Decreased Expression of Hepatic Low-Density Lipoprotein Receptor–Related Protein 1 in Hypothyroidism: A Novel Mechanism of Atherogenic Dyslipidemia in Hypothyroidism

Background: The atherogenic effects of hypothyroidism on lipid metabolism could result, in part, from the reduced clearance of remnant lipoproteins. In this study, we investigated the expression of hepatic low-density lipoprotein receptor–related protein 1 (LRP1), a receptor for remnant lipoproteins, in hypothyroidism and the effect of 3,3′,5-triiodo-L-thyronine (T3) treatment on hepatic LRP1 expression. Methods: C57BL/6 mice were fed a normal diet (control group) or a low-iodine diet supplemented with 0.15% propylthiouracil (PTU/LI group) for 4 weeks. Mice in the PTU/LI group were injected intraperitoneally with T3 (0, 30, and 150 μg/kg of body weight) for 7 days. HepG2 cells were incubated in fetal bovine serum or charcoal-stripped fetal bovine serum with various concentrations of T3. The expression and function of LRP1 in liver samples and cells were analyzed. Results: Hypothyroidism was successfully induced in PTU/LI mice. Hepatic LRP1 protein expression was lower in the PTU/LI group than in the control group. T3 treatment upregulated hepatic LRP1 protein expression in PTU/LI mice. LRP1 expression in HepG2 cells was reduced after incubation in the medium containing charcoal-stripped fetal bovine serum, which mimics hypothyroidism in vitro, and was recovered by T3 treatment. The protein expression of LRP1 in HepG2 cells was increased by T3 treatment in a dose-dependent manner up to 2.0 nM T3. However, LRP1 mRNA transcription was not affected by hypothyroidism conditions or T3 treatment, either in liver samples or in HepG2 cells. T3 treatment on HepG2 cells increased cellular uptake of lipid-conjugated apolipoprotein E through LRP1. Conclusions: Our data demonstrate that hepatic LRP1 expression and function decrease in hypothyroidism and are regulated by the thyroid hormone. These results suggest that in hypothyroidism, decreased expression of hepatic LRP1 may be associated with reduced clearance of circulating remnant lipoproteins.ope