Abstract: The present invention relates to animal models that expresses SR-BI?CT knockin. The present invention further includes animal models that express SR-BI?CT and also have reduced expression or activity of ApoE and/or LDLR, wherein the latter can be accomplished by use of a compound or genetic manipulation of the gene. The present invention relates to mouse models crossed with SR-BI?CT knockin mice. Specifically, the present invention relates to SR-BI?CT knockin mice crossed with apolipoprotein E (ApoE) knockout mice (SR-BI?CT/apoE KO), a hypoE mouse (also referred to as ApoeR61h/h which expresses an impaired ApoE protein (SR-BI?CT/ApoeR61h/h)), or a LDLR knockout mouse (SR-BI?CT/LDLR KO). Screening methods and compounds using these mouse models are also encompassed.

Abstract: This application describes compounds and methods that can inhibit Scavenger receptor class B, type I (SR-BI) activity, which compounds and methods can used, for example, to mediate high-density lipoprotein (HDL) lipid uptake and treat hepatitis C viral infections.

Abstract: This application describes compounds and methods that can inhibit Scavenger receptor class B, type I (SR-BI) activity, which compounds and methods can be used, for example, to mediate high-density lipoprotein (HDL) lipid uptake and treat hepatitis C viral infections. The compounds have the formula: wherein R1 and R2 are independently H, halogen, cyano, haloalkyl, haloalkyloxy or OMe; or R1 and R2 together are —O—CH2— or —O—CF2—O—; R3 is H, halogen, cyano, haloalkyl or haloalkyloxy; R4 is C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylmethyl or C3-6cycloheteroalkyl, wherein the heteroatom is N or O; R5 is H or CH3; R6 is C1-6alkyl or C3-6cycloalkyl; and A, B, D and E are each, independently, CH, N, O or S, wherein at least one of A, B, D and E is N, and another of A, B, D and E is N, O or S.

Abstract: The invention provides methods for treating tissue damage associated with impaired blood flow using ApoD, or an active variant thereof, or an agent that increases the expression of ApoD. The invention also encompasses active variants of ApoD for use in the methods.

Abstract: The invention provides methods for treating tissue damage associated with impaired blood flow using ApoD, or an active variant thereof, or an agent that increases the expression of ApoD. The invention also encompasses active variants of ApoD for use in the methods.

Abstract: This application describes compounds and methods that can inhibit Scavenger receptor class B, type I (SR-BI) activity, which compounds and methods can used, for example, to mediate high-density lipoprotein (HDL) lipid uptake and treat hepatitis C viral infections.

Abstract: The invention provides methods for treating tissue damage associated with impaired blood flow using ApoD, or an active variant thereof, or an agent that increases the expression of ApoD. The invention also encompasses active variants of ApoD for use in the methods.

Abstract: This application describes compounds and methods that can inhibit Scavenger receptor class B, type I (SR-BI) activity, which compounds and methods can be used, for example, to mediate high-density lipoprotein (HDL) lipid uptake and treat hepatitis C viral infections. The compounds have the formula: wherein R1 and R2 are independently H, halogen, cyano, haloalkyl, haloalkyloxy or OMe; or R1 and R2 together are —O—CH2— or -0- CF2—O—; R3 is H, halogen, cyano, haloalkyl or haloalkyloxy; R4 is C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylmethyl or C3-6cycloheteroalkyl, wherein the heteroatom is N or 0; R5 is H or CH3; R6 is C1-6alkyl or C3-6cycloalkyl; and A, B, D and E are each, independently, CH, N, 0 or S, wherein at least one of A, B, D and E is N, and another of A, B, D and E is N, 0 or S.

Abstract: A cholesterol-regulating complex of SIRT1 and LXR and methods of use are disclosed. SIRT1 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 SIRT1-dependent effect of an LXR are disclosed.

Abstract: An animal model of coronary heart disease has been developed where myocardial infarct can be induced by altering the animal's diet. In all embodiments, this animal model is a result of reduced activity of scavenger receptor class BI (SR-BI) and apolipoprotein E (ApoE). In a preferred embodiment, the model is a result of crossbreeding two transgenic mouse lines: a knockout of SR-BI (SR-BI?/?) and an impaired ApoE expressor (hypoE). The impaired ApoE gene results in only 2-5% expression of ApoE and a reduction in cholesterol homeostasis. Resulting animals are predisposed to hypercholesterolemia but can live longer than a year on a normal low fat diet. Serum plasma levels can be significantly elevated by changing the animal's diet to one containing high levels of fat and cholesterol. Within a month on a high fat, high cholesterol diet, animals develop atherosclerosis and myocardial infarction occurs.

Abstract: Transgenic animals that do not express functional SR-BI and ApoE develop severe atherosclerosis, by age four weeks in transgenic mice. Moreover, these animals exhibit progressive heart dysfunction by as early as age four weeks, and die by age nine weeks. This animal model has now been demonstrated to be useful as a screen for compounds which alleviate the symptoms of atherosclerosis and heart disease. Animals (Apo E?/? SR-BI+/?) were fed PROBUCOL beginning at the time of mating. Offspring are weaned at three weeks and fed PROBUCOL. In contrast to animals (Apo E?/? SR-BI?/?) not fed PROBUCOL, 50% of whom are dead at six weeks, all animals (Apo E?/? SR-BI?/?) on PROBUCOL have a normal phenotype (MRI of heart function, ECG, echocardiogram, histology) at six weeks. At seven to eight months, there is evidence of atherosclerosis and some myocardial infarction. This demonstrates that the compound has a preventative action. Animals who are taken off of the PROBUCOL all die within ten to twelve weeks.

Abstract: SR-BI is present at relatively high levels on the membranes of hepatocytes and steroidogenic tissues, including the adrenal gland, testes, and ovaries, where it mediates the uptake and transport of cholesteryl ester from high density lipoproteins. It has been demonstrated that transgenic animals which do not produce SR-BI are healthy, with the exception that the females are infertile. SR-BI KO females have abnormal HDLs, ovulate dysfunctional oocytes and are infertile. Surgical, genetic and pharmacologic methods were used to show that the fertility of SR-BI KO females (or their transplanted oocytes) can be restored in the absence of ovarian and/or extraovarian SR-BI expression by manipulations that modify the structure, composition and/or abundance of their abnormal plasma lipoproteins. These manipulations included inactivation of the apolipoprotein A-I gene and administration of the cholesterol-lowering drug PROBUCOL™.

Abstract: Two distinct scavenger receptor type proteins having high affinity for modified lipoproteins and other ligands have been isolated, characterized and cloned. HaSR-BI, an AcLDL and LDL binding scavenger receptor, which is distinct from the type I and type II macrophage scavenger receptors, has been isolated and characterized and DNA encoding the receptor cloned from a variant of Chinese Hamster Ovary Cells, designated Var-261. dSR-CI, a non-mammalian AcLDL binding scavenger receptor having high ligand affinity and broad specificity, was isolated from Drosophila melanogaster. The isolated receptors are useful in screening for drugs that inhibit uptake of cholesterol in endothelial or adipose cells or macrophages, respectively. They are also useful as probes for the isolation of other lipoprotein receptors and in research the roles of these receptors.

Abstract: Methods for regulation of lipid and cholesterol uptake are described which are based on regulation of the expression or function of the SR-BI HDL receptor. The examples demonstrate that estrogen dramatically downregulates SR-BI under conditions of tremendous upregulation of the LDL-receptor. The examples also demonstrate the upregulation of SR-BI in rat adrenal membranes and other non-placental steroidogenic tissues from animals treated with estrogen, but not in other non-placental non-steroidogenic tissues, including lung, liver, and skin. Examples further demonstrate the uptake of fluorescently labeled HDL into the liver cells of animal, which does not occur when the animals are treated with estrogen. Examples also demonstrate the in vivo effects of SR-BI expression on HDL metabolism, in mice transiently overexpressing hepatic SR-BI following recombinant adenovirus infection. Overexpression of the SR-BI in the hepatic tissue caused a dramatic decrease in cholesterol blood levels.

Abstract: An animal model of coronary heart disease has been developed where myocardial infarct can be induced by altering the animal's diet. In all embodiments, this animal model is a result of reduced activity of scavenger receptor class BI (SR-BI) and apolipoprotein E (ApoE). In a preferred embodiment, the model is a result of crossbreeding two transgenic mouse lines: a knockout of SR-BI (SR-BI?/?) and an impaired ApoE expressor (hypoE). The impaired ApoE gene results in only 2-5% expression of ApoE and a reduction in cholesterol homeostasis. Resulting animals are predisposed to hypercholesterolemia but can live longer than a year on a normal low fat diet. Serum plasma levels can be significantly elevated by changing the animal's diet to one containing high levels of fat and cholesterol. Within a month on a high fat, high cholesterol diet, animals develop atherosclerosis and myocardial infarction occurs.

Abstract: Methods for regulation of lipid and cholesterol uptake are described which are based on regulation of the expression or function of the SR-BI HDL receptor. The examples demonstrate that estrogen dramatically downregulates SR-BI under conditions of tremendous upregulation of the LDL-receptor. The examples also demonstrate the upregulation of SR-BI in rat adrenal membranes and other non-placental steroidogenic tissues from animals treated with estrogen, but not in other non-placental non-steroidogenic tissues, including lung, liver, and skin. Examples further demonstrate the uptake of fluorescently labeled HDL into the liver cells of animal, which does not occur when the animals are treated with estrogen. Examples also demonstrate the in vivo effects of SR-BI expression on HDL metabolism, in mice transiently overexpressing hepatic SR-BI following recombinant adenovirus infection. Overexpression of the SR-BI in the hepatic tissue caused a dramatic decrease in cholesterol blood levels.

Abstract: Genetically modified cell lines that express a UDP-galactose 4-epimerase (GALE) capable of interconverting UDP-galactose (UDP-gal) and UDP-glucose (UDP-glc), but essentially incapable of interconverting UDP-N-acetylgalactosamine (UDP-galNAc) and UDP-N-acetylglucosamine (UDP-glcNAc).

Abstract: Methods for regulation of lipid and cholesterol uptake are described which are based on regulation of the expression or function of the SR-BI HDL receptor. The examples demonstrate that estrogen dramatically downregulates SR-BI under conditions of tremendous upregulation of the LDL-receptor. The examples also demonstrate the upregulation of SR-BI in rat adrenal membranes and other non-placental steroidogenic tissues from animals treated with estrogen, but not in other non-placental non-steroidogenic tissues, including lung, liver, and skin. Examples further demonstrate the uptake of fluorescently labeled HDL into the liver cells of animal, which does not occur when the animals are treated with estrogen. Examples also demonstrate the in vivo effects of SR-BI expression on HDL metabolism, in mice transiently overexpressing hepatic SR-BI following recombinant adenovirus infection. Overexpression of the SR-BI in the hepatic tissue caused a dramatic decrease in cholesterol blood levels.

Abstract: SR-BI is present on the membranes of hepatocytes and steroidogenic tissues, including the adrenal gland, testes, and ovaries, where it mediates the uptake and transport of cholesteryl ester from high density lipoproteins. It has been demonstrated that transgenic animals which do not produce SR-BI are perfectly healthy, with the exception that the females are infertile. This provides evidence that inhibition of uptake, binding or transport of cholesteryl ester to SR-BI can be used to inhibit pregnancy. The same pathway can also be used to decrease production of steroids, and therefore be used as a therapy for disorders involving steroidal overproduction.

Abstract: Using an animal model, transgenic animals that do not express functional SR-BI and apoE which develop severe atherosclerosis, by age four weeks in transgenic mice, a class of drugs, PROBUCOL (4,4′-(isopropylidenedithio) bis(2,6-di-tert-butylphenol)) and monoesters of PROBUCOL, and BO 653, 2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butyl-benzofuran, has been discovered which is useful in normalizing abnormal lipoprotein levels and/or characteristics, such as those found in lipoprotein X-associated disease. These animals are good models for screening of drugs useful in the treatment and/or prevention of cardiac fibrosis, myocardial infarction, defects in electrical conductance, atherosclerosis, unstable plaque, and stroke, as well as for lipoprotein disorders such as cholestasis and lipoprotein X associated disorders.