Harukuni Akita

Unique character and metabolism of high density lipoprotein (HDL) in fetus

Lipid and lipoprotein profiles, and enzymes for the lipid metabolism were compared between cord and adult blood. Consistent with previous reports, the major lipoprotein in cord blood was high-density lipoprotein (HDL), and that in adult blood was low-density lipoprotein (LDL). The level of apolipoprotein E (apo E) in cord blood was almost equivalent to that in adult blood, while other apolipoproteins and lipids were all lower than the adult level. In cord blood, apo E-rich HDL cholesterol represented more than 30% of total HDL cholesterol (around 11% in adult), and the concentration was about twice of that in adult blood. This apo E-rich HDL cholesterol was poorly esterified (E/T 56%) compared with that in adults (93%). The lecithin:cholesterol acyltransferase (LCAT) activity in cord blood was extremely low, while the activity and mass of cholesteryl ester transfer protein (CETP) were higher than those in adult blood. The apo E genotype did not show influences on total cholesterol, LDL cholesterol, total HDL cholesterol, and apo E rich HDL cholesterol levels in cord blood, as opposed to those in adult blood. The association of D442G mutation of the CETP gene with the increased HDL cholesterol in adult blood was not seen in cord blood. Rather, the mutation was associated with low total cholesterol and LDL cholesterol levels in cord blood. These results indicate that, in fetus, the character and metabolism of HDL, especially of apo E-rich HDL cholesterol, are distinct from those in adults.

Human CD36 deficiency is associated with elevation in low-density lipoprotein-cholesterol.

To find out whether CD36 plays a role in the human lipoprotein metabolism, we studied lipoprotein profiles in subjects with CD36 deficiency. Apparently healthy Japanese volunteers (n = 790) were classified by flow cytometry into three groups of normal (platelet and monocyte CD36+, n = 741, 93.8%), type-II deficiency (platelet CD36- and monocyte CD36+, n = 45, 5.7%), and type-I deficiency (platelet and monocyte CD36-, n = 4, 0.5%). At least one of reported mutations in the CD36 gene was found in all four subjects with type-I deficiency and in 23 of the 45 subjects with type II. Among 779 subjects (731 normals, 44 type II, and four type I) with serum triglyceride levels of <400 mg/dL, serum total cholesterol and low-density lipoprotein (LDL) cholesterol were significantly elevated in type-II deficiency (P = 0.0095 and 0.0382 versus normal, respectively, Scheffes F-test), while differences were not significant in triglyceride and high-density lipoprotein-cholesterol. Similar tendency was observed in type-I deficiency, although the differences were not statistically significant because of small sample size. We conclude that CD36 deficiency elevates LDL cholesterol, indicating a contribution of CD36 to LDL metabolism.

Evaluation of G-to-A substitution in the apolipoprotein A-I gene promoter as a determinant of high-density lipoprotein cholesterol level in subjects with and without cholesteryl ester transfer protein deficiency

The effect of a polymorphism, guanine (G) to adenine (A) substitution in the promoter of apolipoprotein A-I gene at a position 78 bp upstream of the transcription initiation site, on the serum high-density lipoprotein (HDL)-cholesterol level was studied in 168 Japanese subjects with HDL-cholesterol levels ranging from 26 to 171 mg/dl. Considering the significant effect of cholesteryl ester transfer protein (CETP) on the HDL-cholesterol level and the common occurrence of its deficiency, we performed statistical analyses separately for two groups: one without CETP deficiency (n=126) and the other with CETP deficiency (n=42). In the group without CETP deficiency, in which the numbers of G/G, G/A, and A/A genotypes were 92 (73.0%), 28 (22.2%), and 6 (4.8%), respectively, the frequency of the A allele in the subjects with HDL-cholesterol levels of ≥70 mg/dl did not differ from subjects with HDL-cholesterol levels of ≤69 mg/dl, irrespective of gender: 0.154 and 0.145 in males, and 0.182 and 0.174 in females, respectively, for the ≥70 mg/dl and ≤69 mg/dl groups. Additionally, the HDL-cholesterol levels for the subjects with the G/G genotype did not differ from those for the subjects with the A allele: 64 ±22, 58±14, 77±14 and 62±16 mg/dl, respectively, for the G/G, G/A, A/A, and G/A+A/A in males, and 72 ±18, 74±24, 63±4, and 73±23 mg/dl in females. For the group with CETP deficiency, in which the numbers of G/G and G/A+A/A genotypes were 25 (59.5%) and 17 (40.5%), the HDL-cholesterol levels also did not differ: 98±24 mg/dl and 99±30 mg/dl, respectively, for the G/G and G/A+A/A genotypes. Thus, there is no evidence that the polymorphism has any effect on serum HDL-cholesterol levels regardless of CETP status. We conclude that the G-to-A substitution in the promoter of apolipoprotein A-I gene does not significantly alter serum HDL-cholesterol level.

Effect of ageing on plasma lipoprotein(a) levels

Background Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerosis and increases with age. The purpose of this study was to determine the effect of ageing on Lp(a) for three different apo(a) phenotypes. Methods We measured plasma Lp(a) concentrations in 551 unrelated Japanese subjects (20-88 years of age). We performed statistical analyses separately for three apo(a) phenotypes: the low-molecular-weight (LMW) phenotype with the F, B or S1 isoform, the intermediate-molecular-weight (IMW) phenotype with the S2 isoform and the high-molecular-weight (HMW) phenotype with the S3 or S4 isoform. Results For each phenotype, the mean plasma Lp(a) concentration and the frequency of Lp(a) concentrations ≥ 250 mg/L increased with age. Further, a statistically significant difference was always found between the younger subjects (20-39 years of age) and the elderly (over 60 years). The frequency of coronary heart disease increased with age, particularly for the LMW and IMW phenotypes. Conclusions We conclude that ageing elevates plasma Lp(a) concentrations, which may have a role in the prevalence of coronary heart disease in the elderly, especially those with the LMW or IMW phenotypes.

Decreased longevity in Japanese men, associated with low-molecular-weight apolipoprotein(a) phenotypes

Lipoprotein(a) [Lp(a)] is an established risk factor for atherosclerosis. High plasma Lp(a) concentrations are associated with low-molecular-weight (LMW) apolipoprotein(a) (apo a) phenotypes, which raises the question of whether LMW apo a phenotypes occur less frequently in the elderly. To assess this possibility, we studied apo A phenotype and allele frequencies in Japanese subjects ≥80 years old (men:women=40:34) in comparison with those <80 years old (men:women= 221:296). Significantly fewer LMW phenotypes and LMW alleles were observed in ≥80 year old men compared with those <80 years old: 2·5% versus 16·1% for the LMW phenotype frequency and 1·3% versus 9·7% for the LMW allele frequency (P<0·05, Fishers exact probability test). Similar differences were not found in the women. Consistent with this, plasma Lp(a) concentrations were significantly lower in the men ≥80 years old than in the younger group. These results indicate that LMW apo a phenotypes are associated with a shorter lifespan in men but not in women, possibly reflecting the higher susceptibility of men to atherosclerosis.

Effects of triamcinolone on brain and cerebrospinal fluid apolipoprotein E levels in rats

The effects of the short term administration of triamcinolone (0.5 mg per 100 g body weight, 5 days) on apolipoprotein E and A-I concentrations in cerebrospinal fluid (CSF), brain extract and serum were studied in male Wistar rats using enzyme immunoassays. ApoE was significantly increased by triamcinolone in apoE-rich HDL1 in serum; 40+/-13 (mean+/-SD) vs. 68+/-23 mg/dl (15 saline-treated rats vs. 11 triamcinolone-treated rats)(P<0.01), which was paralleled by an increase in serum apoA-I (76+/-21 vs. 184+/-24 mg/dl), while serum lipids also increased significantly. No significant difference was observed in the apoE concentrations in CSF (296+/-170 vs. 269+/-67 microg/dl) or brain extract (5.0+/-1.6 vs. 5.7+/-1.8 microg/g wet weight). The apoA-I concentrations found in CSF and brain extract were much lower than those for apoE and were not appreciably affected by triamcinolone: 7.7+/-5.5 vs. 4.5+/-3.1 microg/dl for CSF and <0.5 vs. <0.5 microg/g wet weight for brain extract. The apo E metabolism in the rat central nervous system appears to be refractory to the short term administration of triamcinolone and to changes in the serum lipoprotein metabolism. ApoA-I appears unlikely to play a significant role in the rat central nervous system.

A Remarkable Increase in High‐Density Lipoprotein‐Cholesterol by Alcohol Intake in a Homozygous Patient with Cholesteryl Ester Transfer Protein Deficiency

MASATO NISHIWAKI, TOSHITSUGU ISHIKAWA, TOSHIMITSU ITO, KOJI TOMIYASU, KATSUNORI IKEWAKI, NAOKI WAKIMOTO? SHIRO MURAKOSHI,a HARUKUNI AKITAF MITSUHIKO KATSURADAF HIROMITSU HAGA? HIDEYUKI HASHIMOTOP AND HARUO NAKAMURA First Department of Internal Medicine National Defense Medical College 3-2 Namiki, Tokorozawa Saitama, 359 Japan aSapporo General Hospital of Self Defense 12-1-32 Ichijo, Hiragishi Toyohira, Sapporo Hokkaido, 062 Japan bDaiichi Pure Chemical Company 5-5-12 Narihira, Sumida Tokyo, 130 Japan

Lipoprotein(a), Apolipoprotein(a) Phenotypes, and Nephropathy in NIDDM Patients

criteria) by blood test, either at our center or in any other clinic. Evidence for seasonality was tested using the test of Kendal and Ord (3). This is based on ranks, a simple adaptation of the nonparametric analysis of variance that ranks the figures within each year from the minimum to the maximum, from 1 to 12, for the monthly data. The test for seasonality was applied for the total group (n = 499) and for men and women separately. It was also done separately for those with age at diagnosis of ^15 years and for those >15 years. Although slight peaks were observed in January (cold weather) and in August (rainy season), and a trough in May (summer), the test for seasonality showed that the differences between the months were nonsignificant (x = 19.7, df 11, P 0.08). Nonsignificant values were obtained for both sexes and the different age-groups tested separately. The increased incidence of viral infections in cooler months has been implicated as a causative factor for the high incidence of IDDM in European children in winter. Although the EURODIAB study showed that seasonality was present in almost all populations across Europe, interestingly there was a lack of seasonality in high-risk populations in Scandinavian countries (1). Similarly, a study from the Liguria region in Italy, with a high incidence of IDDM, also reported lack of significant differences in seasonal pattern, probably explained by the fact that there are many different influences unrelated to the initial trigger of the disease (4). Is this true of low-risk populations? A study from Libya, although it had more cases during cooler months, failed to show a significant difference in seasonality (5). It is possible that both degree of risk of the population and the geographical location may be determinants of seasonality. The lack of wide variations in temperature in the tropical climate in areas like southern India may be one of the factors responsible for the lack of seasonality.