The effects of hypothyroidism,age, and nutrition on LDL catabolism in the rat

To determine the effects of thyroid deficiency on LDL metabolism and degradation, the plasma clearance of ¹²⁵I-LDL was determined in normal rats and rats fed chow containing propylthiouracil (PTU) 0.1% w/w and KI $\text{0.16 gm}\text{1}$ in the drinking water. After two weeks, T₄ levels were significantly lower in the PTU groups compared to controls and plasma LDL cholesterol increased from $\text{17.5 ± 1.2}{}^1\text{1}\text{Results given as mean ± SEM.}\text{mg}\text{100 ml}$ in controls to $\text{32.5 ± 3.0 mg}\text{100 ml}$ in the hypothyroid animals. Human ¹²⁵I-LDL (d 1.019–1.045) was injected intravenously under light anesthesia and tail tip blood was sampled repeatedly over 33–100 hr periods. In a semi-log plot the curve of ¹²⁵I-LDL clearance described a log-linear profile suggesting a two-pool model. Compartmental analysis according to Matthews revealed two exponential curves, an initial rapid phase representing equilibration with an extravascular compartment (exponential 2), and a later slow phase of irreversible degradation (exponential 1). There was a marked delay in clearance of ¹²⁵I-LDL in the hypothyroid rats as the slope of exponential 1 was 0.043 ± 0.001 ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 16.2 hr}$) versus 0.065 ± 0.002 ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 10.7 hr}$) in controls (P < 0.01). Additionally, the fractional catabolic rate of LDL was reduced (P < 0.01) from 0.079 ± 0.003 in normals to 0.054 ± 0.002 (pools/hr) in hypothyroid rats. The delay in LDL clearance which occurred in hypothyroidism occurred in both growing and mature rats. Pair-feeding excluded any artifact due to the weight loss commonly seen in hypothyroid rats. LDL clearance was age-dependent as the slope of exponential 1 was significantly lower in mature (521 ± 3 gms) as compared to growing (256 ± 12 gm) rats. Experiments performed after a 24 hr fast showed that acute starvation did not affect LDL clearance. The data suggest that the hypercholesterolemia of hypothyroidism is at least partly secondary to an acquired catabolic defect of LDL, and implies that the LDL catabolic pathway(s) is influenced by thyroid hormones.