Our aim was to identify and quantify the major in vivo pathways of lipoprotein cholesteryl ester transport in humans. Normal (n ؍ 7), bile fistula (n ؍ 5), and familial hypercholesterolemia (FH; n ؍ 1) subjects were studied. Each received isotopic free cholesterol in HDL, LDL, or particulate form, along with another isotope of free or esterified cholesterol or mevalonic acid. VLDL, intermediate density lipoprotein (IDL), LDL, HDL, blood cells, and bile were collected for up to 6 days for analysis of radioactivity and mass of free and esterified cholesterol. These raw data were subjected to compartmental analysis using the SAAM program. Results in all groups corroborated net transport of free cholesterol to the liver from HDL, shown previously in fistula subjects. New findings revealed that 70% of ester was produced from free cholesterol in HDL and 30% from free cholesterol in LDL, IDL, and VLDL. No evidence was found for tissue-produced ester in plasma. There was net transfer of cholesteryl ester to VLDL and IDL from HDL and considerable exchange between LDL and HDL. Irreversible ester output was from VLDL, IDL, and LDL, but very little was from HDL, suggesting that selective and holoparticle uptakes of HDL ester are minor pathways in humans. It follows that 1) they contribute little to reverse transport, 2) very high HDL would not result from defects thereof, and 3) the clinical benefit of high HDL is likely explained by other mechanisms. Reverse transport in the subjects with bile fistula and FH was facilitated by ester output to the liver from VLDL plus IDL. -Schwartz, C. C., J. M. Approximately 70% of cholesterol molecules in normal human plasma are esterified, mostly to long-chain fatty acids (1, 2). Cholesteryl ester is insoluble in water and is a major component of the hydrophobic core of all plasma lipoprotein particles. Its relevance in human pathophysiology is highlighted by atherosclerosis, the sequel of low HDL or high intermediate density lipoprotein (IDL) and LDL cholesterol.Cholesteryl ester is produced by LCAT from free cholesterol on the surface of plasma HDL and resides in the core of the HDL particle (1, 2). Ester in the core of plasma VLDL is believed to originate by transfer from HDL and from the hepatocyte, where lipids are assembled into VLDL (3). The ester may remain in the core while a VLDL particle is delipidated to IDL and then to LDL (3). In 1978, Pattnaik and colleagues (4) challenged the notion that ester molecules were core-locked within any human lipoprotein. In the presence of certain plasma proteins in vitro, esters readily transfer to VLDL from HDL and LDL and exchange between HDL and other lipoproteins (5). Cholesteryl ester transfer protein (CETP) was identified in 1989 (6). It can remodel the composition, size, and function of lipoproteins by exchanging HDL ester for VLDL triglyceride, for example (5, 7); it can also promote a futile cycle of bidirectional ester exchange (8). Lipid transfer inhibitor protein (LTIP) can modify ester transport between lipoprotei...
These studies demonstrate that IL-13 peptide-conjugated gadolinium metallofullerenes could serve as a platform to deliver imaging and therapeutic agents to tumor cells.
IntroductionOur aim was to identify and quantitate cholesterol pools and transport pathways in blood and liver. By studying bile fistula subjects, using several types of isotopic preparations, simultaneous labeling of separate cholesterol pools and sampling all components of blood and bile at frequent intervals, we developed a comprehensive multicompartmental model for cholesterol within the rapidly miscible pool. Data in six components (bile acids, esterified cholesterol in whole plasma, and free cholesterol in blood cells, bile, a lipoproteins, and ,B lipoproteins) were modeled simultaneously with the SAAM program. The analysis revealed extensive exchange of free cholesterol between HDL and liver, blood cells, and other tissues. There was net free cholesterol transport from HDL to the liver in most subjects. The major organ that removed esterified cholesterol from blood was the liver. A large portion (4,211 gmol) of total hepatic cholesterol comprised a pool that turned over rapidly (t1/2 of 72 min) by exchanging mainly with plasma HDL and was the major source of bile acids and biliary cholesterol. Only 6% of hepatic newly synthesized cholesterol was used directly for bile acid synthesis: the analysis showed that 94% of newly synthesized cholesterol was partitioned into the large hepatic pool (putative plasma membrane free cholesterol) which exchanged rapidly with plasma lipoproteins. Bile acid synthetic rate correlated directly with the size of the large hepatic pool.In conclusion, hepatic and blood cholesterol pools and transports have been quantitated. HDL plays a central role in free cholesterol exchange/transport between all tissues and plasma. In humans, the metabolically active pool comprises a large portion of total hepatic cholesterol that, in part, regulates bile acid synthesis. (J. Clin. Invest. 1993. 91:923-938.)
Herein we continue the study of matrix metalloproteinase-1 (MMP-1) with respect to glioblastoma multiforme (GBM) cell tumorigenicity and angiogenesis. A model of tumorigenicity with cells stably altered to over-express or knock-down MMP-1 revealed that it significantly increases tumor incidence and size. Organized endothelial growth in human umbilical vein endothelial cell (HUVEC)-GBM co-cultures was significantly increased in the presence of MMP-1. CD31 analysis of model tumors elucidated a substantial recruitment of endothelium in MMP-1 enhanced samples. Antibody arrays indicated an inverse expression of certain anti-angiogenic factors with respect to MMP-1, the most notable of which was a significant increase in tissue inhibitor of metalloproteinases-4 (TIMP-4) in the absence of MMP-1, as validated by immunoblot.
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