Early metabolic ward studies by Mattson et al. (7) documented predictions that serum cholesterol in humans would increase 8 to 10 mg/dL for every 100 mg CHOL increment per 1000 cal/day. While other free-living studies in outpatient settings suggested that dietary CHOL has little effect on blood TC, metabolic studies demonstrated that increased intake of CHOL consistently produced a rise in serum lipid levels (8). Larger increases in plasma cholesterol levels are observed in hypercholesterolemic subjects than in the general population (9). The NCEP ATP I Step I Diet recommended reduction of dietary CHOL to <300 mg/day. The ATP III TLC diet recommended a population strategy to further reduce CHOL to <200 mg/day to maximize LDL-C lowering. The AHA population guidelines list a higher CHOL recommendation of <300 mg/day. Dietary CHOL is found only in animal products and the major sources in the U.S. diet are egg yolk, dairy products, and meat.

The proposed mechanism for the effect of increased blood cholesterol levels from dietary CHOL is transport of chylomicron remnants that contain an increased amount of CHOL to the liver, thereby increasing the hepatic content of cholesterol (see also Chapters 7, 8, and 23). This leads to the suppression of synthesis of LDL receptors (LDLR), which raises the LDL-C concentration through delayed clearance of circulating LDL-C and decreased uptake of very low density lipoprotein (VLDL) remnants (see also Chapters 8 and 23).

In the early 1960s, metabolic ward work of Keys et al. (10) suggested that the adverse effect of SFA on serum TC was twice the potential beneficial affect of polyunsaturated fatty acid (PUFA). Evidence showing favorable responses to dietary interventions to lower intake of SFA, total fat (TF), and CHOL came from early clinical trials such as the Multiple Risk Factor Intervention Trial (MRFIT) (11); the Lipid Research Clinics Coronary
Primary Prevention Trial (CPPT) (12); and the Dietary Approaches to Stop Hypertension (DASH) Trial (13). The ATP I Step I diet recommended lowering SFA to <10% of calories for the general population with further reduction to <7% of calories in the Step II diet for treatment of elevated total cholesterol when patients were nonresponsive to Step I diet. According to a meta-analysis reported in 1997 by Howell et al. (14) for every 1% change in total calories from SFA, a 1 % mg/dL change in LDL-C can be expected. Another meta-analysis conducted by Yu-Poth et al. (15) in 1999 reported results from studies of Step II diet with SFA at <7% of calories and CHOL at <200 mg/day in conjunction with weight loss. An average of 3 to 6 kg, a 16% decrease in LDL-C was reported with this combined approach. The ATP III TLC Program guidelines incorporated these results concluding that a 1% reduction in SFA would reduce serum LDL-C by approximately 2%. The major sources of SFA in the U.S. diet are fats from animal sources, primarily meat and dairy products, as well as tropical oils.

The activity of LDLR is reduced by saturated fatty acids (SFAs), resulting in a delayed clearance of both LDL-C and VLDL remnants. The mechanism is that SFAs are not preferred substrates for acyl cholesterol acyl transferase (ACAT) compared to monounsaturated fatty acids (MUFAs) (see following text), leading to decreased esterification of free cholesterol and an increase in the cholesterol pool in the liver, which decreases LDLR through the sterol receptor element-binding protein (SREBP) pathway (see also Chapter 8). However, marked differences exist between the various fatty acids that are defined as SFA. The influence of medium-chain SFAs on LDL-C is considered to be small but lauric acid, the intermediate-chain SFA, can raise both TC and LDL-C by 11% to 12% with no significant effect on HDL-C. Two long-chain SFAs are hypercholesterolemic—myristic being more potent than palmitic. Stearic acid, another long-chain SFA found in cocoa butter and meat, has been shown to lower plasma TC and LDL-C when substituted for other SFAs. Dietary fats are blends of various fatty acids, so it is important to understand their composition when making recommendations.

TFAs are unsaturated fats, either monounsaturated or polyunsaturated, containing trans-isomer fatty acids. The trans form that results from hydrogenation of fat is straight compared to the kinked shape of the carbon chain found in the cis-configuration (see also Chapter 20). Strong observational and experimental evidence exists linking increased risk of CVD with higher intakes of TFA. Similar to the effect of SFA, TFA raises the level of LDL-C, but unlike SFA, also decreases the level of HDL-C. In 1997, Hu et al. (16) reported that in the Nurses’ Health Study, CVD risk doubled for each 2% increase in TFA calories consumed. The net increase in the LDL-C/HDL-C cholesterol ratio with TFA is approximately double than the effect from SFA.

The TLC Program recommended <7% of calories from SFA and TFA combined and the AHA recommends a diet that contains <7% of calories from SFA and <1% of calories from TFA. On January 1, 2006, mandatory trans fat labeling was introduced making it easier for consumers to identify and limit their TFA intake. Many food companies substituted partially hydrogenated fats with those made with liquid vegetable oils, but in some cases, tropical fats, which are higher in SFA, have been used instead. Likewise, many food service establishments have replaced trans fats used in cooking TFA with liquid vegetable oils (see Chapter 20 for additional information regarding TFA and dyslipidemia).

Decreasing SFA and TFA is essential to lipid lowering but it is also important to include unsaturated fatty acids (UFAs) in the diet, categorized as MUFA and PUFA. Oleic acid is the most prevalent MUFA and initially was considered to have a neutral effect on LDL-C but when substituted for SFA, there is a decrease in LDL-C, little or no decrease in HDL-C, and no increase in TG. The TLC Program recommended MUFA intake up to 20% of calories. The primary food sources of MUFA are olive oil, canola oil, and nuts.

PUFAs reduce LDL-C when substituted for SFA and TFA but responses are variable with regard to smaller reductions in HDL-C and TG. Results from clinical trials have shown that substitution of PUFA for SFA reduces the risk for CVD, but in the absence of any evidence from major population groups with sustained increased intake of PUFA, the TLC diet indicated a range of PUFA up to 10% of total calories. Practical applications of this approach are challenging and emphasis on monounsaturated sources of fatty acids as evident in the olive oil-rich Mediterranean diet may have an easier adaptation.

There are two distinct types of PUFA—omega-6 (ω-6) and omega-3 (ω-3). Linoleic acid is an essential ω-6 fatty acid and α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are essential ω-3 fatty acids. A ratio favoring ω-3 has been advocated but long-term affects are not well documented. In 2004, the U.S. Food and Drug Administration (FDA) allowed a qualified health claim to EPA and DHA ω-3 fatty acids showing a benefit in reducing the risk of CVD. Both ω-3 and ω-6 fatty acids are essential but it is believed that the ideal ω-6 intake should be no more than four to five times that of ω-3 intake. Dietary sources of ω-6 include corn, safflower, sunflower, and soybean oils as well as nuts, whole grains, eggs, and poultry. Flaxseed and eggs are the main sources of ALA but the efficiency for conversion into EPA and DHA is low. The most widely available food source of EPA and DHA is cold-water oily fish such as salmon, herring, mackerel, anchovies, and sardines but these fish also have the potential for containing undesirable heavy metals and fat-soluble pollutants. The FDA recommends that total dietary intake of ω-3 fatty acids from fish not exceed 3 g/day of which no more than 2 g/day is from nutritional supplements. This translates to two servings of fish or approximately 8 ounces cooked weight per week. Chapter 21 provides additional information regarding the use of fish oils in treatment of dyslipidemia.

In 2006, Howard et al. (17) reporting results from the Women’s Health Initiative (WHI) indicated no statistically
significant differences in CVD mortality among women randomized to the diet modification (DM) intervention recommending <20% of calories from TF. The primary outcome measure of the low-fat intervention was breast cancer and no cardiovascular dietary intervention was specifically advocated. The WHI DM intervention also recommended higher intakes of fruits, vegetables, and grains but the primary focus was low fat with no further focus on physical activity or weight loss. Although it was presumed that reductions in TF of that magnitude would automatically include reductions in SFA, the results suggest that focusing on TF alone is inadequate to achieve the maximal reduction of LDL-C or any improvement in HDL-C. This shows that targeted messages in dietary fat intake are needed for maximizing lipid levels. Since UFA do not raise LDL-C when substituted for carbohydrates in the diet, it is not necessary to restrict TF intake to reduce LDL-C, if SFA and TFA are reduced to goal levels. However, fat is a source of calories, which can promote obesity. Alternatively, high carbohydrate (CHO) intake at the level ≥60% of calories can also aggravate lipid and nonlipid risk factors associated with the metabolic syndrome. The TLC Program recommends that TF intakes should range from 25% to 35% of calories but those individuals at risk of the metabolic syndrome should aim at 30% to 35% of total calories with an emphasis on a higher ω-3 to ω-6 ratio and including a higher intake of MUFA than recommended for the general population. Since dietary fat, especially SFA and TFA, has such a major effect on lipid levels, guidelines on interpreting fat intake are provided in Table 19.1.