FXR and LXRα regulation of lipoprotein metabolism

From LipidomicsWiki

Both FXR and LXRα play important roles in regulation of lipoprotein metabolism, RCT, and triglyceride metabolism. The target genes of FXR and LXR overlap indicating that these two receptors may coordinately regulate lipid metabolism. Both FXR and LXRα induce phospholipids transfer protein (PLTP) (Urizar et al. 2000; Cao et al. 2002), ApoCII (Kast et al. 2001) and ApoE (Mak et al. 2002; Lafitte et al. 2001; Venkateswaran et al. 2000). In addition, LXRα induces lipoprotein lipase (LPL) (Zhang et al. 2001) and cholesteryl ester transfer protein (CETP) (Luo and Tall 2000). These genes are involved in RCT from peripheral tissues to the liver for conversion to bile acids. Ablation of the Fxr gene in mice increases plasma cholesterol and triglyceride, very low density lipoprotein (VLDL), and intestinal cholesterol absorption, but decreases expression of hepatic genes involved in RCT including hepatic lipase, cholesterol ester hydrolase, lecithin cholesteryl acyl transferase (LCAT), PLTP, and scavenger receptor type BI (SR-BI), a high density lipoprotein (HDL) receptor (Lambert et al. 2003). It has been reported that FXR inhibits ApoAI gene expression by direct binding to a negative element (Claudel et al. 2002). Oxysterols are derived from cholesterol and bile acid synthesis pathways and are potent regulators of cholesterol synthesis and lipid metabolism. Oxysterols produced in macrophages and extrahepatic tissues are excreted into circulation and may be transported to the liver to be converted to bile acids. This is analogous to RCT and may be a defense against atherosclerosis. LXRα induces ABCA1 and ABCG1 (Costet et al. 2000), which effluxes cholesterol and phospholipids from macrophages and the peripheral tissues for synthesis of HDL (Bodzioch et al. 1999). HDL plays a central role in lipoprotein metabolism by providing apoCII and ApoE to VLDL and chylomicron (CM). Mutations of the ABCA1 gene have been identified in the Tangier disease patients who have severe defects in lipoprotein metabolism and atherosclerosis (Bodzioch et al. 1999). LXRα induces expression of the entire ApoE/C-I/C-IV/C-II gene cluster in mouse and human macrophages (Mak et al. 2002). PPARγ has been implicated in the induction of LXRα (Chawla et al. 2001). In the intestine, LXRα and RXRα agonists induce ABCA1 (Repa et al. 2000), but the evidence against the role of LXR in the regulation of ABCA1 and cholesterol efflux has been reported (Plosch et al. 2002). Over expression of ABCG5/ABCG8 induces biliary cholesterol excretion, reduces fractional cholesterol absorption, and increases fecal bile acid excretion in mice (Yu et al. 2002). LXRα induces ABCG5/G8 gene expression to excrete sitosterol (plant sterol) and may be also cholesterol, thus reducing intestinal absorption of dietary cholesterol Yu et al. 2002). Mutations of the ABCG5 and ABCG8 genes have been identified in sitosterolemia patients (Lee et al. 2001; Berge et al. 2000). LXRα plays a major role in protecting against

atherosclerosis and cardiovascular diseases (Tontonoz and Mangelsdorf 2003).