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Cholesterol: Synthesis, Metabolism, Regulation

Biosynthesis of Cholesterol

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High-density lipoprotein - Wikipedia

There are several challenges in drug discovery and development when targeting HDL: 1) the mechanisms of HDL functions, HDL metabolism and HDL compositions/regulators are not completely understood; 2) good animal models have not been identified where both lipoprotein profile and atherosclerotic plaque composition represent the human condition; 3) very long and expensive large scale outcome trials are required because HDL levels are not yet accepted as a surrogate for therapeutic outcome; 4) and no surrogate endpoint has been validated. The total amount of cholesterol uptake by liver may be a better indication since an increased liver cholesterol pool inhibits de novo cholesterol synthesis by down-regulating SREBP-1 and/or enhancing excretion by up-regulating genes involved in bile acid synthesis and secretion (e.g. CYP7α1, BSEP and ABCG5/8).

Slightly less than half of the cholesterol in the body derives from biosynthesis de novo

HDL mimetic peptides with 18-22 amino acids are designed to mimic apoA-I's ability to form class A amphipathic helices without sharing sequence similarity to apoA-I protein. On one hand, their sequence diversity offers a potential opportunity to surpass apoA-I's atheroprotective effects. On the other hand, mimicking all of the atheroprotective properties of apoA-I protein (243 amino acids) that contains 10 amphipathic helices with one peptide containing a single helix could be a challenge. Both mutagenesis studys and human genetic data suggest that different regions of apoA-I are important for different functions. For example, the mutations at the N-terminal (2-7 helices) are associated with familial amyloidosis while the mutations at the C-terminal (4-10 helices) are associated with LCAT activation, despite the fact that these mutations are all associated with low HDL level in plasma. The binding specificity of apoA-I with SR-BI is not affected substantially by the deletion of the first helix (1-59 amino acid) or of the helices 8-10 (185-243 amino acid) of apoA-I, however the double mutations of apoA-I at helix 4 (D102A/D103A), or at helix 6 (R160V/H162A) alter its interaction properties with SR-BI [,]. In this paper, we have assessed whether D-4F, a single amphipathic helix, can represent wild type apoA-I protein to form HDL-like particles and to off-load cholesteryl ester into the liver cells. We prepared the synthetic (apoA-I or peptide) particles containing phospholipids, CE, TG and apoA-I or D-4F. These particles exhibited similar size and shape to native HDL. The off-loading experiments were performed with HepG2 (human) and 1C1C (mouse) hepatoma cell lines (data not shown). Compared to rHDL and the apoA-I particles, D-4F particles are more efficient in delivering its CE core with more than a 14- and 20-fold higher Vmax / Kt, respectively, indicating that D-4F is superior in its ability to deliver CE into HepG2 cells.

Cholesterol HDL LDL Ratio: Graphic Chart, The Good, …

High-density lipoproteins (HDL) are one of the five major groups of lipoproteins

To demonstrate that the synthetic particles deliver their CE core into cells through SR-BI, we used a Doxycycline-regulated inducible SR-BI recombinant cell line. Doxycycline-regulated systems which allow a high degree of control over the expression levels of a protein of interest, provide a tool for studying protein regulation and function in eukaryotic cells []. A Doxycycline-inducible HEK293 cell line expressing SR-BI was generated using Clonetech's Tet-on inducible expression system. The expression of SR-BI was induced by adding Doxycycline into culture medium for 48 h. Western blots shown in Figure A demonstrate that SR-BI expression is induced in a dose-dependent manner. CE-selective uptake was observed when DiO-HDL particles (or Bodipy-CE labeled particles, Figure ) were incubated with HEK293 cells expressing SR-BI. Figure B shows that the amount of fluorescence getting into the cell was dependent on the amount of SR-BI expressed on the surface of the HEK293 cells. This observation indicates that SR-BI is at least one of the transporters that mediated CE uptake.

Cholesterol HDL LDL ratio information and the new findings.

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