Elsevier

Biochemical Pharmacology

Volume 56, Issue 1, 1 July 1998, Pages 121-129
Biochemical Pharmacology

Horomones and Growth Factors
Effects of l-Triiodothyronine and the Thyromimetic L-94901 on Serum Lipoprotein Levels and Hepatic Low-Density Lipoprotein Receptor, 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase, and Apo A-I Gene Expression

https://doi.org/10.1016/S0006-2952(98)00119-1Get rights and content

Abstract

The mechanisms by which thyroid hormone (triiodothyronine (T3)) and a thyromimetic, 2-amino-3-(3,5-dibromo-4-[4-hydroxy-3-(6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxyl]-phenyl)-propionic acid (L-94901), lower plasma low density lipoprotein (LDL) cholesterol and raise plasma high density lipoprotein (HDL) cholesterol levels was investigated in thyroidectomized and sham-operated rats. Thyroidectomy resulted in a 77% increase in plasma LDL cholesterol, a 60% decrease in plasma triglycerides, and a modest reduction in HDL cholesterol. Daily oral dosing with T3 (10–170 nmol/kg) or L94901 (100–1000 nmol/kg) for 7 days decreased plasma LDL cholesterol in thyroidectomized rats by 60–80%, respectively. This reduction in LDL cholesterol was accompanied by a dose-dependent increase in HDL cholesterol levels of up to 60%. Thus, the ratio of LDL to HDL was decreased from 1.01 to 0.12 after treatment with L-94901 and to 0.25 after dosing with T3. In sham-operated animals, T3 and L-94901 lowered LDL cholesterol by 61 and 46%, respectively, and increased HDL cholesterol by 25 and 53%, respectively. Immunoblotting analysis of liver membranes prepared from thyroidectomized or sham-operated rats demonstrated that LDL receptor protein levels were increased by up to eight-fold. Northern blotting analysis revealed similar large increases in hepatic LDL receptor mRNA levels that accounted for the increases in LDL receptor protein levels. Hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA, protein, and activity were increased 2- to 3-fold. The T3- and L-94901-mediated increases in serum HDL levels were associated with 2- to 3-fold increases in apo A-I mRNA levels. In contrast with most other hypocholesterolemic agents, T3 and L-94901 significantly increase HDL cholesterol levels in addition to decreasing LDL cholesterol levels due to induction of hepatic apo A-I and LDL receptor gene expression.

Section snippets

Experimental Animals and Design

Surgically thyroparathyroidectomized and sham-operated control male Sprague–Dawley rats weighing between 200 and 250 g, from Charles Rivers, were housed in a reversed-cycle light-controlled room (light from 3:00 p.m. to 3:00 a.m.). These animals carry about 30% of their cholesterol in the form of LDL and 65% in HDL (see Table 1). Upon thyroidectomy, the portion carried in LDL increases to 50%. In many respects, these changes closely parallel the responses to thyroid dysfunction and thyroid

Alterations in Plasma Lipid and Lipoprotein Concentrations in Response to Thyroidectomy

Hypothyroidism induced by surgical thyroidectomy of rats caused marked alterations in circulating lipid and lipoprotein concentrations relative to sham-operated control animals. This is similar to that previously noted in animals rendered hypothyroid either surgically or by treatment with propylthiouracil [16]. As shown in Fig. 1, total plasma cholesterol concentrations were essentially unaffected by thyroidectomy. However, plasma TG concentrations were reduced by 60%. Fractionation of serum

Discussion

The results of this study demonstrate that both the thyroid hormone and the thyromimetic L-94901 induce the hepatic LDL receptor, leading to significant decreases in LDL cholesterol levels. In addition, they also caused substantial increases in HDL levels, likely due to induction of apo A-I. Thus, the ratio of LDL to HDL in thyroidectomized rats was reduced from 1.01 to 0.25 in response to T3 and to 0.12 upon treatment with L-94901. Unlike the bile acid binding resins and the statins, T3 and

Acknowledgements

We thank Donald E. Wilder for conducting the FPLC separation of lipoprotein subclasses, Kelly A. Martin for measurement of plasma T4 concentrations, Robert L. Dow for preparing the thyromimetic L-94901 used in these studies, and Pfizer, Inc. for a grant to G. C. N., supporting these studies.

References (32)

Cited by (87)

  • Effects of endocrine disorders on lipids and lipoproteins

    2023, Best Practice and Research: Clinical Endocrinology and Metabolism
  • Relationship between higher serum selenium level and adverse blood lipid profile

    2018, Clinical Nutrition
    Citation Excerpt :

    Previous studies have investigated the function of selenoprotein in cardiovascular disease by analysis of oxidative stress under conditions of selenium supplementation or deficiency. Animal experiments showed significant increases in the activity of LDL-receptor and the expression of mRNA after selenium supplementation, which may be mediated by the iodothyronine deiodinases (DIOs) [33,34]. DIOs are selenoproteins involved in the activity of thyroxine to triiodothyronine, which increases the expression of LDL-receptor gene [35].

  • Vitamin E Protection Against Hyperthyroidism-Induced Liver Oxidative Stress

    2018, The Liver: Oxidative Stress and Dietary Antioxidants
  • Thyroid hormone induction of human cholesterol 7 alpha-hydroxylase (Cyp7a1) in vitro

    2014, Molecular and Cellular Endocrinology
    Citation Excerpt :

    T3 similarly induces some genes that play important regulatory roles in cholesterol metabolism in both species, such as liver LDL receptor (Bakker et al., 1998). While T3 strongly induces Cyp7a1 expression in rodents (Gullberg et al., 2002; Johansson et al., 2005; Shin et al., 2006; Hashimoto et al., 2006; Kamiya et al., 2003; Ness et al., 1994, 1998; Hylemon et al., 1992), several lines of evidence suggest that the human Cyp7a1 gene could respond differently. First, assessment of cholic acid (CA) levels in humans have indicated that CA secretion rates into the intestine, CA synthesis and pool size are all decreased in hyperthyroid patients and restored by normalization of TH levels (Sauter et al., 1997).

View all citing articles on Scopus
View full text