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Regulation of hepatic lipo protein receptors in the dog rapid regulation of apo lipo protein b e receptors but not apo lipo protein e receptors by intestinal lipo proteins and bile acids

Journal of Clinical Investigation 71(4): 816-831

Regulation of hepatic lipo protein receptors in the dog rapid regulation of apo lipo protein b e receptors but not apo lipo protein e receptors by intestinal lipo proteins and bile acids

Two distinct lipoprotein receptors can be expressed in the dog liver. One is the apolipoprotein (apo-) B,E receptor. This receptor binds apo-B-containing low density lipoproteins (LDL), as well as apo-E-containing lipoproteins, such as the cholesterol-induced high density lipoproteins (HDLc). The 2nd hepatic lipoprotein receptor is the apo-E receptor. It binds apo-E HDLc and chylomicron remnants, but not LDL. Short-term (acute) regulation of the 2 receptors was studied to determine whether it can occur in response to perturbations in hepatic cholesterol metabolism. The design used 3 groups of experimental animals: immature dogs (with both hepatic apo-B,E and apo-E receptors expressed); adult dogs (with predominantly the apo-E receptor expressed and little detectable apo-B,E receptor binding activity); and dogs treated with the bile acid sequestrant cholestyramine or those that have undergone biliary diversion (with apo-E receptors and induced apo-B,E receptors). In the 1st series of experiments, changes in hepatic lipoprotein receptor expression were studied by delivering cholesterol to the liver via intestinal lymph lipoproteins. Dog lymph (5-11 mg of triglycerides/min per kg of body wt, 0.15-0.3 mg of cholesterol/min per kg) or saline were infused i.v. for 6-8 h into matched pairs of dogs. Serial liver biopsies were obtained at intervals of 1-2 h. A progressive loss of specific (Ca-dependent) binding of LDL was seen in hepatic membranes from both immature and cholestyramine-treated dogs. After 4-6 h of lymph infusion, almost no apo-B,E receptor binding could be detected. The decrease in binding of apo-E HDLc to the same membranes was much less pronounced, and could be explained by a loss of binding of HDLc to the apo-B,E receptor; there was little or no effect on apo-E receptor binding. In the 2nd series of experiments, the effects of a diminished hepatic demand for cholesterol on lipoprotein receptor expression were studied by suppressing bile acid synthesis. The bile acid taurocholate (2-3 .mu.mol/kg per min) was infused i.v. over a 6-h interval. This resulted in a progressive loss of LDL binding to liver membranes of immature or cholestryamine-treated dogs. The infusion of taurocholate for 6 h did not significantly alter the expression of the apo-E receptor binding activity, whereas apo-B,E receptor activity was rapidly down-regulated. Preparation of a bile fistula in adult dogs markedly induced the expression of the apo-B,E receptor. In this state, the binding activity of the apo-B,E receptor could be almost totally abolished by reinfusion of taurocholate for 6 h, without profoundly affecting apo-E receptor binding. Evidence from the analysis of plasma lipoprotein patterns and tissue culture reactivity suggested that changes in assayed hepatic lipoprotein receptor activity occurred in concert with changes in plasma lipoproteins. The 2 canine hepatic lipoprotein receptors differ in their metabolic regulation. The apo-B,E receptor responds rapidly to changes in hepatic requirements for cholesterol. The apo-E receptor appears to be more refractory to acute regulation. The rapidity of the changes in the activity of the apo-B,E receptor (within 2-4 h) suggests that the binding activity of this receptor may be regulated by factors independent of protein synthesis.

Accession: 006288412

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