Gene-environment interactions in wet beriberi: effects of thiamine depletion in CD36-defect rats.

Selective vulnerability to thiamine deficiency is known to occur between individuals and within different tissues. However, no comprehensive explanation for this has been found, and there are no reports that reproduce the cardiovascular manifestations of human wet beriberi in animals. We hypothesized that the distinction of substrate reliance, namely, the primary dependency on glucose as substrate, could be an underlying factor in the selective vulnerability of thiamine deficiency. In the setting of impaired fatty acid entry, which occurs in CD36-defect rats, substrate reliance shifts from fatty acid to glucose, which would be expected to lead to a susceptibility to thiamine deficiency. Genomic DNA was analyzed for CD36 defects in three cognate strains of rats [spontaneously hypertensive rats (SHR)/NCrj, SHR/Izm, and Wistar-Kyoto (WKY)/NCrj], which identified the presence of a CD36 defect in SHR/NCrj rats but not in SHR/Izm and WKY/NCrj rats. Treatment with 2 wk of thiamine-depleted chow on 4-wk-old rats of each of these strains resulted in increased body and lung weight in the SHR/NCrj rats but not in the SHR/Izm and WKY/NCrj rats. The increased lung weight in the SHR/NCrj rats was accompanied with histological changes of congestive vasculopathy, which were not observed in either the SHR/Izm or the WKY/NCrj rats. Thiamine-deficient 12-wk-old SHR/NCrj rats demonstrated increased body weight (305.6 +/- 6.2 g in thiamine-deficient rats vs. 280.8 +/- 9.1 g in control; P < 0.0001), lactic acidemia (pH, 7.322 +/- 0.026 in thiamine-deficient rats vs. 7.443 +/- 0.016 in control; P < 0.0001; lactate, 2.42 +/- 0.28 mM in thiamine-deficient rats vs. 1.20 +/- 0.11 mM in control; P < 0.0001) and reduced systemic vascular resistance (4.61 +/- 0.42 x 104 dyn.s.cm-5 in thiamine-deficient rats vs. 6.55 +/- 1.36 x 104 dyn.s.cm-5 in control; P < 0.0001) with high cardiac output (186.0 +/- 24.7 ml in thiamine-deficient rats vs. 135.4 +/- 27.2 ml in control; P < 0.0019). In conclusion, SHR/NCrj rats harboring a genetic defect of long-chain fatty acid uptake present the relevant clinical cardiovascular signs of human wet beriberi, strongly indicating a close gene-environment interaction in wet beriberi.

CD36 genotype and long-chain fatty acid uptake in the heart.

Homozygous or compound heterozygous mutation of the CD36 gene (CD36-/-) in humans results in severe defects of the uptake of long-chain fatty acids (LCFAs) in the heart. Because the effect of a single mutation of this gene (CD36+/-) on the LCFA uptake is not known, it was evaluated in 29 subjects with the CD36 wild-type gene (WT) (6 healthy subjects, 10 patients with heart disease), CD36+/- (4 healthy subjects, 5 patients) and CD36-/- (4 patients). The CD36 genotype was identified in the coding region of genomic DNA, and the expression of CD36 protein was examined by flow cytometry after staining with monoclonal anti-CD36 antibody. The LCFA uptake in the heart was assessed as the radioactivity accumulation ratio of heart to mediastinum after intravenous administration of iodine-123 15-(p-iodophenyl)-3-R, S-methylpentadecanoic acid (H/M ratio). The H/M ratios in WT, CD36+/- and CD36-/- were 2.28 +/- 0.10, 1.90 +/- 0.06 and 1.40 +/- 0.11, respectively (p < 0.0001, among groups). The H/M ratio between healthy subjects and patients with heart disease for WT and CD36+/- did not differ significantly (ie, those of WT and CD36+/- in healthy subjects and patients were 2.29 +/- 0.08 vs 2.27 +/- 0.12 and 1.90+/- 0.07 vs 1.89 +/- 0.05, respectively). Not only CD36-/- but also CD36+/- resulted in a significant reduction of the LCFA uptake in the heart independent of heart disease, suggesting genotype dependency and that CD36 might be a fundamental determinant of myocardial LCFA uptake.

Genomic heterogeneity of type II CD36 deficiency.

BACKGROUND: CD36 deficiency has been classified in two types, i.e., type I and type II CD36 deficiency. Possible pathological involvement of CD36 deficiency has been suggested in humans, but is still confounding. Homozygous or compound heterozygous mutations (CD36(-/-)) were demonstrated in type I CD36 deficiency, while the genomic or molecular background of type II CD36 deficiency is still unclear, which may bring confounding interpretations of the cause-and-effect events in human CD36 deficiency. In this study, we analyzed the genotype and frequency of type II CD36 deficiency in Japanese populations, and its hereditary pattern in three families. METHODS: Genotypes and protein expression levels of CD36 were examined in 238 Japanese subjects. Genotype was analyzed in the coding region of the CD36 gene. The expression level of CD36 protein was analyzed by flow cytometry after staining with monoclonal anti-CD36 antibody and assessed as mean fluorescence intensity (MFI). RESULTS: Among 238 subjects, subjects for wild-type gene (WT), a single mutation (CD36(+/-)), and CD36(-/-) were 141, 44 and 53, respectively. Monocyte MFI (mean+/-SD) in subjects for WT, CD36(+/-), and CD36(-/-) were 35.7+/-8.5, 15.2+/-3.4, and 0.4+/-0.3, respectively (P<0.0001, between groups). Those of platelets in subjects for WT, CD36(+/-), and CD36(-/-) were 27.1+/-10.6, 11.5+/-6.3, and 0.5+/-0.3, respectively (P<0.0001, between groups). Subjects of both WT and CD36(+/-) were observed in type II CD36 deficiency. Monocyte and platelet MFI in family members of type II CD36 deficiency and 218 unrelated Japanese suggested that the expression level of CD36 protein in monocytes was directly dependent on genotypes. On the other hand, those in platelets were affected by additional heritable factor(s) in addition to the coding region genotype. CONCLUSIONS: MFI in monocytes showed a strong gene-dosage-dependency. On the other hand, MFI in platelets was affected by heritable factor(s) in addition to the coding region genotype, which resulted in heterogeneity of type II CD36 deficiency.