Review articleNuclear receptors in cholesterol catabolism: molecular biology of the enterohepatic circulation of bile salts and its role in cholesterol homeostasis
Section snippets
Cellular biology, physicochemistry, and the physiology of cholesterol homeostasis with relevance to the EHC of bile salts
The eukaryote cell, in its evolution from its prokaryote precursor, acquired the ability to synthesize cholesterol to ensure its availability for additional intracellular membrane structures, thereby allowing the multiplicity of membrane functions demanded by advanced life forms. Notwithstanding the cell’s need to synthesize cholesterol for membrane viability and steroid-hormone synthesis, it also needed to be able to catabolize cholesterol very efficiently to avoid hypercholesterolemia.1 The
General considerations
Seminal studies described several decades ago revealed that molecular regulation of intracellular cholesterol synthesis was under highly regulated genetic control. The laboratories of Brown and Goldstein showed that cells use signaling molecules to invoke these genetic controls.39, 40 They found that non-nuclear membrane–bound transcription factors, SREBPs, existed in the endoplasmic reticulum. SREBPs are activated by low intracellular oxysterol levels, which, as metabolites of cholesterol,
Speculations and therapeutic opportunities for targeted nuclear hormone receptor modulation
Nuclear hormone receptors exist to sense disturbances of cellular metabolism and respond by specific genetic signaling for transactivation of genes, often involving networking with other nuclear hormone receptors and other cell signals for targeted transcribed protein expression. They then effect change through promoter genes for protein expression from downstream target genes. Therefore they have the potential to be modulators of gene activity that might ameliorate molecular genetic disorders.
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