Unique features of high-density lipoproteins in the Japanese: in population and in genetic factors

Abstract

Despite its gradual increase in the past several decades, the prevalence of atherosclerotic vascular disease is low in Japan. This is largely attributed to difference in lifestyle, especially food and dietary habits, and it may be reflected in certain clinical parameters. Plasma high-density lipoprotein (HDL) levels, a strong counter risk for atherosclerosis, are indeed high among the Japanese. Accordingly, lower HDL seems to contribute more to the development of coronary heart disease (CHD) than an increase in non-HDL lipoproteins at a population level in Japan. Interestingly, average HDL levels in Japan have increased further in the past two decades, and are markedly higher than in Western populations. The reasons and consequences for public health of this increase are still unknown. Simulation for the efficacy of raising HDL cholesterol predicts a decrease in CHD of 70% in Japan, greater than the extent by reducing low-density lipoprotein cholesterol predicted by simulation or achieved in a statin trial. On the other hand, a substantial portion of hyperalphalipoproteinemic population in Japan is accounted for by genetic deficiency of cholesteryl ester transfer protein (CETP), which is also commonly unique in East Asian populations. It is still controversial whether CETP mutations are antiatherogenic. Hepatic Schistosomiasis is proposed as a potential screening factor for historic accumulation of CETP deficiency in East Asia.

Figure 1

HDL-cholesterol (HDL-C) data in the National Health and Nutrition Survey, mean ± SD, for male (squares) and female (circles). The slopes are 0.35 mg/dL/year and 0.5 mg/dL/year for male and female, respectively, with p <0.001 for both [6].

Figure 2

Apolipoprotein A-I (ApoA-I) measured commercially in the SRL laboratory, mean ± SD, for male (squares) and female (circles). The slopes are 0.485 mg/dL/year and 1.064 mg/dL/year for male and female, respectively, with p < 0.001 for both [6].

Figure 3

Age-adjusted risk of myocardial infarction (MI) dependent of plasma lipoprotein-cholesterol for each sex. The risk is expressed as events per 1000 population per year (MI/1K/1Y) in J-LIT trial [25].

Figure 4

Prevention of ischemic heart disease in Japanese by decreasing LDL-cholesterol (LDL-C) and increasing HDL-cholesterol (HDL-C). Simulation for prevention of myocardial infarction (MI) based on the graphs in Figure 3 and demographic data of Japanese, for males and females, according to the data represented in Table 2 and Table 3. Solid lines represent the inverse of NNT (×1000) as an indicator of the treatment efficacy for managing lipoproteins to a target. The value of each horizontal segment is the efficacy when reaching a target LDL or HDL level at the left or right end of the segment, respectively, in all Japanese at ages covered by the JLIT. Each horizontal segment of broken lines represents the number of MI patients when LDL is decreased or HDL is raised to the left end of the segment.

Figure 5

Lipoprotein requirement for embryonation of the S. japonicum eggs after eight days in culture [7,8,9,10]. (A): incubation of the eggs with and without human serum (10%) after pre-exposure of the parents while laying the eggs to 5% and 10% of human serum. Embryonation proceeds when the parents or eggs have access to adequate human serum. Preincubation with 5% serum is applied hereafter; (B): Embryonation is not influenced even when apoB-lipoprotein is removed from human serum (apoB (-)); (C): Embyonation requires the HDL fraction of human serum. LPDS; lipoprotein deficient serum; (D): The effect of mouse serum on the egg embryonation. Embryonation is poor with wild-type mouse serum that lacks CETP and proceeds with CETP-transgenic mouse serum (CETP-tg). Adding human CETP to the wild-type serum partially restored embryonation; (E): Embryonation of the S. japonicum eggs after eight days in culture with CETP-deficient human serum, taken from the reference [8]. Embryonation is estimated in the culture of the eggs in 10% normal human sera (N1 and N2) and that of CETP-deficient subjects (D1 and D2). Embryonation is retarded in CETP-deficient serum (A) and adding CETP recovers this (B). Normal HDL is adequate for the embryonation but not HDL from CETP-deficiency (C). ** p < 0.01 and * p < 0.05 from serum (-) (A), serum (C), WT (D), normal HDL (E).

Figure 5

Lipoprotein requirement for embryonation of the S. japonicum eggs after eight days in culture [7,8,9,10]. (A): incubation of the eggs with and without human serum (10%) after pre-exposure of the parents while laying the eggs to 5% and 10% of human serum. Embryonation proceeds when the parents or eggs have access to adequate human serum. Preincubation with 5% serum is applied hereafter; (B): Embryonation is not influenced even when apoB-lipoprotein is removed from human serum (apoB (-)); (C): Embyonation requires the HDL fraction of human serum. LPDS; lipoprotein deficient serum; (D): The effect of mouse serum on the egg embryonation. Embryonation is poor with wild-type mouse serum that lacks CETP and proceeds with CETP-transgenic mouse serum (CETP-tg). Adding human CETP to the wild-type serum partially restored embryonation; (E): Embryonation of the S. japonicum eggs after eight days in culture with CETP-deficient human serum, taken from the reference [8]. Embryonation is estimated in the culture of the eggs in 10% normal human sera (N1 and N2) and that of CETP-deficient subjects (D1 and D2). Embryonation is retarded in CETP-deficient serum (A) and adding CETP recovers this (B). Normal HDL is adequate for the embryonation but not HDL from CETP-deficiency (C). ** p < 0.01 and * p < 0.05 from serum (-) (A), serum (C), WT (D), normal HDL (E).

Figure 6

Suppression of cholesteryl acylester (CE) uptake (A) and embryonation of the S. japonicum eggs (B) by the antibody raised against the extracellular domain peptide representing the residues 249–408 of CD36RP. Blank AB, nonimmunized rabbit antibody, Control AB, antibody against the intracellular domain of CD36RP (residues 331–348) [9,10].

Figure 7

Egg embryonation and the liver lesion development in the wild-type and CETP-transgenic mice infected with S. japonicum. (A): Number of the eggs embolizing in the liver and ectopic embryonation of the eggs counted microscopically; (B): Granulomatosis lesion in the liver. The eggs and granulomatous lesions were identified microscopically in the liver specimens. The total area of the lesion per egg was calculated for each section. The area per egg was calculated as an average ± SE of the 12 mice, for each of which 12 random liver sections were examined. Asterisks indicate difference at p < 0.05 from the wild type [8,10].

Figure 8

Source of food intake by the age groups of Japanese, according to the National Health and Nutrition Survey [1].