A major risk factor for development of atherosclerosis is the concentration of circulating low density lipoprotein (LDL)-cholesterol (C). The concentration of this lipoprotein is determined by at lest four major factors: a) the rate of LDL-C production (Jt), b) the rate of maximal receptor-dependent LDL-C transport (Jm), c) the affinity of the LDL particle for its receptor (Km), and the rate of receptor-independent LDL-C transport (P). Using new quantitative techniques to measure each of these processes, in vivo, these studies will determine how dietary lipids alter these processes and elucidate the underlying physiological differences that account for variability in the response of the plasma LDL-C. One group of studies will investigate the effects of dietary additions on each of these parameters in the hamster and, in particular, will explore the relationships between dietary cholesterol and different triacylglycerols. The specific effect of chain-length in saturated fatty acids and the number of double bonds in unsaturated fatty acids will be examined. After feeding the various experimental diets, absolute rates of cholesterol synthesis and receptor-dependent and receptor-independent LDL transport will be measured in every organ and other regulated metabolic pathways will be undertaken in different animal species intestine. A second group of experiments will be undertaken in different animal species in which the liver contributes a variable proportion of total-body cholesterol synthesis. by making detailed measurements of each transport process, it will be possible to determine the reasons for the variable response of the LDL-C concentration to identical dietary lipid intakes in the different species. Finally, a third group of studies will characterize in detail cholesterol and LDL-C transport in responding and nonresponding Cynomolgus monkeys. If this difference is proven to reside within the intestine, then measurements also will be made of unstirred layer resistance and microvillus hydrophobicity. Overall, these very detailed, quantitative investigations should provide important new insights into how different dietary components alter the specific parameters of LDL-C metabolism and should elucidate what factors are responsible for variability in the response of the plasma LDL-C concentrations to similar dietary intakes between different animal species as well as between different individuals of the same species.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL009610-26
Application #
3334297
Study Section
Metabolism Study Section (MET)
Project Start
1975-06-01
Project End
1995-05-31
Budget Start
1990-06-01
Budget End
1991-05-31
Support Year
26
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Lopez, Adam M; Chuang, Jen-Chieh; Turley, Stephen D (2018) Impact of loss of SOAT2 function on disease progression in the lysosomal acid lipase-deficient mouse. Steroids 130:7-14
Lopez, Adam M; Chuang, Jen-Chieh; Posey, Kenneth S et al. (2017) Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis. Brain Res 1654:77-84
Chuang, Jen-Chieh; Lopez, Adam M; Turley, Stephen D (2017) Quantitation of the rates of hepatic and intestinal cholesterol synthesis in lysosomal acid lipase-deficient mice before and during treatment with ezetimibe. Biochem Pharmacol 135:116-125
Lopez, Adam M; Chuang, Jen-Chieh; Posey, Kenneth S et al. (2017) 'Corrigenda to ""Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis"" [Brain Res. 1654 (2017) 77-84]'. Brain Res 1657:383
Lopez, Adam M; Chuang, Jen-Chieh; Posey, Kenneth S et al. (2015) PRD125, a potent and selective inhibitor of sterol O-acyltransferase 2 markedly reduces hepatic cholesteryl ester accumulation and improves liver function in lysosomal acid lipase-deficient mice. J Pharmacol Exp Ther 355:159-67
Jones, Ryan D; Lopez, Adam M; Tong, Ernest Y et al. (2015) Impact of physiological levels of chenodeoxycholic acid supplementation on intestinal and hepatic bile acid and cholesterol metabolism in Cyp7a1-deficient mice. Steroids 93:87-95
Ramirez, Charina M; Lopez, Adam M; Turley, Stephen D (2015) Lysosomal Acid Lipase Activity: A Tool for the Detection and Management of Fatty Liver Disease? EBioMedicine 2:638-9
Lopez, Adam M; Terpack, Sandi J; Posey, Kenneth S et al. (2014) Systemic administration of 2-hydroxypropyl-?-cyclodextrin to symptomatic Npc1-deficient mice slows cholesterol sequestration in the major organs and improves liver function. Clin Exp Pharmacol Physiol 41:780-7
Chuang, Jen-Chieh; Lopez, Adam M; Posey, Kenneth S et al. (2014) Ezetimibe markedly attenuates hepatic cholesterol accumulation and improves liver function in the lysosomal acid lipase-deficient mouse, a model for cholesteryl ester storage disease. Biochem Biophys Res Commun 443:1073-7
Aqul, Amal; Lopez, Adam M; Posey, Kenneth S et al. (2014) Hepatic entrapment of esterified cholesterol drives continual expansion of whole body sterol pool in lysosomal acid lipase-deficient mice. Am J Physiol Gastrointest Liver Physiol 307:G836-47

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