The Metabolism of Chylomicron Cholesterol Ester in the Rat

Abstract

The lymphatic transport of cholesterol is of great quantitative importance in the over-all metabolism of cholesterol. It is now well established that exogenous cholesterol is absorbed almost exclusively by way of the intestinal lymph (1, 2), where most of the newly absorbed cholesterol is found esterified, in the chylomicron fraction (3,4). Estimates of the extent of esterification have varied from 90 per cent at the peak of cholesterol absorption (3) to an average of 72 + 6 per cent over a wide range of absorption (4). In addition, a considerable amount of endogenous cholesterol from the bile and the intestinal mucosa is absorbed and transported in an identical fashion.Surprisingly little detailed information exists, however, on the metabolic history of newly absorbed cholesterol after the cyhlomicra have entered the vascular compartment. Most of this cholesterol is first taken up by the liver (5, 6), where there is a delay of several hours before subsequent mixing with the cholesterol of blood and other tissues (5). During the first 1 to 2 hours after the intravenous injection into rats of chyle containing absorbed H3-cholesterol, the specific radioactivity of the esterified cholesterol in liver was several times higher than that of the free cholesterol (6). In contrast, a number of studies have revealed much of the details of the metabolism after absorption of the major component of chyle, the triglyceride fatty acids (7-11).One of the reasons for the relative lack of information about the metabolism of chylomicron. cholesterol is the uncertainty arising from the exchangeability of the free cholesterol in chyle and in blood. Both in vivo (12) and in vitro (13) studies have shown that free cholesterol in chylomicra, plasma, and red blood cells is readily exchangeable, so that labeled cholesterol in one of these locations can partially equilibrate with the others in only a few minutes. This property tends to reduce the validity of metabolic interpretations based on the distribution of labeled cholesterol.In the present study, an attempt was made to remove most of the readily exchangeable free C14-cholesterol in chylomicra by preliminary in vitro equilibrations with blood. The resulting chylomicra, containing almost 90 per cent of the label as esterified cholesterol, were then injected into intact rats, and the tissue distribution and free: ester ratio of C14-cholesterol observed for 24 hours. METHODSOne hundred microcuries of 4-C14-cholesterol (17 mg per mc, Nuclear-Chicago) dissolved in 0.6 ml olive oil were given by gastric intubation to a rat whose cysterna chyli had been cannulated the previous day. During the subsequent 24 hours, 60 ml of milky chyle containing a total of 54 /Ac of C'4 was collected. This chyle was used in all experiments herein reported.Equilibrations in vitro were performed in Erlenmeyer flasks, with gentle shaking in a metabolic incubator at 370 C. Chylomicra were separated from other components and simultaneously washed by being placed under isotonic saline in a plastic centrifuge tube...

Different patterns of postprandial lipoprotein metabolism in normal, type IIa, type III, and type IV hyperlipoproteinemic individuals. Effects of treatment with cholestyramine and gemfibrozil.

“…These correlations suggest that the hepatic enzyme plays a role in the process of chylomicron remnant removal from plasma. It has been established that chylomicron remnants avidly interact with specific receptors on hepatocytes, and that this interaction is followed by rapid uptake and degradation ofthe particles (3,32,34,36). Our data suggest that before their catabolism via the receptormediated pathway that the chylomicron remnant particles interact with HTGL.…”

“…Initially, the particles interact with lipoprotein lipase in extrahepatic tissues resulting in triglyceride hydrolysis and delivery offree fatty acids to the tissues (1, 2, 31). After most triglycerides are hydrolyzed, remnant particles are formed (3,32) that are removed from the circulation by hepatocyte receptors that recognize apo E (33)(34)(35)(36)(37). The exact stage when chylomicrons become remnants is not known, and there are no methods currently available to physically separate the two.…”

Remnants of lipoproteins of intestinal and hepatic origin in familial dysbetalipoproteinemia.

“…35 " 37 Nestel et al 38 showed in dogs that functional hepatectomy caused a retention in the serum of cholesteryl esters, but not of triglycerides, after the injection of chylomicrons. This observation was confirmed in rats by Redgrave. 39 Mjas et al 40 isolated remnant particles of intestinal origin after an injection of chylomicrons in functionally hepatectomized rats.…”

Tissue-specific knockouts of ACAT2 reveal that intestinal depletion is sufficient to prevent diet-induced cholesterol accumulation in the liver and blood

“…From lymph duct cannulation studies in our laboratory, chylomicrons from ACAT2 Ϫ / Ϫ mice have more TG mass compared with wildtype mice ( 8 ). However, due to rapid and effi cient clearance of chylomicron remnants from the circulation by liver ( 22,23 ), this would not appear to be a major mechanism of TG increase in the plasma. It is possible that, as a result of chylomicrons delivering less CE to the liver in ACAT2 SI Ϫ /SI Ϫ mice, a CE-poor lipid droplet may result in the liver, leading to a similar effect on TG mobilization as was observed in mice with the loss of hepatic ACAT2 ( 6,7 ).…”