ABSTRACT
Disturbances in cerebral cholesterol metabolism have been implicated in the pathogenesis of Alzheimer's disease (AD). Here, we provide evidence that alterations in brain cholesterol homeostasis also can be a consequence of disease progression. We found that APPSLxPS1mut mice, at the age of 9 months when AD-like pathology starts to develop, display increased levels of the cholesterol precursor desmosterol and of the cholesterol metabolite 27-hydroxy(OH)cholesterol in their cerebellum in comparison with wild-type controls. At the age of 21 months, when APPSLxPS1mut brain contains abundant amyloid deposits, desmosterol levels had further increased (> 200% in comparison with wild-type mice) in all brain regions examined. 24(S)-OHcholesterol levels were increased in hippocampus and cerebellum of the APPSLxPS1mut mice, while 27-OHcholesterol levels were increased in cerebellum exclusively. Brain cholesterol levels remained unaffected. In line with the fact that desmosterol and 24(S)-OHcholesterol are Liver X Receptor (LXR) activators, the LXR-target genes Abca1 and Apoc1 were upregulated predominantly in hippocampus of APPSLxPS1mut mice at both ages evaluated. The reduced expression of the enzyme that converts desmosterol into cholesterol, the Selective AD indicator 1 gene (Seladin-1/Dhcr24), in both cortex and cerebellum may underlie the increased desmosterol levels in 21 month-old APPSLxPS1mut mice.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/genetics , Brain/metabolism , Cholesterol/genetics , Cholesterol/metabolism , Disease Models, Animal , Presenilin-1/genetics , Age Factors , Alzheimer Disease/enzymology , Amyloid beta-Protein Precursor/biosynthesis , Animals , Brain/enzymology , Brain/pathology , Cholesterol/biosynthesis , Desmosterol/antagonists & inhibitors , Desmosterol/metabolism , Mice , Mice, Inbred C57BL , Mice, Neurologic Mutants , Mice, Transgenic , Nerve Tissue Proteins/genetics , Oxidoreductases Acting on CH-CH Group Donors/genetics , Presenilin-1/biosynthesisABSTRACT
Cholesterol homeostasis, defined as the balance between absorption and synthesis, influences circulating cholesterol concentrations and subsequent coronary heart disease (CHD) risk. Statin therapy targets the rate-limiting enzyme in cholesterol biosynthesis and is efficacious in lowering CHD events and mortality. Nonetheless, CHD events still occur in some treated patients. To address differences in outcome during pravastatin therapy (40 mg/day), plasma markers of cholesterol synthesis (desmosterol, lathosterol) and fractional cholesterol absorption (campesterol, sitosterol) were measured, baseline and on treatment, in the Prospective Study of Pravastatin in the Elderly at Risk trial participants with (cases, n = 223) and without (controls, n = 257) a CHD event. Pravastatin therapy decreased plasma LDL-cholesterol and triglycerides and increased HDL-cholesterol concentrations to a similar extent in cases and controls. Decreased concentrations of the cholesterol synthesis markers desmosterol (-12% and -11%) and lathosterol (-50% and -56%) and increased concentrations of the cholesterol absorption markers campesterol (48% and 51%) and sitosterol (25% and 26%) were observed on treatment, but the magnitude of change was similar between cases and controls. These data suggest that decreases in cholesterol synthesis in response to pravastatin treatment were accompanied by modest compensatory increases in fractional cholesterol absorption. The magnitude of these alterations were similar between cases and controls and do not explain differences in outcomes with pravastatin treatment.
Subject(s)
Coronary Disease/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Pravastatin/therapeutic use , Aged , Aged, 80 and over , Cholesterol/agonists , Cholesterol/analogs & derivatives , Cholesterol/blood , Cholesterol, HDL/agonists , Cholesterol, HDL/blood , Cholesterol, LDL/antagonists & inhibitors , Cholesterol, LDL/blood , Coronary Disease/blood , Coronary Disease/mortality , Desmosterol/antagonists & inhibitors , Desmosterol/blood , Female , Homeostasis/drug effects , Homeostasis/physiology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Male , Phytosterols/agonists , Phytosterols/blood , Pravastatin/administration & dosage , Sitosterols/agonists , Sitosterols/blood , Triglycerides/antagonists & inhibitors , Triglycerides/bloodABSTRACT
The cytostatic and cytolytic action of 22R - hydroxydesmosterol on hepatoma cells cultured in a medium containing 10% newborn-calf serum can be reversed within certain concentration limits by adding cholesterol to the culture medium. In contrast, under the same conditions, the cytotoxicity of 7 beta -hydroxycholesterol could not be reversed, whatever the concentrations of cholesterol added. However, in a lipoprotein-poor and in a chemically defined medium, the cytolytic action of both hydroxysterols can be reversed by adding cholesterol, but growth inhibition cannot be suppressed. This demonstrates the importance of serum lipids and lipoproteins for the toxicity of the hydroxysterols and for the antagonistic effect of cholesterol. Our results suggest that the action mechanisms of 7 beta-hydroxycholesterol and 22R - hydroxydesmosterol on HTC hepatoma cells are not fully identical.
Subject(s)
Cholesterol/pharmacology , Desmosterol/analogs & derivatives , Hydroxycholesterols/antagonists & inhibitors , Liver Neoplasms, Experimental/pathology , Animals , Cell Division/drug effects , Cell Line , Cell Survival/drug effects , Culture Media , Desmosterol/antagonists & inhibitors , Lipids/pharmacology , RatsABSTRACT
Biliary cholesterol secretion was studied in dogs with chronic bile fistulas, using glucagon, an inhibitor of biliary cholesterol secretion, and triparanol, an inhibitor of cholesterol synthesis. Glucagon inhibited neutral sterol secretion before and after triparanol administration. Triparanol caused a significant accumulation in bile of the cholesterol precursor desmosterol which comprised a significant portion of the neutral sterol in bile but not in blood. Glucagon inhibited both biliary desmosterol and cholesterol secretions to a similar degree. These findings suggest that biliary cholesterol is derived from newly synthesized hepatic sterol as well as from equilibrated sources. Furthermore, glucagon suppressed biliary secretion of both equilibrated as well as newly synthesized neutral sterol, suggesting that glucagon inhibits the movement of neutral sterol to or through the canalicular membrane.
