Xol INXS: role of the liver X and the farnesol X receptors

Cholesterol and bile acid metabolism is tightly controlled by nuclear receptors. The liver X receptor, an oxysterol-activated nuclear receptor, limits cholesterol accumulation in the body both by stimulating reverse cholesterol transport and by inhibiting intestinal cholesterol absorption. The liver X receptor stimulates the adenosine triphosphate binding cassette transporter (types 1 and 8)-mediated cholesterol efflux from peripheral tissues to apolipoprotein AI and the expression of the cholesterol ester transfer protein, hence facilitating cholesterol transfer to the liver. In the liver, the liver X receptor alpha induces the cholesterol 7alpha-hydroxylase (CYP7A1) gene, which controls the rate-limiting step in bile acid synthesis, the major cholesterol excretion pathway. The liver X receptor also limits cholesterol entry in the body by promoting cholesterol efflux from enterocytes into the intestinal lumen, again via an adenosine triphosphate binding cassette transporter type-mediated process. Whereas the liver X receptor is a master controller of cholesterol metabolism, the farnesol X receptor, a bile acid-activated receptor, coordinates bile acid homeostasis. Bile acids facilitate the solubilization of dietary lipids and their subsequent absorption. Bile acids enter the enterocyte through the ileal bile acid transporter and activate the farnesol X receptor, which upregulates the ileal bile acid binding protein, a carrier protein facilitating their re-uptake by the gut. Bile acids are then delivered into the portal blood and taken up in the hepatocytes by the sodium taurocholate co-transporting polypeptide. Inside the hepatocytes, activated farnesol X receptor will decrease further bile acid uptake by reducing the levels of sodium taurocholate co-transporting polypeptide, and stimulating the export of bile acid by increasing the expression of the bile salt export pump. Furthermore, the farnesol X receptor induces the small heterodimer partner, an atypical nuclear receptor, which attenuates bile acid synthesis by inhibiting the action of the orphan nuclear receptor, liver receptor homolog-1, which is a competence factor for CYP7A1 transcription. The farnesol X receptor hence stimulates bile acid re-uptake and controls bile acid production through a regulatory circuit involving both a nuclear receptor regulatory cascade and a number of specific transporter proteins.

Regulation of lipoprotein metabolism by thiazolidinediones occurs through a distinct but complementary mechanism relative to fibrates

Johan Auwerx

Thiazolidinediones are antidiabetic agents, which not only improve glucose metabolism but also reduce blood triglyceride concentrations. These compounds are synthetic ligands for PPAR gamma, a transcription factor belonging to the nuclear receptor subfamily of PPARs, which are important transcriptional regulators of lipid and lipoprotein metabolism. The goal of this study was to evaluate the influence of a potent thiazolidinedione, BRL49653, on serum lipoproteins and to determine whether its lipid-lowering effects are mediated by changes in the expression of key genes implicated in lipoprotein metabolism. Treatment of normal rats for 7 days with BRL49653 decreased serum triglycerides in a dose-dependent fashion without affecting serum total and HDL cholesterol and apolipoprotein (apo) A-I and apo A-II concentrations. The decrease in triglyceride concentrations after BRL49653 was mainly due to a reduction of the amount of VLDL particles of unchanged lipid and apo composition. BRL49653 treatment did not change triglyceride production in vivo as analyzed by injection of Triton WR-1339, indicating a primary action on triglyceride catabolism. Analysis of the influence of BRL49653 on the expression of LPL and apo C-III, two key players in triglyceride catabolism, showed a dose-dependent increase in mRNA levels and activity of LPL in epididymal adipose tissue, whereas liver apo C-III mRNA levels remained constant. Furthermore, addition of BRL49653 to primary cultures of differentiated adipocytes increased LPL mRNA levels, indicating a direct action of the drug on the adipocyte. Simultaneous administration of BRL49653 and fenofibrate, a hypolipidemic drug that acts primarily on liver through activation of PPAR alpha both decreased liver apo C-III and increased adipose tissue LPL mRNA levels, resulting in a more pronounced lowering of serum triglycerides than each drug alone. In conclusion, both fibrates and thiazolidinediones exert a hypotriglyceridemic effect. While fibrates act primarily on the liver by decreasing apo C-III production, BRL49653 acts primarily on adipose tissue by increasing lipolysis through the induction of LPL expression. Drugs combining both PPAR alpha and gamma activation potential should therefore display a more efficient hypotriglyceridemic activity than either compound alone and may provide a rationale for improved therapy for elevated triglycerides.

1997

Nuclear receptors and the control of metabolism

Johan Auwerx

The metabolic nuclear receptors act as metabolic and toxicological sensors, enabling the organism to quickly adapt to environmental changes by inducing the appropriate metabolic genes and pathways. Ligands for these metabolic receptors are compounds from dietary origin, intermediates in metabolic pathways, drugs, or other environmental factors that, unlike classical nuclear receptor ligands, are present in high concentrations. Metabolic receptors are master regulators integrating the homeostatic control of (a) energy and glucose metabolism through peroxisome proliferator-activated receptor gamma (PPARgamma); (b) fatty acid, triglyceride, and lipoprotein metabolism via PPARalpha, beta/delta, and gamma; (c) reverse cholesterol transport and cholesterol absorption through the liver X receptors (LXRs) and liver receptor homolog-1 (LRH-1); (d) bile acid metabolism through the farnesol X receptor (FXR), LXRs, LRH-1; and (e) the defense against xeno- and endobiotics by the pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR). The transcriptional control of these metabolic circuits requires coordination between these metabolic receptors and other transcription factors and coregulators. Altered signaling by this subset of receptors, either through chronic ligand excess or genetic factors, may cause an imbalance in these homeostatic circuits and contribute to the pathogenesis of common metabolic diseases such as obesity, insulin resistance and type 2 diabetes, hyperlipidemia and atherosclerosis, and gallbladder disease. Further studies should exploit the fact that many of these nuclear receptors are designed to respond to small molecules and turn them into therapeutic targets for the treatment of these disorders.

2003

Regulation of lipoprotein metabolism by thiazolidinediones occurs through a distinct but complementary mechanism relative to fibrates

Johan Auwerx

1997