Plasma Total HDL and LDL Cholesterol Concentrations

Numerous studies in humans have examined the effects of dietary cholesterol on plasma total and lipoprotein cholesterol concentrations (Tables 9-2 and 9-3, Figures 9-1 and 9-2), and empirical formulas have been derived to describe these relationships. Although most studies have

550 DIETARY REFERENCE INTAKES

TABLE 9-2 Effects of Adding Dietary Cholesterol to Defined Diets with Strict Control of Dietary Intake on Serum Cholesterol Concentration

Baseline

Dietary Added Dietary

Cholesterol Cholesterol

Reference

n

(mg/d)

(mg/d)

Beveridge et al.,

6

13

81

1960

9

13

140

9

13

280

9

13

621

6

13

1,282

10

13

2,481

9

13

4,490

Connor et al.,

2

0

475

1961a

2

0

950

2

0

1,425

Connor et al.,

3

0

2,400

1961b

1

0

1,650

1

0

1,900

1

0

4,800

Steiner et al., 1962

6

0

3,000

Wells and Bronte-

3

0

17

Stewart, 1963

3

0

42

3

0

67

3

0

88

3

0

142

3

0

267

3

0

517

3

0

1,017

3

0

1,517

3

0

3,017

Connor et al., 1964

6

0

729

5

0

725

Erickson et al.,

6

0

742

1964

6

0

742

Hegsted et al., 1965

10

116

570

10

306

380

10

116

Change in

Serum Total

Percent of

Cholesterol

Calories from

(mmol/L)

Fat

P:S Ratio

0.06

30

0.08

0.10

30

0.08

1.17

30

0.08

0.43

30

0.08

0.59

30

0.08

1.20

30

0.08

0.87

30

0.08

1.71

40

0.76

1.64

40

0.76

1.99

40

0.76

1.47

40

0.88

2.43

40

0.88

2.97

40

0.88

2.53

40

0.88

1.30

40

0.68

0.44

15

0.56

15

0.66

15

0.80

15

0.96

15

1.03

15

1.18

15

1.09

15

1.29

15

1.23

15

1.03

40

0.25

0.74

40

1.7

0.61

41

1.6

0.69

41

1.6

0.75

39

5.4

0.29

39

0.05

0.70

39

0.68

DIETARY REFERENCE INTAKES

TABLE 9-2 Continued

Reference

Baseline Dietary

Cholesterol (mg/d)

Added Dietary

Cholesterol (mg/d)

Keys et al., 1965

22 22 22 22 22

50 50 50 50 50

470 1,410 33 1,400 1,410

National Diet-Heart Study Research Group,1968

81 81 57 57

126 126 401 154

495 495 495 495

44 53.5

2,441 499 197 4,002

Mattson et al., 1972

14 14 14

297 594 888

Anderson et al., 1976

12 12

291 291

Nestel and Poyser, 1976

210 257 334 103

500 500 532 439

3,250

Bronsgeest-Schoute et al., 1979a, 1979b

98 98 124 124

567 567 607 607

Lin and Connor, 1980

1,081

McMurry et al., 1981

Change in

Serum Total Percent of

Cholesterol Calories from

0.36 40

0.70 40

0.41 40

0.74

554 DIETARY REFERENCE INTAKES

TABLE 9-2 Continued

Baseline

Dietary

Added Dietary

Cholesterol

Cholesterol

Reference

n

(mg/d)

(mg/d)

McMurry et al.,

8

0

905

1982

Nestel et al., 1982

6

200

1,500

Schonfeld et al.,

11

300

750

1982

9

300

1,500

6

300

750

6

300

1,500

6

300

750

6

300

1,500

Maranhao and

13

40

1,350

Quintdo, 1983

Applebaum-

9

137

897

Bowden et al.,

1984

Beynen and Katan,

6

114

526

1985b

Katan et al., 1986

94

110

500

Zanni et al., 1987

9

130

745

9

130

745

Johnson and

10

200

400

Greenland, 1990

Ginsberg et al.,

20

128

155

1994

20

128

340

20

128

730

Sundram et al.,

17

192

7

1994

17

192

13

Fielding et al.,

20

200

403

1995

22

200

435

Ginsberg et al.,

13

108

169

1995

13

108

Change in

Serum Total

Percent of

Cholesterol

Calories from

(mmol/L)

Fat

P:S Ratio

0.88

20

0.7

0.42

31

1

0.47

40

0.32

0.72

40

0.32

0.13

40

0.8

0.70

40

0.8

0.05

40

2.5

0.26

40

2.5

1.19

40

0.93

0.28

40

0.82

0.25

42

0.46

0.5

42

0.16

0.58

31

2.1

0.39

31

0.64

0.26

30

1.5

0.14

27

0.89

0.16

27

0.93

0.29

28

0.87

0.06

31

0.21

-0.35

31

0.25

0.50

39

0.81

0.76

36

0.28

0.16

28

0.89

0.41

28

0.86

556 DIETARY REFERENCE INTAKES

TABLE 9-3 Effects of Adding Dietary Cholesterol to Self-Selected Diets with Strict Control of Dietary Intake on Serum Cholesterol Concentration

Reference

Cholesterol (mg/d)

Added Dietary Cholesterol (mg/d)

Slater et al., 1976

25

314

482

Kummerow et al.,

21

250

470

1977

Porter et al., 1977

55

301

235

59

301

235

Flynn et al., 1979

56

260

540

60

260

540

Mistry et al., 1981

37

522

1,500

14

480

750

Roberts et al.,

16

196

532

1981

Packard et al.,

7

180

1,290

1983

Beynen and

6

207

1,596

Katan, 1985a

6

207

1,596

Oh and Miller,

21

474

654

1985

Edington et al.,

33

120

188

1987

135

120

188

McNamara et al.,

39

192

628

1987

36

288

575

Kestin et al., 1989

10

180

686

15

204

735

Clifton et al., 1990

Normal: 11

185

681

Hypercholesterolemic

diet-insensitive: 22

185

681

Hypercholesterolemic

diet-sensitive: 23

185

Change in Serum Total Cholesterol (mmol/L)

Percent of Calories from Fat

P:S Ratio

-0.09

0.05

40

0.16 0.03

38 38

0.49 0.00

38 38

0.75 0.62

41 41

0.40

40

1.47

38

0.17

0.48 0.61

46 46

0.5 0.5

0.27

35

0.62

0.13 0.12

26 35

0.8 0.6

0.16 0.13

35 35

1.45 0.27

-0.02 0.04

41 36

0.37 0.85

0.06

29

0.6

0.19

29

0.6

0.36

29

0.6

continued

558 DIETARY REFERENCE INTAKES

TABLE 9-3 Continued

Reference

Cholesterol (mg/d)

Added Dietary Cholesterol (mg/d)

Kern, 1994

8

585

2,393

8

548

2,462

McCombs et al.,

12

213

938

1994

11

197

888

Clifton et al., 1995

67

151

691

53

208

939

Sutherland et al.,

12

349

250

1997

14

349

250

Romano et al.,

10

200

800

1998

11

200

♦ Defined Diets—Data from Table 9-2 o Self-Selected Diets—Data from Table 9-3 -Linear (Defined Diets—Data from Table 9-2) — - -Linear (Self-Selected Diets—Data from Table 9-3)

R2= 0.1942

R2= 0.1942

200 400 600 800

Change in Dietary Cholesterol (mg/d)

1000

1200

FIGURE 9-1 Relationship between change in dietary cholesterol (0 to 1,000 mg/d) and change in serum total cholesterol (TC) concentration.

CHOLESTEROL 559

Change in

Serum Total

Percent of

Cholesterol

Calories

(mmol/L)

from Fat

P:S Ratio

0.14

44

0.59

-0.22

44

0.65

0.57

35

0.49

0.16

34

0.54

0.36

35

0.31

0.34

35

0.30

0.18

34

0.15

34

0.29

30

0.46

30

° Defined Diets (data from Table 9-2) * Self-Selected Diets (data from Table 9-3)

FIGURE 9-2 Relationship between change in dietary cholesterol (0 to 4,500 mg/d) and change in serum cholesterol (TC) concentration.

Change in Dietary Cholesterol (mg/d)

FIGURE 9-2 Relationship between change in dietary cholesterol (0 to 4,500 mg/d) and change in serum cholesterol (TC) concentration.

560 DIETARY REFERENCE INTAKES

reported a linear relationship between changes in dietary cholesterol and total serum cholesterol concentration, other studies, including a metaanalysis of 27 controlled metabolic feeding studies of added dietary cholesterol (Hopkins, 1992), have indicated a curvilinear univariate relationship that is quasilinear in the range from 0 to 300 to 400 mg/d of added dietary cholesterol. The range of added dietary cholesterol in the studies was 17 to 4,800 mg/d. The meta-analysis also identified a diminishing increment of serum cholesterol with increasing baseline dietary cholesterol intake. With a baseline cholesterol intake of 0, the estimated increases in serum total cholesterol concentration for intakes from 100 to 400 mg/d of added dietary cholesterol were 0.16 to 0.51 mmol/L, whereas for a baseline cholesterol intake of 300 mg/d, the estimated increases in serum total cholesterol were 0.05 to 0.16 mmol/L (Hopkins, 1992). Another meta-analysis showed that dietary cholesterol raises the ratio of total cholesterol to high density lipoprotein (HDL) cholesterol, therefore adversely affecting the cholesterol profile (Weggemans et al., 2001).

Other predictive formulas for the effect of 100 mg/d of added dietary cholesterol, which did not consider baseline cholesterol intake and are based on compilations of studies with a variety of experimental conditions, have yielded estimates of 0.1 mmol/L (Hegsted, 1986), 0.057 mmol/L (Howell et al., 1997), and 0.065 mmol/L (Clarke et al., 1997), the latter two involving meta-analyses with adjustment for other dietary variables. Furthermore, pooled analyses of the effects of 100 mg/d of added dietary cholesterol on plasma lipoprotein cholesterol concentrations (Clarke et al., 1997) indicated an estimated increase of 0.05 mmol/L in low density lipoprotein (LDL) and 0.01 mmol/L in HDL (ratio of 5 LDL:1 HDL). There is evidence that the increase in HDL is largely accounted for by higher levels of apoE-containing HDL particles (Mahley et al., 1978), but the significance in atherosclerosis protection is not established. Hegsted and coworkers (1993) reported that the majority of the increase in serum total cholesterol concentration with increased cholesterol intake was due to an increase in LDL cholesterol concentration.

The incremental serum cholesterol response to a given amount of dietary cholesterol appears to diminish as baseline serum cholesterol intake increases (Hopkins, 1992). There is also evidence from a number of studies that increases in serum cholesterol concentration due to dietary cholesterol are blunted by diets low in saturated fat, high in polyunsaturated fat, or both (Fielding et al., 1995; National Diet-Heart Study Research Group, 1968; Schonfeld et al., 1982), although this effect has not been observed by others (Kestin et al., 1989; McNamara et al., 1987).

There is considerable evidence for interindividual variation in serum cholesterol response to dietary cholesterol, ranging from 0 to greater than 100 percent (Hopkins, 1992). It has been reported that such responsive-

CHOLESTEROL 561

ness is relatively stable within individuals (Beynen and Katan, 1985b) and appears to be correlated with serum cholesterol response to saturated fatty acids (Katan et al., 1988). Intrinsic differences in intestinal cholesterol absorption (Sehayek et al., 1998), suppression of hepatic cholesterol synthesis by dietary cholesterol (Dietschy et al., 1993; McNamara et al., 1987; Nestel and Poyser, 1976; Quintao et al., 1971), and LDL catabolism (Dietschy et al., 1993; Mistry et al., 1981) may all contribute to the observed variation in dietary cholesterol response.

There is increasing evidence that genetic factors underlie a substantial portion of interindividual variation in response to dietary cholesterol. An instructive case is that of the Tarahumara Indians, who in addition to consuming a diet low in cholesterol, have both low intestinal cholesterol absorption and increased transformation of cholesterol to bile acids (McMurry et al., 1985). However, with an increase in dietary cholesterol from 0 to 905 mg/d, their average plasma cholesterol concentration increased 0.88 mmol/L (from 2.92 to 3.8 mmol/L), the same value predicted by the formula of Hopkins (1992), indicating the likelihood of above-average responsiveness of other aspects of cholesterol or lipoprotein metabolism.

Variations in several genes have been associated with altered responsiveness to dietary cholesterol. The common E4 polymorphism of the apoE gene has been associated with increased cholesterol absorption (Kesániemi et al., 1987) and with increased plasma LDL cholesterol response to dietary saturated fat and cholesterol in some, but not all studies (Dreon and Krauss, 1997). The recent finding that apoE is of importance in regulating cholesterol absorption and bile acid formation in apoE knockout mice (Sehayek et al., 2000) lends support to a possible role for this gene in modulating dietary cholesterol responsiveness in humans. The A-IV-2 variant allele of the apo A-IV gene has been found to attenuate the plasma cholesterol response to dietary cholesterol (McCombs et al., 1994). Recently, the A-IV-2 allele has been associated with reduced intestinal cholesterol absorption in diets high in polyunsaturated fat but not in diets high in saturated fat (Weinberg et al., 2000). However, this has not been confirmed in other studies (Weggemans et al., 2000). Finally, the recent discovery that defects in the ABCG5 and ABCG8 genes can lead to markedly increased intestinal absorption of both cholesterol and plant sterols (Berge et al., 2000) points to the possibility that more common variants of these genes may contribute to variation in cholesterol absorption and dietary cholesterol response in the general population.

There are numerous other candidate genes that could modulate plasma lipid and lipoprotein response to dietary cholesterol by affecting cholesterol absorption, cellular cholesterol homeostasis, and plasma lipo-protein metabolism. Among the most likely candidates are those regulated

562 DIETARY REFERENCE INTAKES

by lipid-responsive nuclear transcription factors, including sterol regulatory element-binding proteins, peroxisome proliferator-activated receptors, and orphan nuclear receptors. Studies in animal models have generated data in support of the possibility that variations among these genes may be of importance in influencing dietary cholesterol response in humans, but to date such human data are lacking. Nevertheless, the existence of marked interindividual variability in dietary cholesterol response among and within various animal models points to the likelihood that some of the mechanisms underlying this variability will also apply to humans.

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