Effects of Dietary Fat Intake on HDL Metabolism

High-density lipoprotein (HDL) is a lipoprotein which has anti-atherogenic property by reversing cholesterol transport from the peripheral tissues to liver. Low HDL-cholesterol (HDL-C) as well as high low-density lipoprotein-cholesterol (LDL-C) is associated with the development of coronary heart diseases (CHD). Various epidemiological studies have suggested that the development of CHD increase in individuals with less than 40 mg/dL of HDL-C. In spite of accumulation of evidences suggesting a significant association between low HDL-C and CHD, effects of dietary factors on HDL metabolism remained largely unknown. We reviewed published articles about effects of dietary fat intake on HDL metabolism. The substitution of fatty acids (FA) for carbohydrates is beneficially associated with HDL metabolism. Monounsaturated FA intake may not affect HDL-C. Trans-FA is significantly associated with reduction of HDL-C, and is also adversely related with total cholesterol/HDL-C. Fish oils consumption, especially docosahexaenoic acid consumption, may be favorably associated with HDL metabolism. Although plant sterols and stanols may not affect HDL-C, policosanol intake is associated with a clinically significant decrease in the LDL/HDL ratio.


Introduction
Atherogenic dyslipidemia is characterized as elevated serum levels of triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C), and low serum levels of high-density lipoprotein-cholesterol (HDL-C). Since HDL is an anti-atherogenic lipoprotein which plays a role in reversing cholesterol transport from the peripheral tissues to the liver, low HDL-C level induces the development of coronary heart diseases (CHD) [1,2], and cerebrovascular diseases (CVD) [3].
A significant influence of low HDL-C on CHD and CVD has been widely known; however, roles of dietary factors for HDL metabolism remained largely unknown. We reviewed published articles about effects of dietary factors, especially dietary fat intake on HDL metabolism. We regarded systematic reviews and meta-analyses as important articles in this review.

Effects of Various Fatty Acids (FA) Intake on HDL Metabolism
Mensink et al calculated the effect of changes in carbohydrate and FA intake on serum lipids, reviewing 27 controlled trials published between 1970 and 1991 (Table 1) [4][5][6][7][8]. They found that all types of FA ingestion elevated HDL-C when substituted for carbohydrates, but the effect decreased with increasing unsaturation of FA. Another meta-analysis was performed to examine the relationship between milk fat containing dairy foods and cardiovascular risk factors [5]. This study indicated that a diet higher in saturated FA (SFA) from whole milk and butter increases HDL-C when substituted for carbohydrates or unsaturated FA (USFA). Results from these two studies indicate that the substitution of FA for carbohydrates is beneficially associated with HDL metabolism, and also suggest that SFA is favorably associated with HDL-C. Mensink et al performed the meta-analysis of 60 selected trials and calculated the effects of the amount and type of fat on the total cholesterol (TC)/HDL-C [6]. TC/HDL did not change if carbohydrates replaced SFA, but it decreased if cis-USFA replaced SFA. The effect on TC/HDL of replacing trans-FA (TFA) with a mix of carbohydrates and cis-USFA was almost twice as large as that of replacing SFA. Briefly, TC/HDL-C was reduced by the replacement of TFA with SFA by 0.019; the replacement with cis-monounsaturated FA (MUFA) by 0.048; and the replacement with cis-polyunsaturated FA (PUFA) by 0.054. Coronary risk was reduced most effectively when TFA and SFA were replaced with cis-USFA.
Salas ucts can affect plasma lipids, and they found that some of studies have observed that various CLA isomers decreases HDL-C [7]. Wendland et al performed systematic review and metaanalysis to determine whether dietary supplementation with alpha linolenic acid (ALA) can modify coronary risk factors [8]. There was a small but clinically non-significant decrease in HDL-C due to ALA ingestion. Schwingshackl et al analyzed long-term, randomized controlled trials (RCTs) to investigate the effects of MUFA on cardiovascular risk factors (Table 2) [9][10][11]. Dietary regimens with a high amount of MUFA (> 12%) were compared to those with ≤ 12%. A total of 12 studies met the inclusion criteria. HDL-C was not significantly affected by the percentage of MUFA.
Recently, TFA has been reported to adversely affect cardiovascular health, and Mozaffarian et al reviewed the evidence for effects of TFA consumption on CHD risks. They found that reduction of HDL-C by TFA consumption was observed in both controlled trials and observational studies [10]. These effects were most prominent in comparison with cis-USFA, and adverse effect of TFA on TC/HDL-C was also found in comparison with SFA. Mozaffarian et al performed a meta-analysis of the effects of TFA on serum lipids in controlled dietary trials. In controlled trials, each 1% energy replacement of TFA with SFA, MUFA and PUFA decreased TC/HDL-C by 0.31, 0.54 and 0.67, respectively [11].

Effects of Fish Oils Intake on HDL Metabolism
Fish oils have been widely reported to be a useful supplement to reduce serum TG levels in individuals with hyperlipidemia; however, effects of fish oils on serum HDL-C remained obscure. Lewis et al reviewed all RCTs from 1994 to 2003 which addressed the efficacy of long-chain omega-3 FA for dyslipidemia, and they found that 10 studies reported longchain omega-3 FA to be effective in the treatment of hypertriglyceridemia (Table 3) [12][13][14][15][16]. According to accumulation of the data obtained from 10 studies, the average increase in HDL-C was 10%. Eslick et al performed the meta-analysis to quantitatively evaluate all RCTs of fish oils in hyperlipidemic individuals [13]. Their final analysis comprised of 47 studies showed that taking fish oils (daily intake of 3.25 g of eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA)) produced a modest increase in HDL-C (0.39 mg/dL, 95% CI: 0.00 -0.77) which was not statistically significant. Pei et al performed a systematic review and meta-analysis of the effect of n-3 PUFA consumption on plasma lipids in patients with end-stage renal disease [14]. They reviewed evidences obtained from 10 RCTs including 557 patients with end-stage re-     [16]. Compared with placebo, DHA raised HDL-C (4.49 mg/dL; 95% CI: 3.50 -5.48), whereas EPA did not raise HDL-C.

Effects of Plant Sterols and Stanols on HDL Metabolism
Plant sterols and stanols have a similar chemical structure and function to cholesterol. Therefore, plant sterols and stanols ingestion are sometimes suggested to beneficially modify serum lipids. Plant sterols have a higher degree of absorption as compared with plant stanols. Talati et al performed a meta-analysis of RCTs to compare the effect of plant sterols with plant stanols on serum lipid levels in healthy individuals and also patients with hypercholesterolemia (Table 4) [17][18][19][20]. Fourteen studies (n = 531) met the inclusion criteria. There was no statistically or clinically significant difference between plant sterols and plant stanols in their abilities to modify HDL-C. Seppo et al conducted a meta-analysis of four RCTs to evaluate the effect of low-fat milk products enriched with plant stanol esters on serum lipids [18]. Each stanol-ester-enriched milk product provided daily 2 g of stanols, and the intervention period was 5 weeks. A total of 199 hypercholesterolemic subjects were included. There were no significant differences between the placebo group and the stanol group in pooled HDL-C. Moruisi et al conducted a systematic review that investigates the efficacy of plant sterols and stanols in modifying serum lipids in subjects with familial hypercholesterolemia (FH) [19]. The subjects studied were heterozygous FH subjects, aged 2 -69 years old with baseline TC and LDL-C concentrations of 270.7 mg/ dL and 208.8 mg/dL, respectively. Result showed that plant sterols and stanols did not affect HDL-C. Policosanol is a very long chain aliphatic alcohol derived from the wax constituent of plants [21]. The original policosanol supplement has been approved as a cholesterol-lowering drug in over 25 countries. Chen et al performed systematic review and meta-analysis of RCTs, to compare the efficacy and safety of plant sterols and stanols as well as policosanol in the treatment of CHD [20]. A total of 4,596 patients from 52 eligible studies were included for their analysis. Policosanol affected HDL-C more favorably than plant sterols and stanols. Policosanol induced a clinically significant decrease in the LDL/HDL ratio.

Conclusion
The substitution of FA for carbohydrates is beneficially associated with HDL metabolism. MUFA intake may not affect HDL-C. TFA is significantly associated with reduction of HDL-C, and is also adversely related with TC/HDL-C, coronary risks. Fish oils consumption, especially DHA consumption, may be favorably associated with HDL metabolism. Although plant sterols and stanols may not affect HDL-C, policosanol intake is associated with a clinically significant decrease in the LDL/ HDL ratio.