1. Investigación

Human very-low-density lipoproteins (VLDL) were subfractionated by heparin-Sepharose chromatography into an unbound (:\I and three bound (B, C and D) populations at increasing ionic strengths. Subfractions were characterized regarding their chemic;,[ composition and efficiency of triacylglycerol hydrolysis by rat adipose tissue LPL. The triacylglycerol content decreased, whcrca, the cholesterol and protein contents increased from subfractions A and B to subfraction D. VLDL-D showed the highest ap<' E/apo C ratio, though all the subfractions contained appreciable apo E. Appearance of VLDL-A resulted from exceeding the binding capacity of the column, since practically all its particles eluted at positions of bound VLDL under re-chromatograph~ Subfractions B, C and D stimulated LPL activity on emulsified tri[ 14C]oleoylglycerol to a similar extent, indicating that their 3P'' C-11 content was equally effective activating LPL. Incubation of tri[ 14C]oleoylglycerol labeled VLDL subfractions with fat pad pieces in the presence or absence of heparin resulted in greater hydrolysis and fatty acid uptake for VLDL-B and -C than f.•1 VLDL-D, a pattern observed over a wide range of LPL activities in the media. We conclude: (1) any VLDL particle can intcr;t,1 with heparin, which is consistent with the presence of apo E in all the subfractions, and (2) triacylglycerols in apo E-rich VLDI are less efficiently hydrolyzed by LPL than those in apo E-poor particles. We propose that richness in apo E impairs LPL acu"r upon VLDL and decreases the rate of delivery of fatty acids to peripheral tissues.

The mechanism that induces maternal hypertriglyceridemia in late normal pregnancy, and its physiologic significance are reviewed as a model of the effects of sex steroids on lipoprotein metabolism. In the pregnant rat, maternal carcass fat content progressively increases up to day 19 of gestation, then declines at day 21. The decline may be explained by the augmented lipolytic activity in adipose tissue that is seen in late pregnancy in the rat. This change causes maternal circulating free fatty acids and glycerol levels to rise. Although the liver is the main receptor organ for these metabolites, liver triglyceride content is reduced. Circulating triglycerides and very-low-density lipoprotein (VLDL)-triglyceride levels are highly augmented in the pregnant rat, indicating that liver-synthesized triglycerides are rapidly released into the circulation. Similar increments in circulating VLDL-triglycerides are seen in pregnant women during the third trimester of gestation. This increase is coincident with a decrease in plasma postheparin lipoprotein lipase activity, indicating a reduced removal of circulating triglycerides by maternal tissues or a redistribution in their use among the different tissues. During late gestation in the rat, tissue lipoprotein lipase activity varies in different directions; it decreases in adipose tissue, the liver, and to a smaller extent the heart, but increases in placental and mammary gland tissue. These changes play an important role in the fate of circulating triglycerides, which are diverted from uptake by adipose tissue to uptake by the mammary gland for milk synthesis, and probably by the placenta for hydrolysis and transfer of released nonesterified fatty acids to the fetus. After 24 hours of starvation, lipoprotein lipase activity in the liver greatly increases in the rat in late pregnancy; this change is not seen in virgin animals. This alteration is similar to that seen in liver triglyceride content and plasma ketone body concentration in the fasted pregnant rat. In the fasting condition during late gestation, heightened lipoprotein lipase activity is the proposed mechanism through which the liver becomes an acceptor of circulating triglycerides, allowing their use as ketogenic substrates, so that both maternal and fetal tissues may indirectly benefit from maternal hypertriglyceridemia. Changes in the magnitude and direction of lipoprotein lipase activity in different tissues during gestation actively contribute both to the development of hypertriglyceridemia and to the metabolic fate of circulating triglycerides. Any deviation in these metabolic adaptations occurring in the human mother may have consequences that modify her lipoprotein profile, even postpartum. Hormone-induced changes in pregnancy mirror those seen with oral contraceptive steroids and provide a teleologic rationale for the lipoprotein changes induced by sex steroids.

To understand the mechanism responsible for maternal hyperlipidemia, 25 healthy pregnant women were studied longitudinally during the three trimesters of gestation and at post-partum, and 11 were studied again at post-lactation. Triglyceride and cholesterol levels increased with gestation in all the lipoprotein fractions. However, the greatest change appeared in low density (LDL) and high density (HDL) lipoproteins, both of which showed an increase in their triglyceride/ cholesterol ratio. The proportional distribution of HDL subfractions showed that the HDL2b fraction was the only one that increased with gestation, whereas both HDL.sa and HDLsb had the greatest decrease. Cholesteryl ester transfer protein activity increased during the second trimester of gestation. While postheparin lipoprotein lipase activity decreased during the third trimester, postheparin hepatic lipase activity progressively decreased from the first trimester. The 17J3-estradiol, progesterone, and prolactin hormones progressively increased from the first trimester of gestation. The lipoprotein-triglyceride values correlated linearly and negatively with the logarithm of either postheparin lipase activities, HDlrtriglycerides showing the highest correlation coefficient when plotted against the hepatic lipase values (r = -0.757). It appeared that the highest correlation between any of the HDL subclasses and the activity of the enzymes was for hepatic lipase activity versus HDL2b (r = -0.456) or HDLsa (r = 0.519). A significant lineal correlation also appeared between the postheparin hepatic lipase activity and the logarithm of any of the sex hormones studied, the highest value corresponding to estradiol (r = -0.783). Ill Therefore, during gestation, the effect of estrogen in enhancing very low density lipoprotein (VLDL) production and decreasing hepatic lipase activity plays a key role in the accumulation of triglycerides in lipoproteins of density higher than VLDL.