Effects of Pravastatin Sodium Alone and in Combination with Cholestyramine on Hepatic, Intestinal and Adrenal Low Density Lipoprotein Receptors in Homozygous Watanabe Heritable Hyperlipidemic Rabbits

Abstract

Pravastatin sodium (pravastatin), a tissue-selective inhibitor of 3-hydroxy-3-methylglu taryl coenzyme A reductase, was administered alone (50 mg/kg) or in combination with cholestyramine, a bile acid sequestrant resin, at the level of 2% in the diet to homozygous Watanabe heritable hyper lipidemic (WHHL) rabbits for 4 weeks. The low density lipoprotein (LDL)-cholesterol levels were re duced by 29% and 56% with pravastatin alone and the combination treatment, respectively. Hepatic LDL receptor activity was increased by 11.2 and 13.9-fold with pravastatin alone and the combination treatment, respectively. The LDL receptor activity in the untreated homozygous WHHL rabbits was only 2.5% of that in the normal rabbits. mRNA for the LDL receptor in the liver was also increased by 2.1 and 3.4-fold with pravastatin alone and the combination treatment, respectively. On the other hand, mRNA for the LDL receptor in the adrenal gland was not affected by pravastatin and the com bination treatment, whereas the mRNA in the intestine was increased in both groups. These results suggest the following: 1) the induction of hepatic LDL receptor activity by the treatment of pravastatin alone or in combination with cholestyramine is the main cause of the reduction of serum cholesterol levels by these treatments even in LDL receptor-deficient animals.2) The induction of the mRNA for the LDL receptor in the liver and intestine, but not that in the adrenal gland, might be a reflection of the tissue-selective inhibition of cholesterol synthesis by pravastatin.

The pravastatin-induced decrease of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis in humans

“…53 This may be mediated by a reduced assembly and secretion of very low-density lipoprotein apolipoprotein B100 21,54 as well as an enhanced turnover of hepatic LDL receptors. 20 As a consequence, a diminished hepatic secretion of very low-density lipoprotein cholesterol into and an enhanced uptake of intermediate-density lipoprotein cholesterol and LDL cholesterol from plasma into liver, intestinal or other extrahepatic 55 tissues may occur. Both the hepatic and extrahepatic mechanisms, which are believed to explain the observed reduction of plasma cholesterol levels, appear to be only secondary to the competitive inhibition of HMG-CoA reductase 52,56 and possibly an only short-lived reduction of cholesterol synthesis by HMG-CoA reductase inhibitors.…”

Roles of the WHHL Rabbit in Translational Research on Hypercholesterolemia and Cardiovascular Diseases

“…The hypolipidemic effects of various drugs have been investigated with WHHL rabbits (Table 2): cholesterol synthesis inhibitors, such as HMG-CoA reductase inhibitors and squalene synthetase inhibitors; inhibitors of microsomal triglyceride transfer protein, which works in the assembly of VLDL particles in liver; anionic exchange resins, which block the enterohepatic circulation of bile acids; omega-3 fatty acids, which are a component of fish oil; fibrates, which lower serum triglyceride levels. In studies with a cholesterol synthesis inhibitor, statin, serum total cholesterol levels of WHHL rabbits were decreased dose-dependently by 10–30% compared with the control group [37, 39]. The mechanisms for the reduction in serum cholesterol levels by statins are an increase in expression of mRNA of LDL receptors in the liver [39] and, decrease in the excretion of VLDL cholesterol from the liver in cases of high-dose treatment [38].…”

“…In studies with a cholesterol synthesis inhibitor, statin, serum total cholesterol levels of WHHL rabbits were decreased dose-dependently by 10–30% compared with the control group [37, 39]. The mechanisms for the reduction in serum cholesterol levels by statins are an increase in expression of mRNA of LDL receptors in the liver [39] and, decrease in the excretion of VLDL cholesterol from the liver in cases of high-dose treatment [38]. The agents that inhibit squalene synthetase, another rate-limiting enzyme in cholesterol synthesis, also decreased the serum cholesterol level by similar mechanisms [51].…”

“…Anion exchange resins absorb bile acids at the duodenum and block the enterohepatic circulation [53]. As a result, cholesterol is utilized in the hepatocytes for the synthesis of bile acids, and then the hepatocytes, which was exhausted the cholesterol pool, increase the number of LDL receptor molecules to acquire external cholesterol [39]. Therefore, the combination of an inhibitor for cholesterol synthesis and an anion exchange resin can decrease the serum cholesterol level markedly, and this was proved using WHHL rabbits [40].…”

The Mechanism of Comparable Serum Cholesterol Lowering Effects of Pravastatin Sodium, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Inhibitor, between Once- and Twice-Daily Treatment Regimens in Beagle Dogs and Rabbits

“…The mechanism of lowering serum cholesterol by HMG-CoA reductase inhibitors is now believed to be as follows: hepatic cholesterol depletion by inhibition of cholesterol synthesis may trigger the induction of hepatic LDL receptor, resulting in the stimulation of LDL removal from the blood, and may decrease the secretion of very low density lipoprotein (VLDL) choles terol (5,7). We (8,9) and other investigators (10,11) reported that pravastatin increased hepatic LDL receptor activity in normal or Watanabe heritable hyperlipidemic (WHHL) rabbits. Kovanen et al (12) reported that when mevinolin (lovastatin), an HMG-CoA reductase inhibi tor, was administered to dogs, an increase in the number of hepatic LDL receptors rather than a reduction in cho lesterol synthetic rate in the liver was responsible for the enhanced clearance of LDL from blood.…”