The Cholesterol Sensor LXR

Cholesterol exerts essential physiological functions as an important constituent of cell membranes and as intermediates in crucial biosynthetic pathways such as synthesis of steroid hormones and bile acids. Cholesterol balance is achieved by equilibrium between dietary and biliary cholesterol absorption, cellular de novo synthesis from acetyl coenzyme A, and hepatic catabolism into bile acids. The liver is considered as the principal cholesterol biosynthetic organ, and it produces up to 50% of newly generated cholesterol for export into the bloodstream and for intrahepatic storage as cholesterol esters. However, nearly all cells in the body contain the enzymatic machinery to synthesize cholesterol from acetyl-CoA. Thus, cholesterol is not an essential nutrient (i. e. the body is capable of synthesizing amounts adequate to meet its needs). However, significant amounts of cholesterol are still obtained by dietary intake (varies widely from 0.1 g for individuals on low-cholesterol diets to nearly 1 g on unrestricted diets) [26, 27]. Conversion of cholesterol to bile acids in the liver is the most important pathway for elimination of cholesterol from the body. A dysregulation of the input and output pathways leads to gallstone formation and hyperlipidemia, which may lead to metabolic disorders such as atherosclerosis.

The first report demonstrating the importance of LXRa for maintenance of cholesterol homeostasis came with results from studies using LXRa-deficient mice. Peet et al. [28] demonstrated that LXRa plays a role in the cholesterol elimination process. The LXRa-knockout mice were reported to appear identical to wild-type littermates with regard to morphology, histology, and parameters such as serum and hepatic cholesterol levels and lipoprotein profiles when the animals were fed a standard chow diet (<0.02% cholesterol). However, striking differences between wild-type mice and LXRa-/- mice were observed when fed a diet enriched in cholesterol (2%). The wild-type mice exhibited an increase in liver CYP7A1 mRNA levels of 3- to 6-fold. This change was accompanied by an increased bile acid pool size and subsequent fecal excretion of bile acids. These effects ultimately resulted in an increased bile acid/cholesterol output to maintain body cholesterol homeo-stasis. LXRa-/- mice fail to make these changes in bile acid status and as a consequence these animals accumulate large amounts of liver cholesterol. Interestingly, LXR/5-/-mice maintain their resistance to dietary cholesterol [29], in contrast to LXRa-/- mice where LXR is unable to compensate for the loss of LXR. However, the LXRa//5 double knockout mouse shows a more severe liver phenotype than the LXRa-/- mouse upon cholesterol ingestion [28-30].

Because the process of cholesterol catabolism is liver-specific, other tissues in the body must deal with elevated cholesterol by effluxing the excess cholesterol back into the serum, where it is transported to the liver by reverse cholesterol transport. This process is achieved through a number of membrane ATP-binding cassette (ABC) transporters that deliver cholesterol to high-density lipoproteins (HDLs) which serve as the primary serum transporter of cholesterol back into the liver. This process is especially important in cells like enterocytes and macrophages, since they can be exposed to large levels of sterols due to unsaturable uptake of free cholesterol from diet and serum.

Several recent studies have defined a pathway for cholesterol efflux from lipid-loaded cells. ABCA1 and ABCG1, two members of the ABC family of transporter proteins are highly induced in macrophages loaded with cholesterol [31-33]. In macrophages, activation of the RXR-LXR heterodimer by either naturally occurring oxysterols or RXR/LXR agonists stimulates transcription of ABCA1 and

ABCG1 (Tab. 11.1) [33-36]. ABCA1 is the protein mutated in Tangier disease, a rare autosomal recessive disorder characterized by extremely low circulating levels of HDL, premature coronary heart disease, and accumulation of cholesterol in macrophages [37]. This condition derives from the inability to transfer cholesterol and phospholipid to apolipoprotein acceptors. Expression of ABCA1 is also upreg-ulated by oxidized low-density lipoproteins (oxLDL). Another receptor, peroxisome proliferator activated receptor y (PPARy), is involved in uptake of oxLDL by the scavenger receptor CD36 in macrophages [38]. In addition to lipid uptake, PPARy is also involved in cholesterol efflux. Ligand activation of PPARy by oxLDL leads to primary induction of LXRa and secondary induction of ABCA1 [39]. In contrast to ABCA1, there is much less information on the function of ABCG1. The results of studies with cultured cells treated with antisense oligonucleotides to ABCG1 suggest that this protein may be involved in controlling the efflux of cellular cholesterol to HDL and/or secretion of apoE [32, 40].

ABCA1 is thought to mediate the active efflux of cholesterol and phospholipids to apolipoproteins (apo) acceptors, most importantly apoA1, the major apolipoprotein of HDL [41]. ApoE is also a possible acceptor for effluxing phospholipids and cholesterol. ApoE expression is increased following activation of LXR both in macrophages and in adipocytes (Tab. 11.1) (42, 43). Moreover, the ability of oxysterols and synthetic ligands to regulate apoE expression in adipose tissue and peritoneal macrophages is reduced in LXRa-/- or LXR/-/- mice and abolished in double knockouts. These findings support a central role for LXR signaling pathways in the control of macrophage cholesterol efflux through the coordinate regulation of apoE, ABCA1, and ABCG1 expression (Tab. 11.1). Interestingly, LXR induces the LXRa gene itself in human macrophages (but not murine) by a process that is dependent on a distally localized LXRE (Tab 11.1) [44-46]. OxLDL, oxysterols, and synthetic LXR ligands all induce the expression of LXR mRNA in human monocyte-derived macrophages. Autoregulation of the LXRa gene is suggested to be an important regulator of this lipid-inducible efflux pathway in human macrophages. Along this line, LXRs might prevent the over-accumulation of sterols in the macrophages by the induction of multiple ABC transporters and acceptor proteins involved in this pathway.

In the small intestine increased dietary and/or secreted biliary cholesterol activates LXR as in macrophages and increases transcription of at least three ABC transporters, ABCA1, ABCG5, and ABCG8 [47]. In enterocytes, these transporters are hypothesized to increase cholesterol efflux into the intestinal lumen and thereby prevent net sterol absorption.

Lower Your Cholesterol In Just 33 Days

Lower Your Cholesterol In Just 33 Days

Discover secrets, myths, truths, lies and strategies for dealing effectively with cholesterol, now and forever! Uncover techniques, remedies and alternative for lowering your cholesterol quickly and significantly in just ONE MONTH! Find insights into the screenings, meanings and numbers involved in lowering cholesterol and the implications, consideration it has for your lifestyle and future!

Get My Free Ebook

Post a comment