Apolipoprotein E competitively inhibits receptor-dependent low density lipoprotein uptake by the liver but has no effect on cholesterol absorption or synthesis in the mouse.

Abstract

This study examines the question of whether apolipoprotein E (apoE) alters steady-state concentrations of plasma cholesterol carried in low density lipoproteins (LDL-C) by acting as a competitive inhibitor of hepatic LDL uptake or by altering the rate of net cholesterol delivery from the intestinal lumen to the liver. To differentiate between these two possibilities, rates of cholesterol absorption and synthesis and the kinetics of hepatic LDL-C transport were measured in vivo in mice with either normal (apoE+/+) or zero (apoE-/1) levels ofcirculating apoE. Rates ofcholesterol absorption were essentially identical in both genotypes and equaled -44% of the daily dietary load of cholesterol. This finding was consistent with the further observation that the rates of cholesterol synthesis in the liver ("2000 nmol/h) and extrahepatic tissues ("3000 nmol/h) were also essentially identical in the two groups of mice. However, the apparent Michaelis constant for receptor-dependent hepatic LDL-C uptake was markedly lower in the apoE-/-mice (44 + 4 mg/dl) than in the apoE+/+ animals (329 ± 77 mg/dl) even though the maximal transport velocity for this uptake process was essentially the same ("400 uig/h per g) in the two groups of mice. These studies, therefore, demonstrate that apoE-containing lipoproteins can act as potent competitive inhibitors of hepatic LDL-C transport and so can significantly increase steadystate plasma LDL-C levels. This apolipoprotein plays no role, however, in the regulation of cholesterol absorption, sterol biosynthesis, or hepatic LDL receptor number, at least in the mouse.

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE −/− Mice

“…Intestinal cholesterol uptake and cholesterol absorption into plasma and liver was determined in wild-type, Npc1l1 Ϫ/Ϫ , apoE Ϫ/Ϫ , and Npc1l1/apoE Ϫ/Ϫ female mice after oral admin-istration of 14 C-cholesterol ( Figure 1). While cholesterol absorption into the plasma and liver of apoE Ϫ/Ϫ mice was equivalent to wild-type mice, Npc1l1/apoE Ϫ/Ϫ and Npc1l1 Ϫ/Ϫ mice absorbed 77% and 83% less cholesterol, respectively, than wild-type mice ( Figure 1A, PϽ0.001).…”

“…LDL-cholesterol concentrations in Npc1l1/ apoE Ϫ/Ϫ mice were also lowered in both diet regimens relative to apoE Ϫ/Ϫ mice, with a 50% reduction in LDLcholesterol in both chow-fed male and female mice Ϫ/Ϫ , apoE Ϫ/Ϫ , and Npc1l1/apoE Ϫ/Ϫ mice. Mice were orally gavaged with 14 C-cholesterol and examined after 2 hours for absorption (A) and proximal intestinal uptake (B) of cholesterol. Cholesterol synthesis in liver (C) and small intestine (D) was evaluated one hour after 14 C-sodium acetate administration.…”

“…For cholesterol absorption, the mice were gavaged with 14 C-cholesterol, 1 Ci with 0.1 mg of unlabeled cholesterol in 0.1 mL corn oil. Two hours later, plasma, livers, and small intestines were analyzed by liquid scintillation counting as previously described.…”

Inhibition of Cholesterol Synthesis Causes Both Hypercholesterolemia and Hypocholesterolemia in Hamsters.

“…32) In the present study, FR194738 decreased both serum HDL cholesterol and non HDL cholesterol levels. Hepatic cholesterol uptake by LDL receptors no doubt underlies the changes because LDL receptors recognize apoE as well as apoB, 33,34) and that, LDL and HDL in hamsters contain apoB and apoE, respectively. 35) Although the larger dose of FR194738 (100 mg/kg) did not significantly increase hepatic cholesterol content, we speculate that the inhibitory activity of the dose on cholesterol synthesis might have overcome the enhancement of cholesterol uptake.…”

LDL composition in E2/2 subjects and LDL distribution by Apo E genotype in type 1 diabetes

“…The cause of the low LDL is controversial and several hypotheses have been put forth. One of the popular hypotheses is that the hepatic LDL receptor is up regulated due to (1) decreased delivery of cholesterol to the liver as a result of defective binding of apo E2-containing lipoproteins [1,6] and/or (2) a reduced competition between the apo E2-containing lipoproteins and apo B-100 containing LDL for the LDL receptor [1,7]. Both mechanisms would lead to more rapid uptake of LDL and thus maintenance of a low LDL level in the presence of normal conversion of VLDL to LDL in plasma.…”