REDUCED HEPATIC LDL-RECEPTOR, 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE AND STEROL CARRIER PROTEIN-2 EXPRESSION IS ASSOCIATED WITH PREGNANCY LOSS IN THE DIABETIC RAT

Hepatic low density lipoprotein receptor (LDLR), 3-hydroxy-3-methylglu taryl coenyzme A reductase (HMGR), cholesterol 7 alpha-hydroxylase, an d sterol carrier protein-2 are important proteins associated with the uptake, synthesis, degradation and transport of cellular cholesterol. Since cholesterol is critically important for steroid hormone synthesi s and is an essential component in membrane biosynthesis, this study i nvestigated whether these proteins are altered in the normal pregnant and streptozotocin (STZ)-induced diabetic pregnant rat. The goal of th ese experiments was to determine whether diabetic reproductive dysfunc tion is associated with a significant change in maternal cholesterol h omeostasis. Diabetic animals were grouped based on their ability or in ability to maintain pregnancy up to day 15 post-conception. LDLR and H MGR mRNA levels were significantly reduced in animals which did not ma intain pregnancy whereas diabetic animals with fetuses had normal LDLR and HMGR mRNA levels. Hepatic LDLR, HMGR, and SCP2 protein levels wer e examined in normal pregnant and diabetic pregnant animals by Western blot analysis. SCP2 levels were reduced in all diabetic animals, part icularly in the diabetic animals which lost their fetuses. The decline in SCP2 was associated with an increase in sterol carrier protein-X ( SCPx), a protein related to SCP2. SCPx has been shown to have thiolyti c activity and is thought to have a role in beta-oxidation of fatty ac ids. HMGR was also significantly reduced in diabetic animals which los t their fetuses. Cholesterol 7 alpha-hydroxylase mRNA was slightly, bu t not significantly, reduced in all diabetic animals. Serum very low d ensity lipoprotein (VLDL) +LDL cholesterol increased significantly in the STZ-treated diabetic rats while the HDL cholesterol levels decline d in these animals. Reduced hepatic LDLR and HMGR mRNA levels were con sistently associated with reduced serum progesterone and an inability to maintain pregnancy. The results of this study suggest that the main tenance of maternal cholesterol metabolism is a critical factor direct ly associated with successful pregnancy outcome in the diabetic rat.