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SERUM CHOLESTEROL RESPONSE TO DIETARY CHOLESTEROL AND APOPROTEIN E PHENOTYPE
1261
My hypothesis is criticised by Dr Marsden (Nov 5, p 1077) on the grounds that comedones do not cause acne. Individual comedones do not necessarily become inflamed" but comedones must be considered an integral part of acne. Their relation to inflammation remains unknown but, as topical corticosteroid therapy for psoriasis shows, hyperproliferative epithelia may be unduly permeable to lipophilic agents. A consequence of hypovitaminosis A of follicular ducts may thus be undue permeability to inflammatory sebum lipids. Marsden is right to suggest that the up-regulation of retinoid receptors should be rapid. But the transit time of follicular duct cells is also rapid, so they may not have time to up-regulate before being shed. If stem cells were to up-regulate, then their daughter cells would start their brief lives up-regulated. But stem cells will be the last to suffer hypovitaminosis A, because they are closest to the blood and furthest from the sebum. Their up-regulation, therefore, may be slow. There are precedents for supposing acne-like conditions to be caused by the actions of follicular duct intracellular receptors. Dioxin, a potent cause of chloracne, acts through nuclear receptors
which, like those of the retinoids, induce gene expression. 12 Marsden suggests that acne may be caused by sebum stasis,
a
consequence of sebum viscosity and narrow follicular ducts. Presumably, this could be tested by studying the rheology of sebum and the elasticity of follicular ducts. My hypothesis makes the testable prediction that sebum vitamin A contents correlate with the severity of acne. It will be fun to discover which of us, if either, is
Serum total and lipoprotein cholesterol levels. N=normal diet; LF+LCh=low-fat/low-cholesterol LF + HCh low-fat/high-cholesterol diet.
diet;
and
=
right. Nuffield Department of Clinical Biochemistry, Oxford University, John Radcliffe Hospital, Oxford OX3 9DU
TERENCE KEALEY*
*Present address. Clinical Biochemistry, Cambridge University,
Cambridge CB2 2QR.
Lee JB, Michaelsson G, Rollman O. Vitamin A in human skin II: concentrations of carotene, retinol and dehydroretinol in various components of normal skin. J Invest Dermatol 1982; 79: 94-97 2 Rollman O, Vahlquist A. Vitamin A in skin and serum: studies of acne vulgaris, atopic dermatitis, ichthyosis vulgaris and lichen planus. Br J Dermatol 1985; 113: 405-13. 3. Wolf G. Multiple functions of vitamin A. Physiol Rev 1984, 64: 873-937. 4. Heller J. Interactions of plasma retinol binding protein with its receptor. J Biol Chem 1.
Vahlquist A,
1975, 250: 3613-19. PD, van den Hurk J. Plasma vitamin A in the common dermatoses. Br J Dermatol 1974; 91: 155-59. 6. Michaelsson G, Vahlquist A, Juhlin L. Serum zinc and retinol binding protein in acne. Br J Dermatol 1977; 96: 283-86. 7 Labadonos D, Cilliers J, Visser L, et al. Vitamin A in acne vulgaris. Clin Exp Dermatol 1987; 12: 432-36. 8 Goldstein JA, Socha-Szott A, Thomsen RJ, et al. Comparative effect of isotretinoin and etretinate on acne and sebaceous gland secretion. J Am Acad Dermatol 1982; 6: 5. Mier
760-65 9. Rollman O, Vahlquist A. Oral isotretinoin (13-cis-retinoic acid) therapy in
drug and vitamin A concentrations in serum and skin. J Invest
severe acne:
Dermatol 1986; 86:
384-89. 10. Rollman O, Vahlquist A Retinoid concentrations in skin, serum and adipose tissue of patients treated with etretinate. Br J Dermatol 1983; 109: 439-47. 1 1. Shuster S. Acne: the ashes of a burnt out controversy. Acta Dermatovener 1985; 120 (suppl): 43-46 12 Whitlock JP The regulation of gene expression by 2,3,7,8-tetrachlorodibenzo-pdioxin. Pharmacol Rev 1987, 39: 147-61
SERUM CHOLESTEROL RESPONSE TO DIETARY CHOLESTEROL AND APOPROTEIN E PHENOTYPE
Sip,—Serum total and low density lipoprotein (LDL) cholesterol levels in a normal male population have been found to be positively related to cholesterol absorption.12 Furthermore, serum cholesterol concentrations are higher in people with apoprotein (apo) e4 allele than in those with the apo-82 allele.3 Under normal conditions effective cholesterol absorption down-regulates faecal elimination of cholesterol, cholesterol synthesis, and LDL apoprotein B receptor activity in apo-E4 individuals, resulting in hypercholesterolaemia,4 while the opposite pattern, including a low efficiency of cholesterol absorption, contributes to low serum cholesterol level in apo-E2 individuals. These differences in pattem suggest that dietary cholesterol feeding might increase serum cholesterol more in apo-E2 than in apo-E4 individuals. To test this hypothesis six E2 males (five E2/3, one E2/2) and ten E4 males (nine
E3/4, one E4/4) were switched from their normal diet to a low-fat/low-cholesterol (150-200 mg daily) diet for 5 weeks, followed by 6 weeks on a low-fat/high cholesterol diet (900 mg daily, from egg yolks). Total cholesterol (see figure) fell significantly in both groups when they were on the low-fat/low-cholesterol diet but, in contrast to an earlier papery total cholesterol was significantly increased only in the E4 men when dietary cholesterol was added. LDL cholesterol level was not altered consistently by dietary manipulation in the E2 group, while in the E4 group LDL cholesterol changes were similar to those in total cholesterol. Addition of dietary cholesterol increased LDL cholesterol by 3% (not significant) in the E2 group and 16% (significant) in the E4 group. Very low density (VLDL) or intermediate density (IDL) lipoprotein levels were unchanged. However, high density lipoprotein (HDL) cholesterol concentrations were significantly decreased in the E4 group by the low-fat/low-cholesterol diet and increased in both groups by the dietary cholesterol addition. Even though other factors may contribute to hyperresponsiveness to dietary cholesterol,6 our findings suggest that the presence of apoprotein 4 allele enhances cholesterol absorption and increases the response of serum cholesterol to dietary cholesterol even without change in fatty acid intake. Thus, in those with the apo E4 phenotype restriction of dietary cholesterol appears to be a beneficial measure to treat hypercholesterolaemia. "Go to work with an egg" (a Finnish breakfast commercial) may be a significant inducer of hypercholesterolaemia, especially in Finland, where the frequency of this apo E4 phenotype is high3 Second Department of Medicine, University of Helsinki, SF-00290 Helsinki, Finland
T. A. MIETTINEN H. GYLLING H. VANHANEN
1. Kesaniemi
YA, Miettinen TA. Cholesterol absorption efficiency regulates plasma cholesterol level in the Finnish population. Eur J Clin Invest 1978, 17: 391-95. 2. Miertinen TA, Kesaniemi YA. Cholesterol absorption regulates cholesterol synthesis, elimination and within-population variations of serum cholesterol levels. Am J Clin Nutr (in press). 3. Davigason J, Gregg RE, Sing CF Apolipoprotein E polymorphism and atherosclerosis. Atherosclerosis 1988; 8: 1-21. 4 Kesaniemi YA, Ehnholm C, Miettinen TA Intestinal cholesterol absorption efficiency in man is related to apoprotem E phenotype. JClin Invest 1987; 80: 578-81.
Brenninkmeijer BJ, Stuyt PMJ, Demacker PMN, Stalenhoef AFH, van’t Laar A. Apo E polymorphism and lipoprotein concentrations during a cholesterol-rich diet Arteriosclerosis 1987; 7: 516a. 6 Katan MB, Beynen AC. Characteristics of human hypo- and hyperresponders to dietary cholesterol. Am J Epidemiol 1987; 125: 387-99. 5
My hypothesis is criticised by Dr Marsden (Nov 5, p 1077) on the grounds that comedones do not cause acne. Individual comedones do not necessarily become inflamed" but comedones must be considered an integral part of acne. Their relation to inflammation remains unknown but, as topical corticosteroid therapy for psoriasis shows, hyperproliferative epithelia may be unduly permeable to lipophilic agents. A consequence of hypovitaminosis A of follicular ducts may thus be undue permeability to inflammatory sebum lipids. Marsden is right to suggest that the up-regulation of retinoid receptors should be rapid. But the transit time of follicular duct cells is also rapid, so they may not have time to up-regulate before being shed. If stem cells were to up-regulate, then their daughter cells would start their brief lives up-regulated. But stem cells will be the last to suffer hypovitaminosis A, because they are closest to the blood and furthest from the sebum. Their up-regulation, therefore, may be slow. There are precedents for supposing acne-like conditions to be caused by the actions of follicular duct intracellular receptors. Dioxin, a potent cause of chloracne, acts through nuclear receptors
which, like those of the retinoids, induce gene expression. 12 Marsden suggests that acne may be caused by sebum stasis,
a
consequence of sebum viscosity and narrow follicular ducts. Presumably, this could be tested by studying the rheology of sebum and the elasticity of follicular ducts. My hypothesis makes the testable prediction that sebum vitamin A contents correlate with the severity of acne. It will be fun to discover which of us, if either, is
Serum total and lipoprotein cholesterol levels. N=normal diet; LF+LCh=low-fat/low-cholesterol LF + HCh low-fat/high-cholesterol diet.
diet;
and
=
right. Nuffield Department of Clinical Biochemistry, Oxford University, John Radcliffe Hospital, Oxford OX3 9DU
TERENCE KEALEY*
*Present address. Clinical Biochemistry, Cambridge University,
Cambridge CB2 2QR.
Lee JB, Michaelsson G, Rollman O. Vitamin A in human skin II: concentrations of carotene, retinol and dehydroretinol in various components of normal skin. J Invest Dermatol 1982; 79: 94-97 2 Rollman O, Vahlquist A. Vitamin A in skin and serum: studies of acne vulgaris, atopic dermatitis, ichthyosis vulgaris and lichen planus. Br J Dermatol 1985; 113: 405-13. 3. Wolf G. Multiple functions of vitamin A. Physiol Rev 1984, 64: 873-937. 4. Heller J. Interactions of plasma retinol binding protein with its receptor. J Biol Chem 1.
Vahlquist A,
1975, 250: 3613-19. PD, van den Hurk J. Plasma vitamin A in the common dermatoses. Br J Dermatol 1974; 91: 155-59. 6. Michaelsson G, Vahlquist A, Juhlin L. Serum zinc and retinol binding protein in acne. Br J Dermatol 1977; 96: 283-86. 7 Labadonos D, Cilliers J, Visser L, et al. Vitamin A in acne vulgaris. Clin Exp Dermatol 1987; 12: 432-36. 8 Goldstein JA, Socha-Szott A, Thomsen RJ, et al. Comparative effect of isotretinoin and etretinate on acne and sebaceous gland secretion. J Am Acad Dermatol 1982; 6: 5. Mier
760-65 9. Rollman O, Vahlquist A. Oral isotretinoin (13-cis-retinoic acid) therapy in
drug and vitamin A concentrations in serum and skin. J Invest
severe acne:
Dermatol 1986; 86:
384-89. 10. Rollman O, Vahlquist A Retinoid concentrations in skin, serum and adipose tissue of patients treated with etretinate. Br J Dermatol 1983; 109: 439-47. 1 1. Shuster S. Acne: the ashes of a burnt out controversy. Acta Dermatovener 1985; 120 (suppl): 43-46 12 Whitlock JP The regulation of gene expression by 2,3,7,8-tetrachlorodibenzo-pdioxin. Pharmacol Rev 1987, 39: 147-61
SERUM CHOLESTEROL RESPONSE TO DIETARY CHOLESTEROL AND APOPROTEIN E PHENOTYPE
Sip,—Serum total and low density lipoprotein (LDL) cholesterol levels in a normal male population have been found to be positively related to cholesterol absorption.12 Furthermore, serum cholesterol concentrations are higher in people with apoprotein (apo) e4 allele than in those with the apo-82 allele.3 Under normal conditions effective cholesterol absorption down-regulates faecal elimination of cholesterol, cholesterol synthesis, and LDL apoprotein B receptor activity in apo-E4 individuals, resulting in hypercholesterolaemia,4 while the opposite pattern, including a low efficiency of cholesterol absorption, contributes to low serum cholesterol level in apo-E2 individuals. These differences in pattem suggest that dietary cholesterol feeding might increase serum cholesterol more in apo-E2 than in apo-E4 individuals. To test this hypothesis six E2 males (five E2/3, one E2/2) and ten E4 males (nine
E3/4, one E4/4) were switched from their normal diet to a low-fat/low-cholesterol (150-200 mg daily) diet for 5 weeks, followed by 6 weeks on a low-fat/high cholesterol diet (900 mg daily, from egg yolks). Total cholesterol (see figure) fell significantly in both groups when they were on the low-fat/low-cholesterol diet but, in contrast to an earlier papery total cholesterol was significantly increased only in the E4 men when dietary cholesterol was added. LDL cholesterol level was not altered consistently by dietary manipulation in the E2 group, while in the E4 group LDL cholesterol changes were similar to those in total cholesterol. Addition of dietary cholesterol increased LDL cholesterol by 3% (not significant) in the E2 group and 16% (significant) in the E4 group. Very low density (VLDL) or intermediate density (IDL) lipoprotein levels were unchanged. However, high density lipoprotein (HDL) cholesterol concentrations were significantly decreased in the E4 group by the low-fat/low-cholesterol diet and increased in both groups by the dietary cholesterol addition. Even though other factors may contribute to hyperresponsiveness to dietary cholesterol,6 our findings suggest that the presence of apoprotein 4 allele enhances cholesterol absorption and increases the response of serum cholesterol to dietary cholesterol even without change in fatty acid intake. Thus, in those with the apo E4 phenotype restriction of dietary cholesterol appears to be a beneficial measure to treat hypercholesterolaemia. "Go to work with an egg" (a Finnish breakfast commercial) may be a significant inducer of hypercholesterolaemia, especially in Finland, where the frequency of this apo E4 phenotype is high3 Second Department of Medicine, University of Helsinki, SF-00290 Helsinki, Finland
T. A. MIETTINEN H. GYLLING H. VANHANEN
1. Kesaniemi
YA, Miettinen TA. Cholesterol absorption efficiency regulates plasma cholesterol level in the Finnish population. Eur J Clin Invest 1978, 17: 391-95. 2. Miertinen TA, Kesaniemi YA. Cholesterol absorption regulates cholesterol synthesis, elimination and within-population variations of serum cholesterol levels. Am J Clin Nutr (in press). 3. Davigason J, Gregg RE, Sing CF Apolipoprotein E polymorphism and atherosclerosis. Atherosclerosis 1988; 8: 1-21. 4 Kesaniemi YA, Ehnholm C, Miettinen TA Intestinal cholesterol absorption efficiency in man is related to apoprotem E phenotype. JClin Invest 1987; 80: 578-81.
Brenninkmeijer BJ, Stuyt PMJ, Demacker PMN, Stalenhoef AFH, van’t Laar A. Apo E polymorphism and lipoprotein concentrations during a cholesterol-rich diet Arteriosclerosis 1987; 7: 516a. 6 Katan MB, Beynen AC. Characteristics of human hypo- and hyperresponders to dietary cholesterol. Am J Epidemiol 1987; 125: 387-99. 5