Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters

Abstract

Infection and inflammation increase serum triglyceride and cholesterol levels in rodents and rabbits. Endotoxin (LPS) has been used as a model of infection and its effects on triglyceride metabolism have been previously characterized. In the present study we demonstrate that both low (100 ng/100 g body weight) and high dose (100 μg/100 g body weight) LPS increase serum cholesterol levels in hamsters. The increase in serum cholesterol is first observed 16 h after LPS and persists for at least 24 h. This increase is primarily due to an increase in low density lipoprotein (LDL) cholesterol. High density lipoprotein (HDL) cholesterol levels decrease after LPS treatment. Both low and high dose LPS increase hepatic cholesterol synthesis (low dose 85%, high dose 205%) and total HMG-CoA reductase activity (low dose 2.97-fold, high dose 9.96-fold). However, the proportion of HMG-CoA reductase in the active form is reduced by LPS treatment. Additionally, the mass of HMG-CoA reductase protein in the liver, measured by Western blotting, is increased after LPS. Moreover, LPS increases hepatic HMG-CoA reductase mRNA levels (low dose 3.1-fold, high dose 14.2-fold). The increase in hepatic HMG- CoA reductase mRNA levels is first seen 4 h after LPS and persists for at least 24 h. In contrast, LPS had only minimal effects on hepatic LDL receptor protein and mRNA levels. These results suggest that LPS increases serum cholesterol levels by increasing hepatic cholesterol synthesis. LPS administration decreases apoE mRNA levels in the liver while having no effect on apoA-I mRNA levels. These results suggest that HMG-CoA reductase is a member of a group of hepatic proteins that are positively regulated by inflammatory stimuli (acute phase proteins) while apoE can be considered a negative acute phase protein in hamsters. It is possible that increases in hepatic HMG-CoA reductase provide cholesterol that allows for the increased production of lipoproteins and elevations in serum lipid levels that may be beneficial to the body's host defense.