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Placental LPL and glucose metabolism in complicated pregnancies

Doktorsavhandling
Författare AnneLiese Magnusson-Olsson
Datum för examination 2006-06-09
ISBN 91-628-6871-3
Publiceringsår 2006
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi
Språk en
Ämnesord placenta, intrauterine growth restriction, insulin dependent diabetes mellitus, lipoprotein lipase, fatty acids, fatty acid binding proteins, cytotrophoblasts
Ämneskategorier Medicin och Hälsovetenskap

Sammanfattning

BACKGROUND: Pregnancies complicated by intrauterine growth restriction (IUGR) or diabetes are associated with alterations in both lipid and glucose metabolism, which may lead to long lasting metabolic disturbances in the fetus and susceptibility for developing metabolic syndrome in postnatal life. Glucose is the major energy source for both the fetus and placenta. Many fetuses suffering from IUGR are hypoglycaemic in utero and we speculated that the IUGR placenta consumes more glucose leaving less for transport to the fetus. The fetal lipid demand increases as gestation proceeds and lipids are used to build cell membranes and for brain development. An insufficient supply could lead to neurological or vascular complications. The IUGR and diabetic newborn have lower and higher fat depots, respectively. We speculated that the placental capacity for fatty acid transfer is altered in these pregnancy complications. Triglyceride hydrolases in the placental are critical in releasing fatty acids (FFA) from maternal lipoproteins, making FFA available for transport to the fetus. METHODS: We determined activity (spectrophotometric method) and protein expression (Western blot) of the glycolytic enzymes phosphofructo kinase (PFK), pyruvate kinase (PK) and hexokinase (HXK) in homogenates of IUGR and normal placentas. Glucose consumption and lactate production in fresh placental villous tissue using a perifusion system was measured. We also studied activity and expression of lipoprotein lipase (LPL) and placenta specific TG hydrolase in microvillous membrane (MVM) and expression of L-FABP and C-FABP in homogenates in placentas from IUGR and diabetic pregnancies. The TG hydrolase activities were assessed by measuring hydrolysis of 3H-Trioleic acid incorporated into Intralipid® micelles. We also investigated regulation of LPL in placental villous tissue (activity and protein expression) or isolated placental cytotrophoblasts (activity protein, and mRNA expression) in response to hormones, free fatty acids, triglycerides and glucose. We investigated LPL activity, protein and mRNA expression (real time RT PCR) in the placenta from a LPL deficient mother with marked hypertriglyceridemia.RESULTS: The activity of PFK was 32% lower in IUGR placentas (p<0.05). Placental glucose consumption in IUGR was not different from AGA whereas lactate production was decreased by 28 % in IUGR (p<0.05). LPL activity was reduced by 47% in preterm IUGR (p<0.05) whereas the LPL activity in IDDM pregnancies was increased by 39% (p<0.05) as compared to controls. The expression of L-FABP was increased by 112% in IDDM (p<0.05) and by 64% in GDM (p<0.05). The LPL activity was 3-fold higher in term as compared to first trimester placentas (p<0.05). No change was seen after incubation for 1 and 3 h but after 24 h incubation with estradiol, insulin, cortisol and IGF-1 LPL activity decreased (p<0.05). In further studies of LPL regulation, we observed an increase in LPL activity after 3 h incubation with physiological concentrations of estradiol (20 ng/ml) (p<0.05) and hyperglycemic media plus insulin (p<0.05). In the placenta from the LPL deficient mother LPL activity was four-fold lower as compared with normal placentas (p<0.05), the LPL protein expression 50% lower (p<0.05) and mRNA expression threefold higher (p<0.05) than that of normal term placentas. Intralipid (a source of triglycerides) (400 mg/dl) decreased LPL activity by 30% (p<0.05) and 400 µM oleic and linoleic acid decreased LPL activity by 62 and 52 %, respectively (p<0.05). CONCLUSIONS: The hypoglycemia in IUGR fetuses is not due to an increased placental glucose consumption but our data supports an altered glycolytic pathway in the IUGR placenta. The alterations demonstrated in MVM LPL activity and L-FABP expression in IUGR and diabetic placentas may contribute to the altered lipid deposition and metabolism in these pregnancies. We suggest that the gestational increase in placental LPL activity represents an important mechanism to enhance placental FFA transport in late pregnancy and that hormonal and lipid regulation of placental LPL activity by insulin, cortisol, IGF-1, estradiol, FFAs and triglycerides may be involved in gestational changes and in alterations in LPL activity in pregnancies complicated by altered fetal growth.

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