Review article
Nuclear receptors in cholesterol catabolism: molecular biology of the enterohepatic circulation of bile salts and its role in cholesterol homeostasis

https://doi.org/10.1016/S0022-2143(03)00088-XGet rights and content

Abstract

Recent advances in bile-salt research have revolutionized thought pertaining to the regulation of cholesterol homeostasis by highlighting the molecular control of reverse cholesterol transport and cholesterol catabolism to bile acids. The latter involves both feed-forward and feedback regulation of bile-acid synthesis within the territory of the enterohepatic circulation of bile salts. Cholesterol is vital to advanced life forms because it has become essential for membrane structure and function and is a precursor to the synthesis of steroid hormones, vitamins A and D, and bile acids. The liver plays a major part in cholesterol metabolism in that it is capable of de novo cholesterol synthesis and uptake from high-density lipoprotein reverse cholesterol transport, low-density lipoprotein, and chylomicron remnant receptors, so that 50% of total body cholesterol is available to be catabolized to bile acids. Cholesterol catabolism to bile acids allows the eukaryote cell to maintain cholesterol homeostasis because it cannot degrade cholesterol’s cyclopentanoperhydrophenanthrene ring. Bile-salt catabolic end products of cholesterol must also be regulated to maintain normal bile-acid pool size, secretion, and elimination to avoid bile-salt hepatocyte toxicity. Nuclear hormone receptors, after sensing inappropriate oxysterol and bile-salt levels, are transcription factors that initiate the genetic transactivation to modulate reverse cholesterol transport, cholesterol catabolism, and bile-acid metabolism contiguous to and within the enterohepatic circulation of bile salts so as to regulate cholesterol and bile-salt homeostasis, respectively. This new knowledge should spawn pharmacologic discoveries that modulate nuclear receptors for the treatment of disorders of 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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