Cardiovascular & Lipid Disorders

Laura Woollett

Laura A. Woollett, PhD

Pathology & Lab Med-North

Professor

Research Summary

During the fetal and neonatal periods, the requirement for sterol is greater than that of the adult due to the rapid growth rate. Our laboratory is interested in understanding the role of exogenous and endogenous cholesterol during different stages of growth. Our projects include the fetus (1), the neonate (2), and the adult (3).

1) A lack of cholesterol in utero will lead to abnormal growth and development. There are 7 known defects in enzymes of the sterol biosynthetic pathway and all lead to neurological disorders. The disorders can be severe or mild depending on the enzyme affected and the type of mutation. Cholesterol plays a key role in development at several different levels. First, it is an integral part of membranes and thus is necessary for tissue growth. Second, it is a precursor for hormone synthesis and bile acid synthesis. Third, cholesterol is necessary to activate and propagate the signal for Sonic hedgehog, a protein involved in special patterning of limbs and the forebrain.

Thus, our goal for these studies is to determine the sources of sterol for the developing fetal tissues. It has been known for many years that the synthesis rates of cholesterol in the fetus, the placenta and the yolk sac were very high when compared to adult tissues. The supporting fetal tissues also take up a significant amount of cholesterol from the maternal circulation in the form of LDL and HDL. We are presently trying to elucidate the mechanisms by which cholesterol is removed from the maternal circulation by these fetal tissues and determine if and how the transport can be regulated.

2) Neonates require lipids, such as cholesterol, essential fatty acids and fat soluble vitamins, for optimal growth. Bile acids aid in absorption of lipids from the intestine. Interestingly, even the neonate, and especially the small preterm infant requires lipids for growth, these animals have a smaller bile acid pool size than do adults.

Our goal for these studies is to understand the regulation of bile acid synthesis, and consequently the absorption of lipids, in the neonate and determine if there are any dietary manipulations that can enhance the process when needed, such as the short bowel syndrome.

3) Sterol balance in the adult is important in defining how an individual will respond to dietary factors, and possibly their risk for development of coronary artery disease. We are presently measuring flux rates of sterol and triglyceride under different metabolic conditions, such as pregnancy, and dietary manipulations, such as dietary bile acids.

Recent Publications

Burke KT, Horn PS, Tso P, Heubi JE, Woollett LA. Hepatic bile acid metabolism in the neonatal hamster: expansion of the bile acid pool parallels increasedCyp7a1 expression levels. Am J Physiol Gastrointest Liver Physiol. 2009Jul;297(1):G144-51. Epub 2009 Apr 23. PubMed PMID: 19389801; PubMed CentralPMCID: PMC2711759.

Burke KT, Colvin PL, Myatt L, Graf GA, Schroeder F, Woollett LA. Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterolconcentrations in the Golden Syrian hamster. J Lipid Res. 2009 Jun;50(6):1146-55.Epub 2009 Jan 3. PubMed PMID: 19122238; PubMed Central PMCID: PMC2681396.

Jones KS, Alimov AP, Rilo HL, Jandacek RJ, Woollett LA, Penberthy WT. A highthroughput live transparent animal bioassay to identify non-toxic small moleculesor genes that regulate vertebrate fat metabolism for obesity drug development.Nutr Metab (Lond). 2008 Aug 27;5:23. PubMed PMID: 18752667; PubMed Central PMCID:PMC2531115.

Woollett LA. Where does fetal and embryonic cholesterol originate and whatdoes it do? Annu Rev Nutr. 2008;28:97-114. Review. PubMed PMID: 18662139.

Yao L, Jenkins K, Horn PS, Lichtenberg MH, Woollett LA. Inability to fullysuppress sterol synthesis rates with exogenous sterol in embryonic andextraembyronic fetal tissues. Biochim Biophys Acta. 2007 Nov;1771(11):1372-9.Epub 2007 Sep 26. PubMed PMID: 17950663; PubMed Central PMCID: PMC2711845.

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