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Aspects of cholesterol metabolism in suckling and adult guinea pigs and term and preterm human infants

University of British Columbia

Early nutrition can affect responses to dietary fat and cholesterol in later life. Normal postnatal cholesterol metabolism must be understood before this phenomenon is explained. In many animal species, including humans, plasma LDL-cholesterol levels increase soon after birth. The mechanism for this is unknown although hypotheses include the onset of feeding, hormonal changes at birth and regression of the fetal zone of the adrenal. An increased rate of cholesterol synthesis and/or decreased LDL receptor number may be involved. The objectives of this thesis were to measure 1) developmental changes in indices of the rate of cholesterol synthesis (using plasma lathosterol levels and hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity) and hepatic LDL receptor mass in postnatal guinea pigs 2) plasma lathosterol in humans at birth and 4 days of age and 3) plasma lathosterol in preterm infants during 10% Intralipid-induced hypercholesterolemia soon after birth. HMG CoA reductase is the rate limiting enzyme of cholesterol synthesis, while lathosterol is a sterol intermediate. Levels of plasma lathosterol, measured by gas-liquid chromatography, have been correlated to hepatic and whole body cholesterol synthesis and are therefore possibly an in vivo index of cholesterol synthesis. Hepatic LDL relative receptor mass was measured by ligand blotting using gold-labelled BVLDL as the ligand. Liver cholesterol levels were also determined to test the hypothesis that plasma cholesterol could be from hepatic stores after birth. In infants, apo AI and B were measured as indicators of the presence of HDL and LDL+VLDL, respectively. In the suckling guinea pig, changes in LDL-cholesterol levels coincided with changes in hepatic HMG CoA reductase activity. Hepatic HMG CoA reductase activity was higher at 4 than at 1 and 8 days of age and was higher still in adults. Plasma lathosterol levels peaked at 8 days of age and were decreased in adults. The LDL receptor mass was equal among the 3 suckling ages and was 2-fold higher in adults. The hepatic content of cholesterol did not change between 1 and 8 days of age. In the term infant, plasma lathosterol levels decreased between birth and 4 days of age despite increased plasma cholesterol and apo B. Among preterm infants, plasma lathosterol levels increased with the infusion of lipid. In infants given negligible lipid, hypercholesterolemia and increased plasma lathosterol levels were not found. Apo AI or B levels did not increase with lipid administration. These data from the guinea pig, indicate 1) that "postnatal hypercholesterolemia" may be related to increased cholesterol synthesis, although the quantitative importance of this is unknown, and 2) that hepatic and extrahepatic cholesterol synthesis may change independently after birth. The changes in guinea pig plasma cholesterol levels during suckling do not appear to be related to a change in guinea pig LDL receptor mass. Interestingly, however, an inverse relationship between LDL receptor mass and plasma cholesterol levels appeared to be present in late suckling versus adult ages. Contrary to results of the guinea pig studies, data from human term infants suggest that the postnatal increase in plasma cholesterol is not coincident with increased cholesterol synthesis. Finally, data from preterm infants support the theory that 10% Intralipid infusion results in the transfer of free cholesterol from cellular membranes to plasma, thus enhancing cholesterol synthesis to replace lost cholesterol. The preterm infant infused with 10% Intralipid may be analogous to laboratory animals in whom early perturbation of cholesterol metabolism has long term effects.

Thesis/Dissertation

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2008-12-16

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http://hdl.handle.net/2429/2936

Pathology

University of British Columbia

UBCV

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