Intestinal Lipoprotein Research Articles

Current Concepts of Cholesterol Metabolism and Their Relationship to Lecithin: Cholesterol Acyltransferase

Fig. 1 represents the general consensus on some of the most important aspects of cholesterol metabolism in man. According to the published literature, there is a single pool of free cholesterol in the liver; most of the dietary, biliary, and intestinal cholesterol absorbed from intestines and removed by the liver enters this pool. Cholesterol synthesized by the liver also enters the same pool. Biliary cholesterol and recently synthesized bile acids come from this pool, and the free cholesterol for synthesis of new lipoproteins is also derived from the same pool. In addition. this pool of free cholesterol undergoes isotopic exchange with plasma free cholesterol. The published literaturc does not indicate the presence of any mechanism for transport of net amounts of plasma cholesterol into the liver. This concept (of a single hepatic pool of free cholesterol) suggests that in conditions associated with increased turnover of plasma lipoproteins increased requirements of free cholesterol for synthesis of new lipoproteins can, after a short lag, be met by increased amounts of cholesterol returning to this pool from catabolism of lipoproteins. Over the last few years we investigated the absorption (l), synthesis (2), catabolism (3), and mobilization (4) of tissue cholesterol in hyperlipemic subjects with and without hypertriglyceridemia. There were no differences in the absorption of dietary cholesterol between them, but studies on cholesterol synthesis and turnover indicated that cholesterol synthesis was significantly greater in hypertriglyceridemic subjects than in those who had normal plasma triglycerides. Similarly, fecal metabolites of endogenous cholesterol were also significantly greater in hypertriglyceridemic than in normotriglyceridemic subjects. Since elevation of plasma triglycerides above normal is primarily due to an increase in plasma very low density lipoproteins (VLDL), and since modest to moderate elevations of VLDL are associated with significant increase in their turnover rates (5), it was suggested by us that cholesterol synthesis as well as its catabolism are related to the turnover of plasma lipoproteins (6). The fact that the continued increases in synthesis and catabolism were observed in conditions associated with hypertriglyceridemia suggested to us that at least some of the cholesterol catabolized in the liver was not available for synthesis of new lipoproteins. On the basis of such reasoning, we proposed that the cholesterol synthesized in the liver and the cholesterol in chylomicra and other intestinal lipoproteins removed by the liver enter into a single pool which supplies the free cholesterol for synthesis of new plasma lipoproteins (Fig. 2). On the other hand, cholesterol derived from catabolism of plasma lipoproteins is transported back into a second pool from which biliary cholesterol and bile acids are derived. Although there may be some transfer of cholesterol from one pool to another, functionally the two pools are viewed as

Ethanol-Induced Fatty Liver: Effect of Intestinal Lymph Fistula

Previous studies have shown that intraduodenal ethanol enhanced the production of nondietary very low density lipoprotein by rat intestine. In this study, this source of endogenous lipid was examined in regard to its possible contributing role in the pathogenesis of ethanol-induced fatty liver. Rats received constant intraduodenal infusions of ethanol (5 g per kg) or isocaloric glucose during the 0 - to 8-hr interval. After intraduodenal ethanol, rats without lymph fistula developed the expected fatty liver at 24 hr. In marked contrast, fistula rats had virtually normal liver triglycerides at this time. The effect of lymph diversion was not due to lipid losses prior to ethanol, nor to minor lymphatic losses of ethanol during the experiment. A similar effect was present at 16 hr in some rats, but not in others. The basis for the variable response at this earlier time was not elucidated, but correlated with plasma free fatty acid concentration. Nondietary intestinal lipoproteins do not seem quantitatively sufficient, by themselves, to account for the ethanol-induced fatty liver. However, they play a significant role in the over-all lipid balance of the rat, and may contribute, with other endogenous sources, to hepatic lipid accumulation in this disorder.

Differences in the Intestinal Absorption of Saturated and Unsaturated Long Chain Fatty Acids

Although considerable progress has been made in the study of long chain fatty acid absorption, and of the contrasts between them and the medium chain fatty acids, relatively little emphasis has been placed on differences in intestinal absorption among the long chain fatty acids themselves. Recent studies, showing that the triglyceride-rich lipoproteins in intestinal lymph during long chain fat absorption were different with saturated and unsaturated fatty acids, suggested the possibility of corresponding and possibly causative differences in their intestinal absorption. After intraduodenal infusion into rats as mixed micelles or emulsions containing 14C-fatty acid, monoolein, and taurocholate, it was found that the saturated palmitic acid consistently required a greater length of intestine for its absorption than did the unsaturated linoleic acid. Moreover, in short term experiments it was noted that even when uptake of the two fatty acids by mucosa was similar, palmitate esterification was significantly less rapid. In vitro studies, utilizing everted sacs incubated in mixed micelles, confirmed that although uptake of palmitate equalled or exceeded that of linoleate, palmitate esterification was significantly less rapid, and in contrast to linoleate esterification was further reduced by high palmitate and low taurocholate concentrations. The initial uptake of both fatty acids conformed to saturation kinetics, with similar Vmax and slightly differing Km's. It is concluded that although intraluminal solubility of palmitate is less than that of linoleate, initial uptake of the two lipids by intestinal mucosa is similar. However, significant differences in rates of entry into the cell and/or rate of microsomal metabolism result, for the saturated fatty acid, in a significantly less rapid reesterification and, therefore, overall absorption. These findings may account for the previously observed differences in intestinal lipoprotein formation and for the greater absorption of unsaturated fatty acids reported in patients with steatorrhea.

Presence of An Intact Cholesterol Feedback Mechanism in the Liver in Biliary Stasis

Acute obstruction of the common bile duct results in a severalfold increase in the rate of cholesterol synthesis by the liver. This study was undertaken to distinguish whether this increase is the result of loss of sensitivity of the liver cell to feedback inhibition or of interruption of the enterolymphatic circulation of cholesterol. Feeding rats with biliary obstruction a diet containing cholesterol and bile acid caused a 40 to 60% suppression of hepatic cholesterogenesis; intravenous infusion of 36 mg per 24 hr of cholesterol in intestinal lipoproteins resulted in a 10fold inhibition. This inhibition was specific for cholesterogenesis in the liver, was the consequence of suppression of β-hydroxy-β-methylglutaryl-coenzyme A reductase in the biosynthetic sequence, and was associated with an increase in the cholesterol concentration of the liver. These studies clearly demonstrate that the feedback regulatory mechanism for the control of cholesterol synthesis is intact in the liver in the presence of cholestasis and, therefore, the enhanced synthetic rate seen after biliary obstruction must be the consequence of interruption of the enterolymphatic circulation of cholesterol.