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AB - The effects of the administration of methyl clofenapate (methyl 2 [4 (p chlorophenyl) phenoxy] 2 methylpropionate) on the inducibility of hepatic microbody (peroxisome) proliferation and catalase synthesis were studied in male rats and in both sexes of wild type (Cs(a) strain) and acatalasemic (Cs(b) strain) mice. These investigations included electron microscopic examination of livers, assay of liver catalase activity, quantitation of catalase protein by immunotitration procedure, and measurements of serum cholesterol and glyceride glycerol levels. In all groups of animals administration of methyl clofenapate at dietary concentrations of 0.015, 0.05 and 0.125% produced a significant and sustained increase in number of hepatic microbody (peroxisome) profiles. There was no appreciable increase in mitochondrial population, but several mitochondria were markedly enlarged and possessed numerous cristae. The hepatic microbody proliferation in male rats and in both sexes of wild type mice following methyl clofenapate administration was associated with a twofold increase in catalase activity and in the concentration of catalase protein. The increase in microbody population in acatalasemic mice, however, was not accompanied by a significant elevation of the catalase activity, which is due to the unusual heat lability of the mutant catalase enzyme. A marked decrease in serum cholesterol and glyceride glycerol levels was observed in male rats following methyl clofenapate administration which paralleled the increase in liver catalase activity. In both strains of mice there was a significant reduction in serum glyceride glycerol concentrations. All the above effects of methyl clofenapate were fully reversed when the drug was withdrawn from the diet of male wild type mice. The demonstration of microbody proliferation and catalase induction with hypolipidemic compounds, ethyl α p chlorophenoxyisobutyrate, nafenopin and, in these studies, with methyl clofenapate suggests a possible but as yet unclarified relation between microbodies and hypolipidemia.
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139. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. 2002;109:1125-1131
142. Brown AJ, Sun L, Feramisco JD. . Cholesterol Addition to ER Membranes Alters Conformation of SCAP, the SREBP Escort Protein that Regulates Cholesterol Metabolism. 2002;10:237-245
despite an overall increase in hepatic cholesterol synthesis [41, 42]
The molecular basis for cholesterol sensitivity of SREBP has been elucidated greatly due to the efforts made by the Brown and Goldstein Lab of the University of Texas Southwestern Medical Center. Each newly translated is inserted into the ER membrane, where its C-terminal regulatory domain binds to the C-terminal of the SREBP cleavage activating protein (SCAP) (). While associated with SREBP, SCAP binds to another ER bound protein known as insulin induced gene 1 (INSIG) (). Interaction between SCAP and INSIG keeps the protein complex firmly in place in the ER. Importantly, this interaction between SCAP and INSIG is cholesterol-sensitive, and thus, acts as the cholesterol sensor of this system (). In cholesterol abundant conditions, membrane-spanning domains of SCAP bind to cholesterol, causing a conformational change in the cytosolic domain between domains 7 and 8, resulting in strong affinity for INSIG (). The cholesterol-absent conformation of SCAP is not associated with INSIG, leaving the SREBP/SCAP complex free to leave the ER in COPII vesicles, which then migrate to the Golgi (). Once there, the N-terminal transcription factor domain of SREBP is cleaved in a two-step process involving proteolytic enzymes site-1 and site-2 proteases (S1P and S2P, respectively) (). The nuclear form of SREBP migrates into the nucleus and activates genes including and , ultimately leading to increased cholesterol concentration in the cell.
Activation of hepatic cholesterol synthesis and 3 …
Transcription levels of both and genes are controlled by promoters with sterol regulatory elements (SREs), which are present on over 30 genes involved with lipid synthesis and uptake (). Experiments using chimeric promoter and reporter gene constructs have localized the area of sterol responsiveness to 8bp of palindromic sequence, (5'-CACCCCAC-3') (). The SRE in the promoter is homologous to SRE, with a substitution of a guanine for the central cytosine on the 3' side (). In both promoters, attachment of transcription factors called SRE binding proteins (SREBPs) is required for efficient production of downstream transcription. There are three types of SREBP, (), which are encoded by two genes. Of the three isoforms, SREBP1a and SREBP2 are more important in cholesterol homeostasis than SREBP1c, which mainly alters expression of fatty acid synthesis genes (). Despite discrepancies in their transcriptional targets, proteolytic activation of each isoform is regulated by cholesterol through a common mechanism. Complete disruption of activation in mice hepatocytes results in 75% decrease in sterol and fatty acid synthesis, 50% reduction in mRNA and LDL clearance, and a significant reduction in total plasma cholesterol ().