Melanocortin signaling in the CNS directly regulates circulating cholesterol.

Cholesterol circulates in the blood in association with triglycerides and other lipids, and elevated blood low-density lipoprotein cholesterol carries a risk for metabolic and cardiovascular disorders, whereas high-density lipoprotein (HDL) cholesterol in the blood is thought to be beneficial. Circulating cholesterol is the balance among dietary cholesterol absorption, hepatic synthesis and secretion, and the metabolism of lipoproteins by various tissues. We found that the CNS is also an important regulator of cholesterol in rodents.

Class B type I scavenger receptor is responsible for the high affinity cholesterol binding activity of intestinal brush border membrane vesicles.

Recent studies have documented the importance of Niemann-Pick C1-like 1 protein (NPC1L1), a putative physiological target of the drug ezetimibe, in mediating intestinal cholesterol absorption. However, whether NPC1L1 is the high affinity cholesterol binding protein on intestinal brush border membranes is still controversial. In this study, brush border membrane vesicles (BBMV) from wild type and NPC1L1-/- mice were isolated and assayed for micellar cholesterol binding in the presence or absence of ezetimibe.

Endocrine modulating actions of a phytosterol mixture and its oxidation products in zebrafish (Danio rerio).

In this study, a phytosterol preparation ("ultrasitosterol"; 80% beta-sitosterol) and an oxidized ultrasitosterol preparation were evaluated for reproductive effects in zebrafish. Adults were exposed in a continuous flow to 10 microg/L and 100 microg/L ultrasitosterol and oxidized ultrasitosterol, and to 0.27 microg/L 17beta-estradiol and 0.

Effects of chenodeoxycholic acid and deoxycholic acid on cholesterol absorption and metabolism in humans.

Quantitative and qualitative differences in intralumenal bile acids may affect cholesterol absorption and metabolism. To test this hypothesis, 2 cross-over outpatient studies were conducted in adults with apo-A IV 1/1 or apo-E 3/3 genotypes. Study 1 included 11 subjects 24 to 37 years of age, taking 15 mg/kg/day chenodeoxycholic acid (CDCA) or no bile acid for 20 days while being fed a controlled diet.

Micellar solubilisation of cholesterol is essential for absorption in humans.

Background And Aims: Intralumenal bile acid (BA) concentrations have a profound effect on cholesterol absorption. We performed studies to assess the effects of markedly reduced lumenal BA on cholesterol absorption in children with inborn errors in BA synthesis and the role of micellar solubilisation of cholesterol on its absorption in an animal model using human intestinal contents.

Methods: We studied five subjects: two with 3beta hydroxy-C27 steroid dehydrogenase isomerase deficiency (3-HSD), two with Delta(4)-3-oxosteroid 5beta reductase deficiency (5beta reductase), and one with 2-methylacyl CoA racemase deficiency (racemase).

Yolk sac cholesteryl ester secretion rates can be manipulated in the Golden Syrian hamster: effect of yolk sac cholesterol concentrations.

The yolk sac is one of two extra-embryonic fetal tissues that separates the fetal and maternal circulations. The yolk sac can secrete lipoprotein particles to the vitelline vessels, which supply yolk sac-derived nutrients to the embryo. The amount and composition of lipoproteins secreted from the rat yolk sac can be manipulated by fatty acid content and gestational age.

Cholic acid supplementation enhances cholesterol absorption in humans.

Background & Aims: Qualitative and quantitative changes in intralumenal bile acid composition may alter cholesterol absorption and synthesis and low-density lipoprotein (LDL) receptor expression. The role of cholic acid (CA) in cholesterol absorption in humans remains unclear and, thus, was examined in the current study.

Methods: In a crossover design outpatient study, 12 adults aged 24-36 years took 15 mg/kg/day (CA) or no bile acid supplement (control) while being fed a controlled diet (AHA heart-healthy diet).

Effect of mouse strain variations and cortisone treatment on the establishment and growth of primary Echinococcus multilocularis hydatid cysts.

The main purpose of this study was to determine the effects of cortisone on the number and size of primary Echinococcus multilocularis cysts developing in a moderately resistant strain of mice, i.e., C3H/HeJ.

Effect of ursodeoxycholic acid on cholesterol absorption and metabolism in humans.

Qualitative and quantitative changes in intraluminal bile acid composition may alter cholesterol absorption and synthesis and LDL receptor expression. In a randomized crossover design outpatient study, 12 adults aged 24-36 years took 15 mg/kg/day ursodeoxycholic acid (UDCA) or no bile acid supplement (control) for 20 days while being fed a controlled diet (AHA Step II). A liquid meal of defined composition was then given and luminal samples collected.

Separation of micelles and vesicles within lumenal aspirates from healthy humans: solubilization of cholesterol after a meal.

Understanding the physico-chemical relationship of lumenal lipids to one another is critical when elucidating the mechanism of components known to impact cholesterol absorption. Presently, there are no studies that describe the proportion of cholesterol carried as micelles or vesicles within human lumenal contents. Part of the reason for the scarceness of data is because of the lack of appropriate methodology required for reproducible sample collection and analysis.

Compensatory phospholipid digestion is required for cholesterol absorption in pancreatic phospholipase A(2)-deficient mice.

Background And Aims: Numerous studies have suggested phospholipid inhibition of dietary cholesterol absorption through the gastrointestinal tract. This study addressed the importance of luminal phospholipid hydrolysis in this process.

Methods: The effect of phospholipase inhibition on cholesterol transport from intestinal lumen to the lymphatics was evaluated in lymph fistula rats.

Apolipoprotein E inhibition of vascular smooth muscle cell proliferation but not the inhibition of migration is mediated through activation of inducible nitric oxide synthase.

Initial experiments revealed that low concentrations of apolipoprotein (apo) E (0.1 to 5 microg/mL) were effective in inhibiting platelet-derived growth factor (PDGF)-directed smooth muscle cell (SMC) migration by 60% to 80%. In contrast, higher concentrations of apoE, at 25 and 50 microg/mL, were necessary to achieve similar inhibition of PDGF-induced SMC proliferation.

Maternal high density lipoproteins affect fetal mass and extra-embryonic fetal tissue sterol metabolism in the mouse.

Previous studies have shown that antibodies to cubulin, a receptor on the yolk sac that binds high density lipoproteins (HDL) and cobalamin, induce fetal abnormalities. Mice with markedly low concentrations of plasma HDL-cholesterol (HDL-C) give birth to healthy pups, however. To establish whether maternal HDL-C has a role in fetal development, sterol metabolism was studied in the fetus and extra-embryonic fetal tissues in wild-type and apolipoprotein A-I-deficient mice (apoAI-/-).

Agouti-related maturation and tissue distribution of alpha-Melanocyte Stimulating Hormone in wild-type (AwJ/AwJ) and mutant (Ay/a,a/a) mice.

Because of ectopic overproduction of agouti protein, yellow alleles (A(y) and A(vy)) of the murine agouti gene may secondarily modulate the synthesis, maturation (i.e., acetylation), and/or tissue deployment of alpha-Melanocyte Stimulating Hormone (MSH).

Isolation, cloning, and sequencing of porcine agouti exon 2 (PorAex2).

In order to isolate, clone, and sequence agouti exon 2 of the pig (Yorkshire), we used an interspecific hybridization strategy. Primers from the 5' and 3' borders of the known human agouti exon 2 sequence were used to amplify (PCR) pig agouti exon 2. Following Southern blotting using a human exon 2 internal primer to authenticate that our PCR amplified product was truly pig exon 2 (PorAex2), the fragment was cloned and sequenced.

Apolipoprotein E inhibits platelet-derived growth factor-induced vascular smooth muscle cell migration and proliferation by suppressing signal transduction and preventing cell entry to G1 phase.

The anti-atherogenic effects of apolipoprotein (apo) E have been attributed to its ability to reduce plasma cholesterol level and to limit foam cell formation. The purpose of this study was to ascertain if apoE also may have cytostatic functions that could attenuate vascular occlusive diseases. Purified apoE inhibited smooth muscle cell migration directed to platelet-derived growth factor (PDGF) or oxidized LDL (oxLDL) (p < 0.

Agouti alleles alter cysteine and glutathione concentrations in hair follicles and serum of mice (A y/a, A wJ/A wJ, and a/a).

Ectopic overexpression of the agouti protein in the lethal yellow (A y/a) mouse causes a yellow coat as well as the lethal yellow syndrome. Presence of thiols like glutathione (GSH) or cysteine (Cys) may regulate the conversion of dopaquinone to phaeomelanin in hair follicle melanocytes. GSH also plays important roles in cellular health and maintenance.

Agouti alleles influence thiol concentrations in hair follicles and extrafollicular tissues of mice (Ay/a, AwJ/AwJ, a/a).

Agouti protein (AP) expression in the wild-type agouti mouse (AwJ/AwJ) coincides with a switch in hair follicle melanogenesis from black (eumelanin) to yellow (pheomelanin). Ectopic overexpression of AP in the lethal yellow (Ay/a) mouse cause a pure yellow coat and the lethal yellow syndrome. Thiol concentrations may control the conversion of dopaquinone to pheomelanin in hair follicle melanocytes.

Enhancement of renal disease in BXSB lupus prone mice after prior exposure to bacterial lipopolysaccharide.

The mechanism, or mechanisms, responsible for enhancement of renal disease after episodes of infection are poorly understood. We used the BXSB mouse as a lupus model of autoimmune disease and we used bacterial lipopolysaccharide (LPS) as a surrogate infectious agent to gain some insight into the mechanism by which infections promote enhancement of autoimmune disease to chronicity. BXSB mice were exposed to LPS for 5 weeks, LPS was withdrawn and various tests and measurements were performed 6 weeks thereafter.

Long-lasting effects of bacterial lipopolysaccharide promote progression of lupus nephritis in NZB/W mice.

Lupus prone NZB/W mice repeatedly exposed to bacterial lipopolysaccharide (LPS) develop enhanced polyclonal B cell activation and exacerbated nephritis by a mechanism that results in increased deposits of immunoreactants in kidneys without measurable impairment of mononuclear phagocyte function. In this paper, we investigate whether the referenced effects of LPS are reversible after withdrawal of LPS, or whether their persistence could contribute to progression of nephritis to chronicity. In NZB/W mice previously exposed to LPS, features of enhanced polyclonal B cell activation, more severe glomerulonephritis with tubulointerstitial involvement, increased deposits of immunoreactants in glomeruli, and altered protein excretion persisted 6 weeks after LPS was discontinued.

Pathogenesis of early nephritis in lupus prone mice with a genetic accelerating (lpr) factor.

We investigated the relative roles of B cell activity, circulating immune complexes, complement concentration and kinetics of disappearance and uptake of immune complexes from the circulation in the pathogenesis of early nephritis of MRL/lpr mice. In comparison to data in control (C57BL/6J) mice, B cell activity was enhanced and the concentration of autoantibodies and endogenous immune complexes in plasma were increased, whereas complement (C3) concentration was not significantly different in MRL/lpr mice. The kinetics of disappearance of radiolabeled immune complexes from the circulation were similar in MRL/lpr and control mice, whereas uptake of radiolabeled immune complexes by the liver was decreased in MRL/lpr mice.

Bacterial lipopolysaccharide causes variable deposits of diverse immunoglobulin isotypes in kidneys of lupus-prone mice.

We investigated the role of immunoglobulin isotypes in the exacerbation of lupus nephritis associated with exposure to bacterial lipopolysaccharide. The data indicate that enhanced polyclonal B-cell activation and exacerbated autoimmune disease evoked by lipopolysaccharide are associated with an increase in the concentration of isotypes in plasma and in renal eluate, that this isotype response is polyclonal and preferential but not restrictive, that all B cells are responsive but all are not equally sensitive to the effects of lipopolysaccharide, and that some expanded isotypes may be more nephritogenic in certain strains of lupus-prone mice.

Autoimmunity, polyclonal B-cell activation and infection.

It is widely believed that autoimmunity is an integral part of the immune system, and that genetic, immunologic, hormonal, environmental and other factors contribute to the pathogenesis of autoimmune disease. Thus, autoimmune disease may represent an abnormal expression of immune functions instead of loss of tolerance to self, and it can be organ specific or systemic in its manifestations. We review the various factors that contribute to the development of autoimmune disease; we also review the mechanisms of polyclonal B-cell activation, with emphasis on the role of infectious agents.