farnesyl-pyrophosphate and Disease-Models--Animal

High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer's disease (AD). Some reports, mostly retrospective epidemiological studies, have observed a decreased prevalence of AD in patients taking the cholesterol lowering drugs, statins. The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding/reducing cholesterol alters amyloid precursor protein (APP) and amyloid beta-protein (Ab) levels. However, there are problems with the cholesterol-AD hypothesis. Cholesterol levels in serum/plasma and brain of AD patients do not support cholesterol as a causative factor in AD.Prospective studies on statins and AD have largely failed to show efficacy. Even the experimental data are open to interpretation given that it is well-established that modification of cholesterol levels has effects on multiple proteins, not only amyloid precursor protein and Ab. The purpose of this review, therefore, was to examine the above-mentioned issues, discuss the pros and cons of the cholesterol-AD hypothesis, involvement of other lipids in the mevalonate pathway, and consider that AD may impact cholesterol homeostasis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Astrocytes; Cell Membrane; Cells, Cultured; Cholesterol; Cholesterol, Dietary; Disease Models, Animal; Humans; Hydroxycholesterols; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Mice; Models, Biological; Neurons; Polyisoprenyl Phosphates; Rabbits; Sesquiterpenes

Minodronic acid hydrate is one of the new-generation bisphosphonates containing nitrogen. The drug has an inhibitory effect on bone resorption by suppressing the osteoclastic function. Minodronic acid hydrate is being developed as a therapeutic drug of osteoporosis. In non-clinical study, the inhibitory effect of minodronic acid hydrate on the decrease in the bone mineral density and on the reduction in the bone intensity in ovariectomized rat osteoporosis models. The results of the clinical studies conducted so far showed that minodronic acid hydrate administered once daily for 36 weeks increases the bone mineral density of lumbar spine (L2-4BMD) significantly compared to the placebo group. It was speculated that minodronic acid hydrate has an increasing effect on the bone mineral density that is at least equivalent to that of alendronate and risedronate. It was also expected that the incidence of digestive diseases with minodronic acid hydrate is lower than that with the existing bisphosphonates. At the moment, the Phase III study is being conducted. We expect that minodronic acid hydrate is used for a number of patients with osteoporosis as a potent and safe domestic bisphosphonate in the near future.

Topics: Animals; Bone Density; Bone Resorption; Clinical Trials, Phase II as Topic; Diphosphonates; Disease Models, Animal; Female; Humans; Imidazoles; Osteoporosis, Postmenopausal; Polyisoprenyl Phosphates; Rats; Sesquiterpenes

Peroxisomes contain enzymes catalyzing a number of indispensable metabolic functions mainly related to lipid metabolism. The importance of peroxisomes in man is stressed by the existence of genetic disorders in which the biogenesis of the organelle is defective, leading to complex developmental and metabolic phenotypes. The purpose of this review is to emphasize some of the recent findings related to the localization of cholesterol biosynthetic enzymes in peroxisomes and to discuss the impairment of cholesterol biosynthesis in peroxisomal deficiency diseases.

Topics: Acyl Coenzyme A; Cholesterol; Disease Models, Animal; Embryonic and Fetal Development; Humans; Peroxisomal Disorders; Peroxisomes; Polyisoprenyl Phosphates; Sesquiterpenes

Previous studies have suggested that metabolites in the mevalonate pathway are involved in hepatic bile acid metabolism, yet the details of this relationship remain unknown. In this study, we found that the hepatic farnesyl pyrophosphate (FPP) level and the ratio of FPP to geranylgeranyl pyrophosphate (GGPP) were increased in mice with acute obstructive cholestasis compared with mice that underwent a sham operation. In addition, the livers of the mice with acute obstructive cholestasis showed lower expression of geranylgeranyl diphosphate synthase (GGPPS), which synthesizes GGPP from FPP. When Ggps1 was conditionally deleted in the liver, amelioration of liver injury, as shown by downregulation of the hepatic inflammatory response and decreased hepatocellular apoptosis, was found after ligation of the common bile duct and cholecystectomy (BDLC). Subsequently, liquid chromatography/mass spectrometry analysis showed that knocking out Ggps1 decreased the levels of hepatic bile acids, including hydrophobic bile acids. Mechanistically, the disruption of Ggps1 increased the levels of hepatic FPP and its metabolite farnesol, thereby resulting in farnesoid X receptor (FXR) activation, which modulated hepatic bile acid metabolism and reduced hepatic bile acids. It was consistently indicated that digeranyl bisphosphonate, a specific inhibitor of GGPPS, and GW4064, an agonist of FXR, could also alleviate acute obstructive cholestatic liver injury in vivo. In general, GGPPS is critical for modulating acute obstructive cholestatic liver injury, and the inhibition of GGPPS ameliorates acute obstructive cholestatic liver injury by decreasing hepatic bile acids, which is possibly achieved through the activation of FXR-induced bile acid metabolism.

Topics: Animals; Apoptosis; Bile Acids and Salts; Cholestasis; Disease Models, Animal; Farnesyltranstransferase; Hepatocytes; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Multienzyme Complexes; Polyisoprenyl Phosphates; Sesquiterpenes

Ras, a small GTPase protein, is thought to mediate Th2-dependent eosinophilic inflammation in asthma. Ras requires cell membrane association for its biological activity, and this requires the posttranslational modification of Ras with an isoprenyl group by farnesyltransferase (FTase) or geranylgeranyltransferase (GGTase). We hypothesized that inhibition of FTase using FTase inhibitor (FTI)-277 would attenuate allergic asthma by depleting membrane-associated Ras. We used the OVA mouse model of allergic inflammation and human airway epithelial (HBE1) cells to determine the role of FTase in inflammatory cell recruitment. BALB/c mice were first sensitized then exposed to 1% OVA aerosol or filtered air, and half were injected daily with FTI-277 (20 mg/kg per day). Treatment of mice with FTI-277 had no significant effect on lung membrane-anchored Ras, Ras protein levels, or Ras GTPase activity. In OVA-exposed mice, FTI-277 treatment increased eosinophilic inflammation, goblet cell hyperplasia, and airway hyperreactivity. Human bronchial epithelial (HBE1) cells were pretreated with 5, 10, or 20 μM FTI-277 prior to and during 12 h IL-13 (20 ng/ml) stimulation. In HBE1 cells, FTase inhibition with FTI-277 had no significant effect on IL-13-induced STAT6 phosphorylation, eotaxin-3 peptide secretion, or Ras translocation. However, addition of exogenous FPP unexpectedly augmented IL-13-induced STAT6 phosphorylation and eotaxin-3 secretion from HBE1 cells without affecting Ras translocation. Pharmacological inhibition of FTase exacerbates allergic asthma, suggesting a protective role for FTase or possibly Ras farnesylation. FPP synergistically augments epithelial eotaxin-3 secretion, indicating a novel Ras-independent farnesylation mechanism or direct FPP effect that promotes epithelial eotaxin-3 production in allergic asthma.

Topics: Animals; Asthma; Bronchi; Bronchial Hyperreactivity; Disease Models, Animal; Enzyme Inhibitors; Eosinophils; Epithelial Cells; Farnesyltranstransferase; Humans; Inflammation; Lung; Male; Methionine; Mice; Mice, Inbred BALB C; Ovalbumin; Polyisoprenyl Phosphates; ras Proteins; Sesquiterpenes; Signal Transduction

Simvastatin (SV) is reported to improve cognition and slow progression of Alzheimer's disease (AD), however underlying mechanism still remains unclear. In hippocampal dentate gyrus (DG), β-amyloid (Aβ) selectively impairs survival and neurite growth of newborn neurons in the 2(nd) week after birth. The aim of this study was to examine the effects of SV on the impairment of neurogenesis and the spatial cognitive deficits in Aβ25-35 (3 nmol)-injected (i.c.v.) mice (Aβ25-35-mice). Herein, we reported that the SV-treatment (20 mg/kg) on days 2-14 after BrdU-injection could dose-dependently protect the survival and neurite growth of newborn neurons, which was blocked by the α7nAChR antagonist MLA or the farnesol (FOH) that can convert to farnesyl pyrophosphate (FPP), but not the α4β2nAChR antagonist DHβE. The SV-treatment in Aβ25-35-mice rescued the decline of Akt phosphorylation and increased the ERK1/2 phosphorylation in hippocampus, which was sensitive to MLA and FOH. The PI3K inhibitor LY294002 could abolish the SV-protected neurogenesis in Aβ25-35-mice, but the MEK inhibitor U0126 had no effects. The SV-treatment could correct the decline of hippocampal BDNF concentration in Aβ25-35-mice, which was blocked by MLA and FOH. Using Morris water maze and Y-maze tasks, we further observed that the SV-treatment in Aβ25-35-mice could improve their spatial cognitive deficits, which was sensitive to the application of FOH. The results indicate that the SV-treatment in Aβ25-35-mice via reduction of FPP can protect neurogenesis through α7nAChR-cascading PI3K-Akt and increasing BDNF, which may improve spatial cognitive function.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain-Derived Neurotrophic Factor; Cognition Disorders; Dentate Gyrus; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Maze Learning; Mice, Inbred ICR; Neurogenesis; Neuroprotective Agents; Peptide Fragments; Phosphatidylinositol 3-Kinases; Polyisoprenyl Phosphates; Proto-Oncogene Proteins c-akt; Sesquiterpenes; Simvastatin