Rates of low density lipoprotein uptake and cholesterol synthesis are regulated independently in the liver.

D K Spady,S D Turley,J M Dietschy

doi:10.1016/s0022-2275(20)34361-3

Abstract

The relationship between rates of hepatic sterol synthesis and rates of hepatic low density lipoprotein (LDL) uptake (clearance) was studied in animals with high (rats), low (female hamsters), and very low (male hamsters) basal rates of hepatic sterol synthesis. In rats and female hamsters, rates of hepatic sterol synthesis were varied over a 110-fold range by feeding cholesterol or cholestyramine; nevertheless, rates of hepatic LDL clearance remained essentially unchanged as did plasma LDL-cholesterol concentrations. In contrast, in male hamsters, which have a very limited capacity to synthesize cholesterol in the liver, cholestyramine feeding increased rates of hepatic LDL uptake by 2.5-fold and this was associated with a 50% reduction in plasma LDL-cholesterol concentrations. The observed increase in LDL uptake was due to an increase in receptor-dependent LDL transport while receptor-independent lipoprotein uptake remained constant. These studies suggest that rates of hepatic cholesterol synthesis and receptor-dependent LDL uptake are regulated independently. Furthermore, the primary response of the liver to changes in cholesterol availability is regulation of sterol synthesis and only when the capacity of this compensatory mechanism is exceeded is the rate of LDL transport altered.

Highlights

The relationship between rates of hepatic sterol synthesis and rates of hepatic low density lipoprotein (LDL) uptake was studied in animals with high, low, and very low basal rates of hepatic sterol synthesis
The results indicate that in the liver, as in the intestine [22], LDL uptake and cholesterol synthesis are regulated independently
In order to examine the putative relationship between the rates of cholesterol synthesis and LDL uptake in the liver in vivo, these studies took advantage of the fact that the capacity of the liver to synthesize sterols varies markedly among different species [17]

Summary

Introduction

The relationship between rates of hepatic sterol synthesis and rates of hepatic low density lipoprotein (LDL) uptake (clearance ) was studied in animals with high (rats), low (female hamsters), and very low (male hamsters) basal rates of hepatic sterol synthesis. In studies in which isolated fibroblasts or hepatocytes were exposed to high concentrations of cholesterol or lipoprotein-cholesterol, there was apparently simultaneous suppression of both the rate of cholesterol synthesis and the rate of LDL uptake [19, 20] Whether regulation of these two processes is linked in the liver and other differentiated tissues under in vivo conditions is currently unknown, there are a variety of observations. In order to assess the regulation of these two important processes, the current studies were undertaken to measure directly the rate of hepatic LDL uptake under circumstances where the rate of hepatic cholesterol synthesis was varied over a very large range These studies were carried out in three different types of experimental animals that are known to vary markedly in their inherent capacities to synthesize sterol in the liver [17, 21]. The results indicate that in the liver, as in the intestine [22], LDL uptake and cholesterol synthesis are regulated independently

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