Minireview: Liver X Receptor β: Emerging Roles in Physiology and Diseases

Abstract

Liver X receptors, LXRα and LXRβ, are nuclear receptors belonging to the large family of transcription factors. After activation by oxysterols, LXRs play a central role in the control of lipid and carbohydrate metabolism as well as inflammation. The role of LXRα has been extensively studied, particularly in the liver and macrophages. In the liver it prevents cholesterol accumulation by increasing bile acid synthesis and secretion into the bile through ATP-binding cassette G5/G8 transporters, whereas in macrophages it increases cholesterol reverse transport. The function of LXRβ is still under investigation with most of the current knowledge coming from the study of phenotypes of LXRβ−/− mice. With these mice new emerging roles for LXRβ have been demonstrated in the pathogenesis of diseases such as amyotrophic lateral sclerosis and chronic pancreatitis. The present review will focus on the abnormalities described so far in LXRβ−/− mice and the insight gained into the possible roles of LXRβ in human diseases.

Studies on the phenotype of LXRβ−/− mice have revealed important roles for LXRβ in controlling not only lipid metabolism but also water transport.

Nuclear receptors are transcription factors that act as intracellular receptors for small biologically active molecules such as lipids and steroid hormones. In contrast to extracellular receptors that bind peptide ligands and activate a cascade of cytoplasmic kinases, nuclear receptors are intracellular, have lipophilic ligands, and directly regulate the expression of target genes by binding to specific DNA sequences (response elements) in the promoters of target genes. Each response element consists of a consensus sequence (AGGTCA) of single or double elements in a direct, everted, or inverted repeat involving binding of nuclear receptors as monomers, homodimers, or heterodimers (1).

Forty-eight members of the nuclear receptor superfamily have been identified in humans. Nuclear receptors share a canonical structure, composed of functionally distinct domains (Fig. 1A): the N-terminal activation function 1 domain, highly variable in sequence and length (2, 3); the very conserved DNA-binding domain (DBD) that contains two zinc fingers, involved not only in DNA binding but also in receptor dimerization (4); and the C-terminal ligand-binding domain (LBD) with a key role in ligand binding, nuclear localization, receptor dimerization, and interaction with coactivators and corepressors (5, 6). Between the DBD and LBD is the hinge domain that provides flexibility between these two domains. Activation function 2 is part of LBD the different conformations of which are dictated by the structure of the ligand bound in the ligand binding pocket and accordingly are recognized by either coactivators or corepressors.

Fig. 1.

A, The canonical structure of nuclear receptors. B, LXR is interacting with corepressors in absence of ligands. C, With ligands, LXR binds to coactivators and promotes the transcription of target genes. AF2, Activation function 2; DR-4, direct repeat 4; RA, retinoic acid.

Over the past 15 yr, thanks to the highly conserved sequence homology of the DBD of nuclear receptors, it has been possible to discover many previously unknown nuclear receptors. Therefore, endocrinology has been fascinatingly reversed (7): the characterization of cloned receptor sequences took place before the identification of natural specific ligands and even before the discovery of any functional role and tissue distribution of many of these nuclear receptors. This reverse endocrinology has, as its final goal, the identification of pharmaceutical compounds that can selectively modulate the activity of nuclear receptors and be a promising treatment for diseases in which nuclear receptors or their target genes are involved.

Liver X Receptors (LXRs)

Liver X receptors, LXRα (nuclear receptor 1H3) and LXRβ (nuclear receptor 1H2), belong to the family of ligand-activated transcription factors with a key role in the control of lipid metabolism and inflammation.

Initially the LXRs were considered orphans because they were cloned on the basis of sequence homology with other receptors, and their ligands were unknown. They have since been adopted by oxygenated cholesterol metabolites that at physiological concentrations are able to bind to and activate these receptors. The most potent ligands for LXRs are 22-hydroxycholesterol, 24(S)-hydroxycholesterol, 24(S), 25-epoxycholesterol, and 27-hydroxycholesterol (8). Recently, high concentrations of d-glucose have been reported to activate LXRs in vitro (9) although the mechanism is still controversial (10). In addition, two nonsteroidal synthetic compounds, GW3965 and T0314407, have been identified as potent and orally active agonists for both LXRs (11, 12). Although subtype-specific ligands have not been synthesized, a subset of natural bile acids has been reported to activate LXRα (13) whereas N-acylthiadiazolines have selectivity for LXRβ but with modest potency (14).

Levels of LXRα mRNA are high in the liver, adipose tissue, adrenal glands, intestine, kidney, macrophages, and lung, whereas LXRβ mRNA is widely distributed throughout the body with high levels in the developing brain (15, 16).

LXRs form obligate heterodimers with retinoid X receptor (RXR) (17). The LXR/RXR complex, which can be activated by ligands of either partner, binds to LXR-responsive elements (LXREs) consisting of direct repeat 4 of the core sequence 5′-AGGTCA-3′ separated by four nucleotides on the promoter of target genes (18). In the absence of ligands (Fig. 1B), LXRs bind to the cognate LXRE in complex with corepressors such as silencing mediator of retinoic acid and thyroid hormone receptor and nuclear receptor corepressor (19, 20). Under these conditions the transcriptional activity of the receptor is suppressed. In the presence of ligands (Fig. 1C), LXR undergoes a conformational change that induces release of corepressors, recruitment of specific coactivators and, subsequently, transcription of target genes (21).

LXR target genes are involved not only in cholesterol, triglyceride, and bile acid metabolism but also in inflammatory response and energy balance. LXRs act as sterol sensors: when the cellular concentration of oxysterols increases, LXR induces the transcription of genes that protect the cell from cholesterol overload.

In the liver, LXR activation promotes cholesterol elimination in two different ways: first, by induction of the expression of cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the classical pathway of bile acid biosynthesis (22); second, by promoting the transcription of genes for ATP-binding cassette transporters, ABCG5 and ABCG8 that transport cholesterol from the hepatocytes to the bile canaliculi (23, 24). At the same time, hepatic LXR activation also increases the synthesis of fatty acids and triglycerides by up-regulating sterol regulatory-binding protein 1c, the key regulator of hepatic lipogenesis (12) and other genes in the pathway such as fatty acid synthase, acyl-coenzyme A carboxylase, and stearoyl-coenzyme A desaturase 1 (25, 26). For this reason, treatment with LXR agonists usually increases hepatic and serum levels of triglycerides, an unwanted side effect for this class of pharmaceuticals.

LXR also offers extrahepatic tissues protection from cholesterol accumulation. Through the control of reverse cholesterol transport in macrophages, LXR ligands induce the expression of ABCA1, ABCG1, and ABCG4 transporters that promote the efflux of cholesterol to high-density lipoproteins (27, 28, 29, 30). In addition LXRs promote the transcription of apolipoproteins (ApoE and ApoC in macrophages and ApoD in adipose tissue) that act as cholesterol acceptors (31, 32, 33). Moreover, LXRs positively regulate lipoprotein lipase, cholesterol ester transfer protein, and the phospholipid transfer protein (34, 35), all of which are involved in lipoprotein remodeling.

In addition to cholesterol and triglyceride metabolism, LXR activation also influences glucose homeostasis. In particular, in the liver, LXR agonists decrease glucose output and increase glucose utilization by inducing glucokinase and repressing phosphoenolpyruvate carboxykinase and glucose 6-phosphatase (36), whereas in white adipose tissue, glucose transporter 4, an insulin-dependent glucose transporter, is induced (37).

In addition to their important physiological roles as antiatherogenic and antidiabetogenic receptors, LXRs are also immunomodulatory. The antiinflammatory action of LXRs is evident from the down-regulation of inducible nitric oxide synthase, COX2, IL6, and IL1β that occurs in LXRα−/−β−/− mice. So far no LXRE has been identified on the promoters of these repressed genes, and the mechanism through which LXRs exert these immunomodulatory effects remains to be elucidated (38).

Studies on Mice Lacking the LXRβ Isoform

A few years after the cloning of LXRs, the identification of oxysterols as LXR activators and the isolation of an LXRE in the promoter of CYP7A1 raised the hypothesis of a key regulatory role of these nuclear receptors in cholesterol homeostasis. Recently, in vivo studies on the phenotype of LXRα−/− and LXRβ−/− mice have not only confirmed this theory, but also demonstrated specific and distinct roles of each isoform in controlling lipid and glucose metabolism, inflammation, and proliferation.

Metabolic phenotype

The most studied phenotype involves metabolic alterations seen during dietary challenge in the three different genotypes: LXRα−/−, LXRβ−/−, and LXRα−/−β−/− mice. On a standard rodent diet (Table 1), LXRα−/−mice differ from wild-type (WT) mice, first in the amount of perigonadal fat, which tends to be reduced with decreased adipocyte size (39), and second, in the serum and hepatic lipid profile. Serum total cholesterol and very low-density lipoproprotein (LDL) triglycerides are in the normal range whereas LDL cholesterol is increased in parallel with a reduction in high-density lipoprotein (HDL) cholesterol (40). Glucose tolerance is the same as in WT mice, as is hepatic cholesterol; triglycerides in the liver are slightly reduced (40). Interestingly, when LXRα−/− mice are fed with a diet containing 2% of cholesterol (Table 1), they are unable to regulate cholesterol catabolism in the liver, where, as a consequence, cholesterol esters accumulate as early as 8 d after the start of feeding (22, 41). WT mice have the capacity to metabolize high concentrations of dietary cholesterol, mainly by increasing the activity of CYP7A1, the rate-limiting enzyme in the classical pathway of bile acid biosynthesis. Excess cholesterol is then eliminated by its conversion to bile acids. This mechanism is missing in LXRα−/− mice so that, even on a standard diet, they exhibit a decreased bile acid pool and a low ratio between cholic acid and muricholic acid (22). Furthermore, during cholesterol feeding of these mice, serum total cholesterol and LDL cholesterol are significantly increased whereas HDL cholesterol is reduced; liver transaminases are higher than in WT mice, but after 90 d they decrease, probably an indication of liver failure.

Table 1.

Metabolic modifications in LXRα−/− mice during dietary challenge

	Standard chow diet							2% Cholesterol
		Sex	Age (months)	Ref.		Sex	Age (months)	Ref.
Body weight	Normal	MF	12	(38 43 )	Unchanged	MF	2–3	(21 )
Perigonadal fat	Reduced	MF	12	(38 43 )	Reduced	MF	2–3	(21 )
Hepatic triglyceride	Tendency to be reduced	–	4	(39 )	Reduced	MF	2–3	(21 )
Hepatic cholesterol	Normal	MF	3–4	(21 39 40 )	Increased	MF	3–4	(21 40 )
Serum cholesterol	Normal	MF	4	(39 40 )	Increased	MF	3–4	(40 )
LDL	Tendency to be increased	–	4	(39 )	Increased	MF	3–4	(40 )
HDL	Tendency to be reduced	–	4	(39 )	–	–	–	–
Very LDL	Normal	–	4	(39 )	–	–	–	–
LDL/HDL ratio	Increased	–	4	(39 )	–	–	–	–
Serum triglycerides	Normal	–	3	(39 )	Tendency to be reduced	MF	3–4	(21 )
Serum glucose	Normal	F	6–9	(38 )	Tendency to be reduced	MF	3–4	(21 )
ALT	Normal	MF	3–4	(40 )	Increased	MF	3–4	(21 40 )
AST	–	–	–	–	Increased	MF	2–3	(21 )
Albumin	–	–	–	–	Normal	MF	2–3	(21 )
BA excretion	Normal	MF	3	(21 )	Reduced	MF	2–3	(21 )
BA pool	Reduced	MF	3	(21 )	Reduced	MF	2–3	(21 )
Ratio CA/MCA	Reduced	MF	3	(21 )	Reduced	MF	2–3	(21 )
Leptin	Normal	F	12	(38 )	–	–	–	–
Adiponectin	Normal	F	12	(38 )	–	–	–	–
Resistin	Normal	F	12	(38 )	–	–	–	–

ALT, Alanine aminotransferase; AST, aspartate aminotransferase; BA, bile acid; CA, cholic acid; F, female; MF, male and female; MCA, muricholic acid.

LXRβ−/− mice, when fed with a standard diet (Table 2), differ from WT mice in terms of a reduction in the amount of perigonadal fat (39), a decrease in hepatic and serum levels of triglycerides (40), and a decrease in serum insulin (39). Surprisingly, on a diet containing 2% cholesterol (Table 2), the response of LXRβ−/− mice is similar to WT mice; in particular, they maintain the physiological capacity to eliminate excess cholesterol by increasing bile acid synthesis. Indeed, in these mice, the expression of enzymes involved in bile acid metabolism (CYP7A1, CYP7B, CYP8B1, CYP27) is not affected (39). Interestingly, in LXRβ−/− mice fed a high-fat diet, body weight and amount of the perigonadal fat pad were lower than in WT mice on the same diet (39). These data together represent compelling evidence that LXRα plays a central role in maintaining cholesterol homeostasis in the liver, whereas LXRβ has a different role in fat metabolism, in particular related to a resistance in gaining weight.

Table 2.

Metabolic modifications in LXRβ−/− mice during dietary challenge

	Standard chow diet							2% Cholesterol							High-fat diet
		Sex	Age (months)	Ref.		Sex	Age (months)	Ref.		Sex	Age (months)	Ref.
Body weight	Normal/reduced	MF	12	(38 43 )	–	–	–	–	Reduced	F	–	(38 )
Perigonadal fat	Reduced	MF	12	(38 43 )	–	–	–	–	Reduced	F	–	(38 )
Food intake	Normal in males/increased in females	MF	6–12	(38 43 )	–	–	–	–	–	–	–	–
O2 consumption	Normal	M	6	(38 )	–	–	–	–	–	–	–	–
Serum insulin	Reduced	MF	6–9	(38 )	–	–	–	–	–	–	–	–
Hepatic triglyceride	Decreased	F	4–12	(38 39 )	–	–	–	–	–	–	–	–
Hepatic cholesterol	Normal	–	4	(39 )	Normal	MF	3–4	(40 )	–	–	–	–
Serum cholesterol	Normal	–	4	(39 )	Normal	MF	3–4	(40 )	–	–	–	–
Serum triglycerides	Tendency to be reduced	–	4–12	(38 39 )	–	–	–	–	–	–	–	–
ALT	Normal	MF	3–4	(40 )	Normal	MF	3–4	(40 )	–	–	–	–
LDL	Normal	–	4	(39 )	–	–	–	–	–	–	–	–
HDL	Normal	–	4	(39 )	–	–	–	–	–	–	–	–
VLDL	Tendency to be reduced	–	4	(39 )	–	–	–	–	–	–	–	–
Leptin	Normal	F	12	(38 )	–	–	–	–	–	–	–	–
Adiponectin	Normal	F	12	(38 )	–	–	–	–	–	–	–	–
Resistin	Normal	F	12	(38 )	–	–	–	–	–	–	–	–

ALT, Alanine aminotransferase; F, female; MF, male and female.

The lack of LXRβ is responsible for the lean phenotype observed in LXRα−/−β−/− mice. On a standard diet the body weight of these mice is reduced as is the size of the perigonadal fat pad and adipocytes (39, 42, 43). Triglycerides are reduced both in liver and serum as in LXRβ−/− mice whereas, as in LXRα−/− mice, total cholesterol and LDL cholesterol are increased, HDL cholesterol is decreased in serum, and hepatic cholesterol is increased. Interestingly, LXRα−/−β−/− mice are also resistant to obesity when fed a Western diet containing 0.2% cholesterol, but they gain weight when only fed a high-fat diet (39).

Pancreatic phenotype

We have investigated the mechanism behind the resistance of LXRβ−/− mice to gain weight and found a malabsorption syndrome due to chronic pancreatitis (44) with the following abnormalities: serum levels of α-amylase and lipase and fecal levels of proteases are drastically reduced; pancreatic ducts are invaded by immune infiltrations, and epithelial cells have a high rate of cell death; and intralobular pancreatic ducts are filled with dense secretion with laminar structures typical of cystic fibrosis. Interestingly, both mRNA and protein expression of aquaporin-1 (AQP-1), a water channel transporting water into the pancreatic lumen, are markedly reduced in LXRβ−/− mice. To determine whether LXR is directly involved in the regulation of pancreatic AQP-1 expression, we treated WT mice with the LXR agonist, TO2030. We found a significant increase in AQP-1 in the pancreatic ductal epithelium indicating a very interesting new role of LXRβ in controlling water transport.

Neurological phenotype

Given that LXRβ−/− mice maintain their capacity to metabolize dietary cholesterol in the liver, the function of LXRβ has been studied in other organs in which cholesterol plays a physiological key role, especially the central nervous system.

Male LXRβ−/− mice at 7 months of age develop a motor impairment, measured as a reduced ability, compared with WT littermates, to stay on a rotor rod. Learning ability and muscle strength are not affected. Histopathological analysis of LXRβ−/− spinal cords revealed a loss of large α motor neurons in the lateroventral horn and, in the few motor neurons left, there were cytoplasmic lipid accumulations and protein aggregates which stained positive for TDP-43 and ubiquitin (45). The number of astrocytes was increased, and an axonal atrophy was detectable (46). These features, evident only in male mice, are typical of the chronic motor neuron disease amyotrophic lateral sclerosis (ALS). In LXRβ−/− mice, accumulation of lipids in motor neurons could be due to a decrease in the expression of transporters such as ABCG5, ABCG8, and ABCA1 and could lead to motor neuron degeneration. Interestingly, in the spinal cord of patients affected by ALS, high levels of sphingomyelin, ceramides, and cholesterol esters have been demonstrated (47). Moreover, mice carrying a Cu/Zn superoxide dismutase 1 mutation, considered to be an animal model of ALS, show accumulation of phytosterols in the spinal cord (47). Plant sterols are transported back to the intestinal lumen by ABCG5 and ABCG8 transporters, and mice lacking these transporters accumulate plant sterols in the brain (48).

In LXRα−/−β−/− mice, as expected, there is a down-regulation of ABCG5 and ABCG8 transporters. This is accompanied by lipid overload in the brain particularly in the choroid plexus with the result that the lateral ventricles are obliterated by lipid-laden cells. There is also proliferation of astrocytes, loss of neurons, and disorganized myelin sheaths (49).

Interestingly, in the population of Guam, when the diet was based on Cycas micronesica, a vegetable rich in β-sitosterol, there was a very high incidence of ALS associated with Parkinson′s dementia (PDC). Feeding of monkeys with up to 2 g of cycad flour does not lead to any neurological disease (50). Thus it is thought that the indigenous Guam population has a genetic predisposition that renders them susceptible to the toxic effects of cycad flour. Our studies (45) suggest that LXRβ could be a genetic factor involved in PDC pathogenesis: LXRβ−/− mice fed β-sitosterol for 3 wk develop a phenotype that resembles PDC. In the spinal cord, there is a drastic reduction in the number of motor neurons whereas in the substantia nigra, dopaminergic neurons were shrunken with reduced numbers of projections, and there was an increase in the number of activated microglia in the pars reticulata.

In regard to cerebral phenotype, histopathological data on LXRβ−/− brain are not yet available, but low mRNA levels of ABCG1 and ABCA1 have been demonstrated (51). Interestingly, after experimental ischemic stroke in mice lacking LXRβ, there was a wider ischemic area (52), and administration of an LXR agonist decreased the volume of the infarct in wild type, but not in LXRβ−/−, mice (52).

Embryonic phenotype

Studies from our own laboratory have demonstrated that LXRβ has an important role in the development of the cerebral cortex. At late stage of embryogenesis (embryonic d 18.5) and in neonates (postnatal d 2), brains of LXRβ−/− mice are smaller than those of WT littermates with a reduction in the number of neurons in the superficial cortical layers. During development, neurons migrate from lower layers to superficial layers. After birth (postnatal d 2), in LXRβ−/− mice the number of neurons is higher in lower cortical layers (IV) whereas in WT mice more neurons are in the upper layer (II–III) indicating that in the absence of LXRβ there is a migration defect (53).

Reproductive phenotype

During pregnancy, cholesterol plays an important role in modulating membrane activity and stability of oxytocin receptor (54). When activated by its specific hormone, oxytocin, this receptor induces contractile activity in the myometrium during labor. A balanced cholesterol distribution in uterus has a central role in contractile function: depletion increases abnormal contraction of uterine smooth muscle cells in vitro, whereas cholesterol accumulation in myometrium reduces the amplitude of contractions during labor (55). In LXRβ−/− mice, there is a high accumulation of cholesterol esters in longitudinal and circular layers of myometrium, probably due to a reduction in the expression of transporters, ABCA1 and ABCG1, which regulate cholesterol efflux and are under the control of LXRβ. As a consequence, uteri of LXRβ−/− mice have an impaired contractile function in response to oxytocin or prostaglandin F2α stimulation, and these mice show several signs of fetal resorption in the uterine horns, unexpulsed pups, or death during delivery (56). Interestingly, this role of LXRβ in cholesterol modulation in uterus seems very specific because LXRα−/− mice do not exhibit any uterine abnormalities (56). Moreover, ovarian function is impaired in LXRα−/−β−/− mice; in particular, oocytes lacking both LXRs fail to resume meiosis after FSH stimulation (57).

LXRβ also controls cholesterol balance in the male reproductive tract: in the testis of LXRβ−/− mice, there is an accumulation of cholesterol as early as at 2.5 months of age in Sertoli cells that provide structural and nutritional support to germ cells (58). There is also a lower proliferation rate of germ cells (59). Furthermore, although Leydig cells are not affected by lipid accumulation in LXRβ−/− mice, the secretion rate of testosterone is markedly reduced in LXRα−/−β−/− mice. No structural or functional alterations are detectable in testis from LXRα−/− mice, indicating a dominant role of LXRβ. In addition, the epithelial structure in the epididymis is affected in LXRα−/−β −/− mice but not in single-mutant mice. This defect results in sperm head fragility (60).

All the described alterations, both in the female and male reproductive tract, may together be responsible for the reduced fertility and decreased number of pups per litter, described in LXRβ−/− mice and LXRα−/−β−/− mice (57). Furthermore, LXRα−/−β−/− mice become completely infertile by 4–5 months of age (58, 59), indicating a more severe phenotype in mice lacking both isoforms.

Immunological phenotype

By the age of 5–6 months, in LXRβ−/− mice there is splenomegaly and lymphoadenopathy with expansion of total number of T and B lymphocytes. A prevalence of B lymphocytes was noticed only in lymph nodes. Moreover, LXRβ−/− T lymphocytes respond to T cell receptor stimulation with a higher proliferative rate than T lymphocytes from LXRα−/− and WT mice (61). Conversely, in WT mouse T lymphocytes in cell culture (but not in LXRβ−/− T lymphocytes), proliferation is inhibited when LXR synthetic agonist, RXR agonist or 22(R)-hydroxycholesterol are added to the culture medium (61). In activated LXRβ−/− T lymphocytes in cell culture, the proliferation rate is higher that that of WT mouse T cells with an increased fraction of cells in S and G₂, M phase (61).

Cardiovascular phenotype

There are abnormalities in the vascular system in LXRα−/−β−/− mice that are most likely due to a combination of both the increase in LDL-cholesterol and of the down-regulation of genes involved in reverse cholesterol transport (ABCG1, ABCA1). In LXRα−/−β−/− mice there is accumulation of foam cells with a significant increase in lipid infiltration all around the intima-media layer in the aortic root. Accumulation of lipid in the aorta is less pronounced in single-mutant mice (40). Except for a report that there is lack of neutral lipid accumulation in cardiac myocytes (56), there is no published information about the cardiac phenotype of LXRβ−/− mice. Interestingly, LXRβ activation in LXRα−/−ApoE−/− mice reduces plasma cholesterol and atherosclerosis (62).

Moreover, LXRβ binds to the promoter of renin, and LXR agonist treatment leads to an up-regulation of renin mRNA in kidney (63). Thus it is anticipated that LXRβ mice might be hypotensive, but, so far, no studies on blood pressure in these mice have been published.

Dermatological phenotype

Oxysterols, ligands for LXRs, stimulate keratinocyte differentiation by increasing the expression of epidermal differentiation markers such as involucrin, filaggrin, and loricrin, in WT and LXRα−/− mice but not in LXRβ−/−mice (64, 59). The epidermis of LXRβ−/− mice is thinner with a reduced number of proliferating cell nuclear antigen-positive cells in the basal layer and a slightly decreased expression of differentiation markers. However, in these mice, no macroscopic cutaneous abnormalities or functional impairments are detectable, indicating that LXRβ−/− mice use some compensatory pathways to overcome the consequences of the lack of keratinocyte differentiation (64).

Bone phenotype

LXRβ−/− female mice exhibit increased levels of alkaline phosphatase and osteocalcin in serum, probably indicating an increased osteoblast activity. In addition, the volume of osteoclasts in the trabecular compartment is lower that that in WT mice (65). However, no particular alterations have been detected in the cortical or in the trabecular compartment of the femurs of these mice.

LXRβ Genetics in Human Diseases

The role of genetic mutations or gene polymorphisms of LXRs in human diseases corresponding to the phenotypes described in the transgenic animals is almost completely unexplored; at the moment only three such studies have been published.

According to the database of National Center for Biotechnology Information, four single-nucleotide polymorphisms (SNPs) of LXRβ (chromosome 19) have been identified: LXR1 in intron 5, LXR2 in intron 7, LXR3 in the 3′-untranslated region, and LXR4 in intron 2. An association between the risk of developing late-onset (age at onset after 60 yr) Alzheimer disease and LXR2 and LXR4 has been shown in an American population of 931 Alzheimer disease patients (66). Although LXR2 seems to be a silent SNP, LXR4 is likely to be functional, residing in either a coding region or in a splicing junction. Moreover, this association has been confirmed also in a Spanish population of 414 Alzheimer disease patients. In this study there was an increased risk if these SNPs (LXR2, LXR4, LXR1) are associated with a SNP in heme-oxygenase-1 (413 TT) (67).

The third study involves a Swedish population of 559 obese patients. This study revealed that one LXRα (rs2279238) and two LXRβ SNPs (LB44732G>A and rs2695121), in the promoter region and in intron 2, are associated with obesity (68).

More studies are required to confirm that these SNPs have a functional role in the susceptibility of Alzheimer disease and obesity.

Conclusions

Studies on the phenotype of LXRβ−/− mice have revealed important roles for LXRβ in controlling lipid metabolism in the central nervous system, in particular in the spinal cord where its deficiency causes lipid accumulation and death of motor neurons leading to a picture resembling ALS. Studies in humans are strongly encouraged to identify possible genetic mutations that could work in concert with environmental factors, such as high phytosterol intake, in the pathogenesis of ALS.

Our studies have revealed that, in addition to lipid metabolism, LXRβ also controls water transport in pancreatic tissue. LXRβ deficiency leads to a down-regulation of AQP-1 and as a consequence, there is dense pancreatic secretion containing laminar structures typically seen in cystic fibrosis. In this perspective, LXRβ could be considered as a water transport regulator and a promising target in the treatment of disease associated with a dysregulation of the fluid balance such as in pancreatic insufficiency or cystic fibrosis.

Table 3.

Metabolic modifications in LXRα−/−β−/− mice during dietary challenge

	Standard chow diet							Western diet + CH							Western diet no CH
		Sex	Age (m)	Ref		Sex	Age (m)	Ref		Sex	Age (m)	Ref
Body weight	Reduced	MF	4–5–12	(41 43 )	Reduced	M	4–5	(42 )	Unchanged	M	4–5	(42 )
Perigonadal fat	Reduced	MF	12–18	(38 41 43 )	–	–	–	–	–	–	–	–
Food intake	normal	MF	12	(43 )	Unchanged	M	4–5	(42 )	Unchanged	M	4–5	(42 )
Fat absorption	Reduced	M	4–5	(42 )	Unchanged	M	4–5	(42 )	Unchanged	m	4–5	(42 )
Serum insulin	Reduced	M	4–5	(42 )	Tendency to be reduced	M	4–5	(42 )	–	–	–	–
Hepatic Triglyceride	Reduced	–	4	(39 )	Reduced	M	4–5	(42 )	–	–	–	–
Hepatic Cholesterol	Increased	–	4	(39 )	Increased	M	4–5	(42 )	–	–	–	–
Serum cholesterol	Normal	–	4	(39 )	Tendency to be reduced	M	4–5	(42 )	–	–	–	–
LDL	Incresed	–	4	(39 )	Increased	M	4–5	(42 )	–	–	–	–
HDL	tendency to be reduced	–	4	(39 )	–	–	–	–	–	–	–	–
LDL/HDL ratio	Increased	–	4	(39 )	–	–	–	–	–	–	–	–
Serum Triglycerides	Reduced	–	4	(39 )	Reduced	M	4–5	(42 )	–	–	–	–
TSH	Normal	M	4–5	(42 )	–	–	–	–	–	–	–	–
T3	Normal	M	4–5	(42 )	–	–	–	–	–	–	–	–
T4	Normal	M	4–5	(42 )	–	–	–	–	–	–	–	–
Leptin	Normal / lower	F	12	(3842 )	Tendency to be reduced	M	4–5	(42 )	–	–	–	–
Adiponectin	Reduced	F	12	(38 )	–	–	–	–	–	–	–	–
Resistin	normal	F	12	(38 )	–	–	–	–	–	–	–	–

NURSA Molecule Pages:

• Ligands: 22α-Hydroxycholesterol | 24(S) | GW 3965;

• Nuclear Receptors: LXRα | LXRβ.