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Cholesterol-regulating complex of sirt1 and lxr and methods of use

A technology of complexes and uses, applied in the fields of biochemical equipment and methods, drug combinations, compound screening, etc., can solve problems such as little understanding

Inactive Publication Date: 2009-08-05
MASSACHUSETTS INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the underlying mechanisms by which genetic factors recognize the environment to mediate these aging-associated diseases are poorly understood

Method used

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  • Cholesterol-regulating complex of sirt1 and lxr and methods of use
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  • Cholesterol-regulating complex of sirt1 and lxr and methods of use

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preparation example Construction

[0435] The method for preparing the carrier disclosed in the present invention is widely known in the fields of molecular biology, cell biology, oncology, and medical related fields, and other fields related to the present invention. By way of non-limiting example, methods for efficiently preparing vectors are described in Molecular Cloning: A Laboratory Manual (3 rd Edition) (Molecular Cloning: A Laboratory Manual (Third Edition)) (Sambrook, J et al. (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY) and Short protocols in molecular biology (5 th Ed.) (Refined Laboratory Manual of Molecular Biology (Fifth Edition)) (Ausubel FM et al. (2002) John Wiley & Sons, New York City).

[0436] Antibody

[0437] As used herein, the term "antibody" refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, ie, molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. Such antib...

Embodiment 1

[0542] Example 1. Plasma cholesterol in wild-type and SIRT1 knockout mice

[0543] In each group, 10 wild-type and 13 SIRT1 + / - , and 13 littermates SIRT1 - / - Male mice were analyzed. Animals were fasted for 4 hours from the daylight cycle, then blood was collected and treated with K 3 - EDTA treatment to obtain plasma. Plasma total cholesterol, HDL, and LDL levels were measured with enzymatic, colorimetric assay kits (Wako Diagnostics, Richmond, Va.). 100 μl from 4 SIRT1 - / - Born with 4 littermates SIRT1 + / + Pooled plasma from male mice was sizefractionated by using two fast-performance liquid chromatography (FPLC) columns (Superose 6B columns, Amersham-Pharmacia Biotech, Piscataway, NJ). Representative profiles are shown from three independent experiments. Fractions from FPLC were analyzed for cholesterol content with an enzymatic, colorimetric assay kit from Wako. A total of 12 SIRT1 were used in the experiment - / - and 12 SIRT1 + / + Littermate male mice were replic...

Embodiment 2

[0546] Example 2. Cholesterol in tissues of wild type and SIRT1 knockout mice.

[0547] To determine total cholesterol levels in mouse tissues, SIRT1 - / - Mice and control littermates were fasted for four hours from the daylight cycle before sacrifice. Tissues were then harvested and weighed. Total cholesterol from liver and testes was extracted and 70，71 GC measurements. Total lipids including triglycerides were also dissolved in a solution containing 60% butanol, 13% methanol and 27% Triton X-100 and measured with an enzymatic, colorimetric assay kit from Wako.

[0548] in SIRT1 - / - In mice, abnormally low plasma HDL (Example 1) was accompanied by increased cholesterol accumulation in two tissues for which HDL is important as a source of foreign cholesterol: the testis, which serves for sterol storage and steroidogenesis while using HDL cholesterol 25 and it is the organ with the highest relative level of SIRT1 protein 26，27 and the liver, which plays a central role in...

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Abstract

A cholesterol-regulating complex of SIRT1 and LXR and methods of use are disclosed. SIRTl forms a complex with LXR bound to an LXR element. Methods of forming the complex, identifying an agent that modulates formation of the complex, increasing the ratio of cholesterol bound to high density lipoprotein (HDL) to total cholesterol in the plasma of a mammal, promoting ABCA1 -mediated cholesterol efflux from a mammalian cell, treating a subject deemed to have a level of SIRT1 activity that is below normal, assessing whether a candidate substance modulates an LXR-dependent process, and assessing whether a candidate substance modulates an SIRTl -dependent effect of an LXR are disclosed.

Description

Background of the invention [0001] Cholesterol homeostasis is maintained by a balance between dietary intake, de novo synthesis, transport, metabolism and excretion. Low levels of high density lipoprotein (HDL) and high levels of low density lipoprotein (LDL) are associated with hypercholesterolemia, hypertriglyceridemia, and increased cardiovascular disease 1 and Alzheimer's disease 2-6 risk, as well as age-related diseases that mainly cause death in middle-aged and elderly people. Both genetic factors and the environment contribute to the development of cardiovascular disease and Alzheimer's disease, and the risk of these conditions increases with age. However, the underlying mechanisms by which genetic factors recognize the environment to mediate these age-related diseases are poorly understood. [0002] Silent information regulator 2 (Sir2) is an important regulator of lifespan in response to environmental changes. The Sir2 gene is yeast, Caenorhabditis elegans (C.ele...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68G01N33/53
CPCG01N2500/02G01N33/92G01N33/6872G01N2800/044G01N2800/323A61P3/06A61P9/10
Inventor 伦纳德·古亚兰迪蒙迪·克里格尔李小玲
Owner MASSACHUSETTS INST OF TECH
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