Mechanism for elevation of hepatic cholesterol synthesis and serum cholesterol levels in triton WR-1339-induced hyperlipidemia

1. During the first 3 h after the intravenous injection of Triton (WR-1339) to rats at a dose of 400 mg/kg (first phase), a 2-fold increase in serum cholesterol levels was accompanied by a 17–35% decrease in hepatic cholesterol levels, but the liver plus serum cholesterol levels (mg/100 g body weight) were essentially unchanged. No increases were seen in the activity of either hepatic 3-hydroxy-3-methylglutaryl-CoA reductase or sterol synthesis during this period. 2. At 6–9 h after Triton injection (second phase), a 3–4-fold increase in serum cholesterol was accompanied by a 2–3-fold increase in hepatic sterol synthesis and a 4–5-fold elevation of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity. During this phase, liver cholesterol levels increased to control level, and the liver plus serum cholesterol levels increased by 14–40%. 3. Treatment with ML-236B, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, had no effect on changes in the first phase but reduced both the liver and serum cholesterol levels in the second phase. 4. These results strongly suggest that the increased serum cholesterol levels in the first phase was mainly caused by removing cholesterol from liver into the serum compartment, and that in the second phase the increased sterol synthesis in liver resulted from the elevation of 3-hydroxy-3-methylglutaryl-CoA reductase may explain the rise of serum cholesterol levels.