Stimulation of Hepatic β-Hydroxy-β-methylglutaryl Coenzyme A Reductase Activity in Hypophysectomized Rats by L-Triiodothyronine

Abstract

Diurnally varying activity of hepatic jB-hydroxy-fl-methylglutaryl coenzyme A reductase (EC 1.1.1.34) was decreased to very low levels in hypophysectomized rats with no discernable diurnal rhythm retained. Administration of triiodothyronine (100 jg/100 g of body weight) produced a supranormal level of reductase activity, about 3-4 times the highest activity found in normal rats. 0-Hydroxy-#-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.1.34) catalyzes the reduction of HMG-CoA to mevalonate, which is the first committed step in the pathway of cholesterol biosynthesis. This reaction has been established as rate-limiting in the over-all conversion of acetate to cholesterol (1, 2). Indeed, changes in HMG-CoA reductase activity accurately reflect changes in the rate of cholesterol synthesis (3, 4). Interestingly, the activity of the reductase undergoes daily changes of as much as 10-fold (5-8). The normal diurnal rise in reductase activity has been shown to be due to an increase in the rate of enzyme synthesis (9). Recently, we have shown (10) that the activity of HMGCoA reductase was stimulated markedly by insulin treatment. We have further demonstrated that reductase activity was reduced to low levels in diabetic rats with only a negligible diurnal rhythm present seven days after the onset of diabetes (11). Administration of insulin restored the activity to nearly normal levels within 2 hr. Other hormones that have been implicated in stimulating cholesterol biosynthesis are thyroid hormones (12, 13) and norepinephrine (14). Guder et al. (13) have shown that hepatic HMG-CoA reductase activity was decreased to less than 50% of normal in hypothyroid rats (produced by 13l1 treatment). A single injection of triiodothyronine (T3) to these hypothyroid rats restored the activity to that of normal animals within 48 hr. In hypophysectomized rats, hepatic cholesterogenesis was reduced to even lower levels (15) than in hypothyroid rats.In this communication we demonstrate that hepatic HMGCoA reductase activity is markedly lowered in hypophysectomized rats with no detectable diurnal rhythm present. Administration of T3 to these animals increases reductase activity to a supranormal level (3-4 times the highest level found in normal rats). MATERIALS AND METHODS Materials. iTriiodothyronine (T3) and [3-14C]0-hydroxy-,-methylglutaric acid were purchased from Sigma Chemical and New England Nuclear Corp., respectively. Other chemicals were of reagent grade.[s-'4C ]b-Hydroxy-g-methylglutaric acid was converted to the anhydride by the dicyclohexylcarbodiimide method of Goldfarb and Pitot (16). The coenzyme A ester was prepared from the anhydride as described by Hilz et al. (17) and then purified by descending paper chromatography on Whatman 3 MM with isobutyric acid-concentrated ammonia-0.1 M EDTA (pH 4.5)-H20 (124:5:2:75) as the solvent system. Treatment of Animals. Young adult male albino rats weighing 140-160 g were purchased from Holtzman. Animals were hypophysectomized by Altech Laboratories of Madison, Wisc. The h...

Specificity of the effect of dietary cholesterol on rat liver microsomal 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity (Short Communication)

“…Secondly, injected thyroid hormone is known to cause the proliferation of liver endoplasmic reticulum and the induction of many microsomal enzymes (Tata, 1968). This is therefore an effect not specific for 3-hydroxy-3-methylglutaryl-CoA reductase and, on the evidence presented here, is unlikely to work in the way suggested by Ness et al (1973).…”

“…For example, thyroid hormone, when injected into experimentally hypothyroid animals, causes a marked increase in the activity of liver 3-hydroxy-3-methylglutaryl-CoA reductase (Guder et al, 1968;Ness et al, 1973). This hormone has been suggested to act by lowering the blood cholesterol, and consequently the amount of cholesterol in the liver, thus relieving the inhibition due to cholesterol (Ness et al, 1973), but available evidence does not support this view.…”

“…For example, thyroid hormone, when injected into experimentally hypothyroid animals, causes a marked increase in the activity of liver 3-hydroxy-3-methylglutaryl-CoA reductase (Guder et al, 1968;Ness et al, 1973). This hormone has been suggested to act by lowering the blood cholesterol, and consequently the amount of cholesterol in the liver, thus relieving the inhibition due to cholesterol (Ness et al, 1973), but available evidence does not support this view. First, although the amount of cholesterol does rise in the livers and circulation of rats fed on cholesterol-rich diets (Shapiro & Rodwell, 1971;Harry et al, 1973;Edwards & Gould, 1974), there is no evidence that this rise must occur if the activity of liver 3-hydroxy-3-methylglutaryl-CoA reductase is to be lowered.…”

Activation of Cardiac TNF-α in Altered Thyroid State-Induced Cardiometabolic Disorder

“…Thyroid hormone stimulates hepatic de novo cholesterol synthesis by inducing the 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase that catalyzes the conversion of HMG-CoA to mevalonate. 38 This causes a rise in intracellular cholesterol concentration in hyperthyroidism and a decline in hypothyroidism. Thyroid hormone also stimulates CETP and LPL.…”

“…27 However, high HDL-cholesterol enhanced endothelial function by augmenting nitric oxide biosynthesis and bioavailability, and suppressing formation of free radicals, thereby preventing the deleterious effect of LDL-cholesterol in vasculature. [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] There are accumulating data to support the role of plasma proteins, especially albumin, as hem rheological factors that play essential role in the development of cardio metabolic disorders. 27 They have been shown to modulate blood and plasma viscosity.…”