Members of the Nuclear Receptor Superfamily Contribute to Cellular and Whole Body Lipid Regulation

In addition to SREBPs, several members of the nuclear receptor superfamily regulate lipid metabolism. Nuclear receptors are transcription factors that are generally activated when bound to specific small-molecule ligands (Chapter 11). Certain nuclear receptors influence whole-body lipid metabolism by regulating the absorption of dietary lipids, cellular synthesis of lipids, transport protein-mediated import and export of lipids, levels of lipoproteins and their receptors, and catabolism of lipids (e.g., fatty acid oxidation in the peroxisome) and their secretion from the body.

Some ligands for nuclear receptors are extracellular molecules that diffuse across the plasma membrane (e.g., steroid hormones) or enter cells through transporters (e.g., bile acids, fatty acids). Alternatively, ligands generated within a cell, including oxygen-modified cholesterol (oxysterols), bile acids, and certain fatty acids and their derivatives, may bind to nuclear receptors within the same cell. Nuclear receptors sense changes in the levels of all key cellular lipids by binding the lipids themselves or their metabolic products. When activated, these receptors stimulate or suppress gene expression to ensure that the proper physiological levels of lipids are maintained (feedback regulation for cellular homeostasis). The binding of multiple types of lipids to an individual nuclear receptor allows the receptor to coordinately control several metabolic pathways.

For example, hepatocytes express LXR (liver X receptor), a nuclear receptor that senses the levels of oxysterols. When cellular cholesterol increases in the liver, oxysterols are generated and activate LXR. Activated LXR stimulates the expression of cholesterol 7a-hydroxylase, the key rate-limiting enzyme in the hepatic conversion of cholesterol into bile acids, a major pathway for disposing of excess cholesterol from the body. LXR also stimulates the expression of the ABC proteins that export cholesterol into the bile (ABCG5/8) or onto lipoproteins in the blood (ABCA1). In addition, LXR promotes lipoprotein production and modification and the expression of SREBP-1c, which then turns on the transcription of genes required for fatty acid synthesis. The resulting increase in fatty acids can contribute to cholesterol esterification and phospholipid synthesis to maintain the proper ratio of cholesterol to phospholipid. Thus sensing of increased cellular cholesterol by LXR results in diverse responses that prevent the accumulation of excess cholesterol.

Another nuclear receptor, called FXR, is activated by the binding of bile acids. Expressed in hepatocytes and intestinal epithelial cells, FXR plays a key role in regulating the en-terohepatic circulation of bile acids. Bile acid-activated FXR stimulates the expression of intracellular bile acid-binding protein (I-BABP) and of transport proteins (e.g., ABCB11, NTCP) that mediate cellular export and import of bile acids (see Figure 18-11). In contrast, active FXR represses the expression of cholesterol 7a-hydroxylase, thereby decreasing the synthesis of bile acids from cholesterol in the liver—another example of end-product inhibition of a metabolic pathway. Both FXR and LXR function as heterodimers with the nuclear receptor RXR.

In the next section, we will see how an understanding of the SREBP and nuclear receptor regulatory pathways has contributed to effective strategies for reducing the risk of atherosclerosis and cardiovascular disease.

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