Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors

Two new trans-(3R, 4R)-amino-β-lactam derivatives and their diastereoisomeric mixtures were synthesized as ezetimibe bioisosteres and tested in in vitro and in vivo experiments as novel β-lactam cholesterol absorption inhibitors. Both compounds exhibited low cytotoxicity in MDCKII, hNPC1L1/MDCKII, and HepG2 cell lines and potent inhibitory effect in hNPC1L1/MDCKII cells. In addition, these compounds markedly reduced cholesterol absorption in mice, resulting in reduced cholesterol concentrations in plasma, liver, and intestine. We determined the crystal structure of one amino-β-lactam derivative to establish unambiguously both the absolute and relative configuration at the new stereogenic centre C17, which was assigned to be S. The pKa values for both compounds are 9.35, implying that the amino-β-lactam derivatives and their diastereoisomeric mixtures are in form of ammonium salt in blood and the intestine. The IC50 value for the diastereoisomeric mixture is 60 μM. In vivo, it efficiently inhibited cholesterol absorption comparable to ezetimibe

Adiponectin Reduces Plasma Triglyceride by Increasing VLDL Triglyceride Catabolism

OBJECTIVE—Adiponectin is an adipocyte-derived hormone that plays an important role in glucose and lipid metabolism. The main aims of this study are to investigate the effects of adiponectin on VLDL triglyceride (VLDL-TG) metabolism and the underlying mechanism

The role of triacylglycerol in cardiac energy provision

Triacylglycerols (TAGs) constitute the main energy storage resource in mammals, by virtue of their high energy density. This in turn is a function of their highly reduced state and hydrophobicity. Limited water solubility, however, imposes specific requirements for delivery and uptake mechanisms on TAG-utilising tissues, including the heart, as well as intracellular disposition. TAGs constitute potentially the major energy supply for working myocardium, both through blood-borne provision and as intracellular TAG within lipid droplets, but also provide the heart with fatty acids (FAs) which the myocardium cannot itself synthesise but are required for glycerolipid derivatives with (non-energetic) functions, including membrane phospholipids and lipid signalling molecules. Furthermore they serve to buffer potentially toxic amphipathic fatty acid derivatives. Intracellular handling and disposition of TAGs and their FA and glycerolipid derivatives similarly requires dedicated mechanisms in view of their hydrophobic character. Dysregulation of utilisation can result in inadequate energy provision, accumulation of TAG and/or esterified species, and these may be responsible for significant cardiac dysfunction in a variety of disease states. This review will focus on the role of TAG in myocardial energy provision, by providing FAs from exogenous and endogenous TAG sources for mitochondrial oxidation and ATP production, and how this can change in disease and impact on cardiac function

Fatty acids liberated from high-density lipoprotein phospholipids by endothelial-derived lipase are incorporated into lipids in HepG2 cells.

We previously reported that endothelial-derived lipase (EDL) efficiently hydrolyses high-density-lipoprotein-derived phosphatidycholine (HDL-PC). In the present study, we assessed the ability of EDL to supply HepG2 cells with non-esterified fatty acids (NEFA) liberated from HDL-phospholipids. For this purpose, HepG2 cells infected with adenovirus encoding human EDL (EDL-Ad), or with control beta-galactosidase-expressing adenovirus (LacZ-Ad), were incubated with (14)C-HDL-PC. The analysis of the cellular lipids by TLC revealed that EDL overexpression led to an increase in the amount of cellular (14)C-lipids, whereby the label was mainly incorporated into phospholipids and triacylglycerols (TAG). Cells expressing mutant enzymically inactive EDL (MUT-EDL-Ad) contained similar amounts of (14)C-TAG but higher amounts of (14)C-phosphatidylcholine (PC) compared with LacZ-Ad-infected cells. The co-expression of CD36 augmented the EDL-mediated accumulation of (14)C-lipids in HEK-293 cells. The quadrupole MS analysis of the cellular lipids revealed an increased content of PC and TAG in EDL-expressing HepG2 cells compared with MUT-EDL-Ad-expressing and control cells. However, the MUT-EDL-Ad-expressing cells contained more PC than control cells. Additionally, EDL overexpression led to a 2-fold decrease in the amount of fatty acid synthase mRNA and, in turn, a slightly, but significantly, decreased rate of fatty acid (FA) synthesis in HepG2 cells. In the present study, we show for the first time that EDL efficiently supplies HepG2 cells with NEFA derived from HDL-PL, thus affecting cellular lipid composition and FA synthesis