Although L-triiodothyronine (L-T3) lowers cholesterol, this hormone is not used to treat hypercholesterolemia because of its cardiotoxic effects. Thyromimetics, such as the novel compound CGS 23425, that mimic the beneficial but lack the detrimental effects of T3, may be useful in the treatment of hypercholesterolemia. To show that CGS 23425 has no cardiotoxicity, atrial contractility and force were both measured and found to be unchanged in rats treated with up to 10 mg/kg drug. The lipid lowering actions of this drug resulted in a 44% decrease in low-density lipoprotein (LDL) cholesterol in hypercholesterolemic rats treated with 10 microg/kg of the compound. Normal rats required a higher dose of 1000 microg/kg to elicit a similar 50% reduction in LDL cholesterol. Both CGS 23425 or T3 (10 nM) increased the specific binding of 125I-labeled LDL to Hep G2 cells and increased LDL receptor number by 44 and 49%, respectively. These data indicate that CGS 23425 enhances hepatic clearance of serum LDL cholesterol. Normal and fat-fed animals treated with the drug showed a dose-dependent increase in apolipoprotein AI, a protein that promotes the efflux of cholesterol from peripheral tissues. Transient transfection of a rat apolipoprotein AI promoter-chloramphenicol acetyltransferase construct, in human hepatoma cells, showed a dose-dependent increase in chloramphenicol acetyltransferase activity with EC50 values of 2 x 10(-12) M and 10(-10) M for thyroid hormone receptors beta1 and alpha1, respectively, with maximal responses at 10(-7) M. These data indicate that CGS 23425 is a thyromimetic that increases apolipoprotein AI expression via thyroid hormone receptor. In summary, CGS 23425 ameliorates hypercholesterolemia by increasing apolipoprotein A1 and the clearance of LDL cholesterol. Therefore, a compound like CGS 23425 may be useful for the prevention and reversal of atherosclerosis.

Hyperglycemia of diabetes is caused in part by perturbation of hepatic glucose metabolism. Hepatic glucokinase (GK) is an important regulator of glucose storage and disposal in the liver. GK levels are lowered in patients with maturity-onset diabetes of the young and in some diabetic animal models. Here, we explored the adenoviral vector-mediated overexpression of GK in a diet-induced murine model of type 2 diabetes as a treatment for diabetes. Diabetic mice were treated by intravenous administration with an E1/E2a/E3-deleted adenoviral vector encoding human hepatic GK (Av3hGK). Two weeks posttreatment, the Av3hGK-treated diabetic mice displayed normalized fasting blood glucose levels (95 ؎ 4.8 mg/dl; P < 0.001) when compared with Av3Null (135 ؎ 5.9 mg/dl), an analogous vector lacking a transgene, and vehicle-treated diabetic mice (134 ؎ 8 mg/dl). GK treatment also resulted in lowered insulin levels (632 ؎ 399 pg/ml; P < 0.01) compared with the control groups (Av3Null, 1,803 ؎ 291 pg/ml; vehicle, 1,861 ؎ 392 pg/ml), and the glucose tolerance of the Av3hGK-treated diabetic mice was normalized. No significant increase in plasma or hepatic triglycerides, or plasma free fatty acids was observed in the Av3hGK-treated mice. These data suggest that overexpression of GK may have a therapeutic potential for the treatment of type 2 diabetes.

To explore the relationship between whole-body taurine status and function, the taurine concentration in plasma and platelets was measured and evaluated in terms of ex vivo collagen-induced platelet aggregation in taurine-depleted cats and taurine-supplemented humans. Taurine status exerted a significant effect on platelet aggregability. Platelets from taurine-depleted cats were twice as sensitive to aggregation as platelets from cats receiving taurine. On the other hand, platelets from humans with normal taurine status increased resistance to aggregation by 30-70% when supplemented with taurine at 400 or 1600 mg/d, respectively. Decreased platelet aggregability was associated with increased platelet taurine and glutathione concentrations and decreased thromboxane release on aggregation. These data indicate that taurine in vivo stabilizes platelets against aggregation such that during taurine depletion platelets become overly sensitive whereas during supplementation their tendency to aggregate is depressed.

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In order to determine the effect of taurine depletion in primates, two species were selected which differed in their taurine conjugtion of bile acids. Consequently, eight cebus (taurine conjugators) and nine cynomolgus monkeys (glycine conjugators) were raised from birth with soybean infant milk formula lacking taurine. Half the monkeys received a 500 ppm taurine supplement. After 5 months the taurine concentration of plasma, urine and several tissues was greatly reduced in the unsupplemented monkeys. The least depletion occurred in retinal tissue of both species and in bile acids of cebus, whereas cynomolgus monkeys increased the glycine conjugation of their bile acids 125%. Taurine depletion was associated with a significant growth depression (16.8%) in the unsupplemented monkeys, but retinal degeneration was not observed. Neither species demonstrated an appreciable capacity to synthesize taurine as measured by cysteinesulfinic acid decarboxylase activity in liver and brain. The data suggest that dietary taurine is essential for maximum growth, as measured by weight gain, of infant nonhuman primates fed a soy protein milk formula.