Cholesterol: Synthesis, Metabolism, Regulation
AB - B cell receptor (BCR) signaling pathway components represent promising treatment targets in diffuse large Bcell lymphoma (DLBCL) and additional B cell tumors. BCR signaling activates spleen tyrosine kinase (SYK) and downstream pathways including PI3K/AKT and NF-κB. In previous studies, chemical SYK blockade selectively decreased BCR signaling and induced apoptosis of BCR-dependent DLBCLs. Herein, we characterize distinct SYK/PI3K-dependent survival pathways in DLBCLs with high or low baseline NF-κB activity including selective repression of the pro-apoptotic HRK protein in NF-κB-low tumors. We also define SYK/PI3K-dependent cholesterol biosynthesis as a feed-forward mechanism of maintaining the integrity of BCRs in lipid rafts in DLBCLs with low or high NF-κB. In addition, SYK amplification and PTEN deletion are identified as selective genetic alterations in primary "BCR"-type DLBCLs.
The Synthesis of Cholesterol. - Cholesterol-And …
AB - The formation of lipid electrophile-protein adducts is associated with many disorders that involve perturbations of cellular redox status. The identities of adducted proteins and the effects of adduction on protein function are mostly unknown and an increased understanding of these factors may help to define the pathogenesis of various human disorders involving oxidative stress. 7-Dehydrocholesterol (7-DHC), the immediate biosynthetic precursor to cholesterol, is highly oxidizable and gives electrophilic oxysterols that adduct proteins readily, a sequence of events proposed to occur in Smith-Lemli-Opitz syndrome (SLOS), a human disorder resulting from an error in cholesterol biosynthesis. Alkynyl lanosterol (a-Lan) was synthesized and studied in Neuro2a cells, Dhcr7-deficient Neuro2a cells and human fibroblasts. When incubated in control Neuro2a cells and control human fibroblasts, a-Lan completed the sequence of steps involved in cholesterol biosynthesis and alkynyl-cholesterol (a-Chol) was the major product formed. In Dhcr7-deficient Neuro2a cells or fibroblasts from SLOS patients, the biosynthetic transformation was interrupted at the penultimate step and alkynyl-7-DHC (a-7-DHC) was the major product formed. When a-Lan was incubated in Dhcr7-deficient Neuro2a cells and the alkynyl tag was used to ligate a biotin group to alkyne-containing products, protein-sterol adducts were isolated and identified. In parallel experiments with a-Lan and a-7-DHC in Dhcr7-deficient Neuro2a cells, a-7-DHC was found to adduct to a larger set of proteins (799) than a-Lan (457) with most of the a-Lan protein adducts (423) being common to the larger a-7-DHC set. Of the 423 proteins found common to both experiments, those formed from a-7-DHC were more highly enriched compared to a DMSO control than were those derived from a-Lan. The 423 common proteins were ranked according to the enrichment determined for each protein in the a-Lan and a-7-DHC experiments and there was a very strong correlation of protein ranks for the adducts formed in the parallel experiments.
Transcriptome analysis of the livers from ERCC1 deficient mice revealed several compensatory changes in response to the increased genotoxic challenge in these animals (). They included suppression of somatotrophic axis, reduced oxidative metabolism, and enhanced DNA repair. The somatotrophic suppression was proposed to be the primary driver for the key phenotypic features associated with ERCC1 defects such as general growth inhibition and accelerated aging (; ). As we have not seen much overlap between the brain and liver transcriptome responses, we speculate that the cholesterol biosynthesis pathway may be the key effector for the somatotrophic axis to stimulate growth of the brain. Hence, lower somatotrophic drive in response to ERCC1 deficiency could suppress cholesterol biosynthesis in the brain reducing growth of that organ. In fact, mutations in several cholesterol biosynthesis genes such as Dhcr24, Nsdhl, or Sc4mol, which are also downregulated in Ercc1-null mice, produce developmental disorders whose manifestations include microcephaly and mental retardation (; ; ). However, further studies are needed to determine (i) what are the effects of ERCC1 deficiency on the levels of cholesterol as well as its precursors and metabolites in the brain, and (ii) whether downregulation of cholesterol biosynthesis genes contributes to the neurological phenotype in ERCC1-deficient mice and humans.
Cholesterol | Definition of Cholesterol by Merriam-Webster
proposed the preferred metabolic pathway from linolenic to docosahexaenoic acid ().
The most important enzymatic site for the regulation of cholesterol metabolism was identified as the endoplasmic reticulum enzyme, the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) ().
Stoffel W et al.
12-12-2006 · Journal of Neurochemistry ..
described a type of membrane lipoproteins, proteolipids, whichare soluble in a mixture of chloroform and methanol ().
First description of the countercurrent separation of "the higher normalfatty acids" (C5-C18) ().
Galactosamine was identified in brain gangliosides ().
First description of the cholesterol lowering effect of a plant sterol (beta-sitosterol)in cholesterol-fed chickens(
cells were utilized to define the ..
suggested for the first time that the primary autoxidationproduct of unconjugated fatty chains is a hydroperoxide formed by the additionof an oxygen molecule to a carbon atom adjacent to the double bond ().
Von Mikusch JD reported the isolation, from alkali-isomerized acids of castoroil, of the first conjugated linoleic acid (10,12-linoleic acid) ().
Matsuda S reported the isolation of docosahexaenoic acid (DHA) from fish oil ().
The role of cholesterol in atherosclerosis was first described in chickens (
Steroid hormone biosynthesis - Reference pathway - …
of the antioxidant properties of tocopherols ().
First synthesis of linoleic acid ()
Kurz H used ethyl alcohol to derivatize fatty acids (FA ethyl esters) beforetheir analysis ().
First data on cholesterol and fatty acid metabolism after using an isotope of hydrogen(deuterium) in mice and chicks ().
Using deuterated acetate, Sonderhoff R et al. have shown that it serves asa precursor for sterols including ergosterol in yeast ().
Paul Karrer received the