_shorthand_formula.PNG
Fats may be classified according to their chemical structure. Fatty acids may be considered either saturated or unsaturated based on the presence or absence of double bonds between carbon atoms Unsaturated fats may be further divided into monounsaturated or polyunsaturated fats.
Saturated fats have no double bonds between carbon atoms (Fig. 6.3). The term saturated refers to the inability to add further hydrogen atoms. Saturated fats tend to have a linear structure, allowing triglyceride molecules to pack closely together, which leads to saturated fats having higher melting points than unsaturated fats.
Figure 6.3.In contrast to unsaturated fats, saturated fats have no double bonds between carbon atoms
Source: https://d2gne97vdumgn3.cloudfront.net/api/file/IuU6OMyBRsmD3wc5YMdPWITHOUT PERMISSION
Unsaturated fatty acids have one or more double bonds between carbon atoms (Fig. 6.3). These double bonds are prone to oxidation, with the risk of oxidation increasing with the number of double bonds. Subsequent oxidation products such as reactive aldehydes and alcohols are involved in various pathological states such as inflammation, atherosclerosis, neurodegenerative diseases and cancer(100, 101).
Unsaturated fatty acids may be either monounsaturated (single carbon-to-carbon double bond) or polyunsaturated (two or more carbon-to-carbon double bonds). The location of the first double bond in relation to the methyl end of the fatty acid chain allows further classification of unsaturated fats. Polyunsaturated fats may have this first double bond after either the 3rdor 6thcarbon atom from the methyl end and are denoted omega-3 and 6 fatty acids respectively. Monounsaturated fats may be either omega-7 or 9, with the first double bond after either the 7thor 9thcarbon atom from the methyl end.
Unsaturated fatty acids may be either ‘cis’ or ‘trans’ isomers, which have different structures despite having the same molecular formula.
Figure 6.4. Cis-isomers contain a ‘kink’ within their structure which prevents them packing closely together. Trans-isomers are relatively straighter; they pack closer together and tend to be solid at room temperature like saturated fats.
Natural foods incorporate these three fat types in varying compositions, although one fat type often predominates. Notably, dairy is the only food group that contains more saturated than unsaturated fat.
Foods contain all three fat types. Animal fats tend to contain mostly saturated fats, while seed (vegetable) oils contain mostly polyunsaturated fats.
Short-chain fatty acids
Fatty acids can also be categorised based on chain length determined by the number of carbon atoms in their tail. Short-chain fatty acids (SCFA), often known as volatile fats, contain fewer than six carbons. SCFAs may be found in small quantities in the diet, usually in the form of butyric acid found in milk, parmesan cheese and butter. Larger quantities of SCFAs may be produced by bacterial fermentation of incompletely digested food stuffs. Short chain fatty acids are readily converted to ketones.
Medium-chain fatty acids
Medium-chain fatty acids (MCFA) have tails containing between 6-12 carbons. Passive absorption of medium chain fatty acids from the gastrointestinal tract directly into the portal circulation bypasses the need for transit through the lymphatic system with no need for bile salts. Following absorption, MCFA enter mitochondria independently of the carnitine transport system, undergoing preferential oxidation. Medium-chain triglycerides are therefore more ketogenic than longer-chain fatty acids.
Long-chain fatty acids
Long-chain fatty acids (LCFA) contain between 13-21 carbons and require incorporation into chylomicrons and transportation through the lymphatic system for absorption. LCFA tend to have higher melting points, as exemplified by tallow (rendered fat from ruminants) with a chain length of 17 carbons. Very long chain fatty acids (VLCFA) have tails containing 22 or more carbons.
Cholesterol is a misunderstood molecule that is essential for life. It is frequently confused with plasma lipoproteins, which are complex structures serving as a transport medium for triglyceride and cholesterol molecules within the circulation. A component of all animal cell membranes, cholesterol is necessary for both structural integrity and fluidity. Cholesterol also serves as a precursor for steroid hormones, bile acid and vitamin D. All animal cells produce cholesterol with the amount produced within the body usually substantially more than that consumed. About 80% of total body cholesterol production occurs in the liver.
Ancel Keys, an American physiologist and epidemiologist, popularised the hypothesis that serum cholesterol (and saturated fat) were causally related to cardiovascular disease(104). Acceptance of this theory led to the introduction of dietary guidelines recommending dietary restriction of both saturated fat and cholesterol. More than 50 years later, the balance of evidence no longer supports this hypothesis, yet changing dietary guidelines to reflect the evidence has been a slow and contentious process(105). The recommended limit on dietary cholesterol has been removed from the most recent editions of the Australian and American dietary guidelines.
The consumption of eggs has long been controversial given their cholesterol content. Observational studies examining egg consumption specifically, rather than dietary cholesterol overall, have not found it to be associated with cardiovascular disease, except maybe in people with diabetes(106). However, randomised controlled trials are yet to find such an association. Current evidence suggests daily egg consumption may even be healthful. A 2018 large prospective cohort study of over 500 000 middle-aged Chinese adults found that daily egg consumption was associated with lower risk of cardiovascular disease, ischaemic heart disease, major coronary events, haemorrhagic stroke and ischaemic stroke. Daily egg consumption was found to be associated with an 18% reduced risk of death by cardiovascular disease and a 28% reduced risk of death by haemorrhagic stroke.
Excess dietary fat, particularly saturated fat, has long been considered to increase the risk of coronary heart disease. This perspective gained prominence in the 1970s thanks to the influence of Keys who promoted his ‘diet-heart hypothesis’. This was based on the belief that total serum lipoprotein, and later more specifically low-density lipoprotein, were significant factors in the pathogenesis of coronary heart disease. In making the case to support his hypothesis, Keys presented data from six countries demonstrating a relationship between mortality and dietary fat. Four years after Keys’ original paper, Yerushalmy and Hillebroe published a paper rebutting Keys’ conclusion, presenting data from a further 15 countries. By this time however, preliminary work on Keys’ (in)famous Seven Countries Study was well underway and Keys’ hypothesis proceeded to influence decades of future dietary policy and guidelines.
Most current dietary guidelines continue to stipulate that saturated fats should represent less than 10% of dietary energy (11% in the UK). This concern regarding saturated fat may be ‘the single most influential recommendation in conventional dietary advice’, providing the basis to recommend low-fat dairy and lean meats over full fat dairy and fattier cuts of meat, and to recommend margarine and vegetable oils instead of butter and animal fats.
Despite the rapid acceptance of the ‘diet-heart hypothesis’, a systematic review and meta-analysis of studies available at the time that the first dietary guidelines were not consistent with the scientific evidence available at the time. It is now well understood that high-density lipoprotein (HDL) has a protective effect on cardiovascular disease, and the ratios between HDL and low-density lipoprotein (LDL), and triglycerides and HDL, are more predictive of cardiovascular risk than LDL in isolation. Increasing dietary saturated fat intake has been shown to increase both HDL and LDL, leading to more favourable ratios.
|Box. The consequences of the original dietary guidelines
· Intake of animal fats, such as red meat, eggs and dairy, was reduced
· ‘Low-fat’ food products with added sugar products flooded the market
· Intake of ultra-processed foods increases
· Use of vegetable oils increased
Not all dietary fats are created equal. Often, fats are referred to as ‘good’ fats or ‘bad’ fats – but what exactly makes a fat ‘good’ or ‘bad’? Here we discuss the health implications of different types of fat.
Saturated fatty acids [D]
Since the 1970s, dietary saturated fat has been widely considered to increase the risk of coronary heart disease based on the ‘diet-heart hypothesis’. However, decades of research have failed to provide substantive support for this theory.
There have been multiple meta-analyses on this topic, with most finding no justification for recommending restricting saturated fat intake. The meta analyses finding possible benefit from restricting saturated fats appear to have included inadequately controlled studies, explaining this apparent heterogeneity. The balance of evidence indicates there is no mortality benefit from replacing saturated fat with polyunsaturated fat. This was illustrated by the PURE study, featured in an above box. Using standardised and validated country-specific food frequency questionnaires, the study’s authors concluded that increased saturated fat consumption was associated with lower risk of mortality. There was no apparent upper limit of saturated fat intake beyond which this benefit was noted. Covariates were extensively controlled for in this study, somewhat addressing concerns that the low-fat diets associated with higher mortality rates could be attributable to poverty. This has implications for existing dietary guidelines, which appear to not be consistent with the best available evidence.
Monounsaturated fatty acids
No significant association between either total or individual monounsaturated fatty acid intake with coronary heart disease has been identified. While mono-unsaturated fats are generally regarded as ‘healthy’, contradictory findings exist between studies. One systematic review concluded that the replacement of dietary saturated fats with monounsaturated fats offered no benefit for secondary prevention of coronary heart disease, while another concluded it is beneficial to replace dietary high-GI carbohydrates and saturated fats with monounsaturated fat(118). This inconsistency of findings is replicated in mechanistic research which has failed to demonstrate a clear effect of monounsaturated fat on atherogenesis. More research with clinical end points is required to permit definitive conclusions on the health impacts of dietary monounsaturated fats.
Polyunsaturated fatty acids – omega-3 and omega-6
Omega-6 (n-6) and omega-3 (n-3) are the two main series of polyunsaturated fatty acids (PUFAs) (122). Short-chain omega fats in the form of linoleic acid (LA) (n-6) and α-linolenic acid (ALA) (n-3) are unable to be synthesised in humans, and longer-chain variants require shorter-chain precursors. Omega fatty acids are therefore essential nutrients requiring a dietary source. Omega-3 fatty acids are generally considered to be anti-inflammatory relative to omega-6 fatty acids.
Polyunsaturated fats have long been considered healthier than saturated fats. This is largely premised on the effects of saturated fat on serum lipids. On balance, evidence available from adequately controlled randomised controlled trials does not demonstrate that replacing dietary saturated fats with polyunsaturated fats confers any benefit with respect to coronary heart disease or total mortality(113).
The standard Western diet provides approximately ten times more linoleic fatty acid compared to α-linolenic fatty acid(124). This intake is consistent with the Australian Dietary Guidelines which state that omega-6 consumption should be ten times greater than omega-3 consumption. It has been suggested however, that reducing the ratio of omega-6 fats to omega-3 fats closer to one is associated with reduced risk of many chronic diseases, including cardiovascular and inflammatory diseases (Simopoulos 2008). Linoleic acid (n-6) and α-linolenic acid (n-3) can both be converted into longer-chain fatty acids within their respective series through desaturation and elongation reactions occurring mainly in the liver.
Conversion of the omega-3 series α-linolenic acid to the more biologically active eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is limited, possibly in the order of 8%. Further, there is competition between the two series for metabolism. In diets where linoleic acid (n-6) is more prevalent than n-3 fatty acids, metabolism of n-6 fatty acids is favoured.
While ALA is present in plant oils, such as flaxseed, soybean, and canola oils, EPA and DHA are not. Given the low rate of conversion of ALA to more biologically active forms, consuming EPA and DHA directly from animal sources or dietary supplements is the only practical way to increase levels in the body.
Findings in epidemiologic studies based on red blood cell membrane levels of EPA and DHA demonstrate a 10-fold lower incidence of sudden cardiac death associated with high levels of n-3 fatty acids compared to lower levels. Large trials of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation have failed to demonstrate any beneficial effects in terms of reductions of total mortality relating to cardiovascular disease. This may be due to failure to adequately restrict n-6 fatty acid intake.
Polyunsaturated fats, including omega-3 and omega-6 fats, are susceptible to oxidation due to the presence of double carbon-to-carbon bonds which are sites where oxidation reactions can occur. The two major oxidation reactions which may occur in polyunsaturated fats are auto-oxidation in the presence of oxygen and photo-oxidation due to exposure to UV radiation. Peroxides, aldehydes and several other compounds may be produced. These oxidation products have potential health implications due to their cytotoxic, mutagenic and neurotoxic actions.
The rate of oxidation of polyunsaturated fats (e.g. vegetable oils) is increased with cooking, producing peroxides, aldehydes and other harmful substances. Cooking with monounsaturated and especially saturated fats is associated with less oxidation than is seen with polyunsaturated fats.
Trans fatty acids
There are two major types of trans fats are present in the Western diet: industrial and ruminant Trans fatty acids are characterised by the presence of a single carbon to carbon double bond. In contrast to monounsaturated fatty acids which also contain a single carbon to carbon double bond, trans fatty acids have a ‘kink’ their structure and are relatively straighter. Mono unsaturated fats are classified as ‘cis’ isomers. The kink in the structure of trans fats allows them to pack closer together, improving their cooking qualities. Both industrial and ruminant trans fats may have their double carbon to carbon bond in a number of locations, however they appear to have distinct ratios of distribution.
Industrial trans fats are produced by vegetable oil hydrogenation, which adds hydrogen atoms at the expense of carbon-to-carbon double bonds. This improves the cooking properties of vegetable oils closer to that of solid saturated animal fats. While complete hydrogenation converts vegetable oils to saturated fats, partial hydrogenation can result in the formation of a trans isomer of the fat. This occurs due to ‘flipping’ around a remaining carbon-to-carbon double bond, altering the structure. Most trans fats in the Western diet are derived from partially hydrogenated vegetable oils, with a small amount present in dairy and meat products from ruminant animals.
Total trans fatty acid intake appears to significantly increase the risk of coronary heart disease mortality. Interestingly, this does not appear to extend to ruminant derived trans fatty acid, despite their structural similarity. Regulations have been introduced in many countries to limit the amount of trans fats in processed foods which appear to have been effective in reducing intake.