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Diabetes 53:S36-S42, 2004
© 2004 by the American Diabetes Association, Inc.

Section II: Nuclear Receptors and Islet Function

Putative Metabolic Effects of the Liver X Receptor (LXR)

Knut R. Steffensen, and Jan-Åke Gustafsson

From the Department of Medical Nutrition and Biosciences, Karolinska Institutet, Huddinge, Sweden


   ABSTRACT
TOP
 ABSTRACT
LXR IN CHOLESTEROL AND...
 LXR IN CARBOHYDRATE METABOLISM
 OTHER METABOLIC EFFECTS OF...
 INFLAMMATORY RESPONSE AND LXR
 SIGNAL TRANSDUCTION AND LXR
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
The nuclear receptors liver X receptor (LXR){alpha} and LXRß are sensors of cholesterol metabolism and lipid biosynthesis. They have recently been found to be regulators of inflammatory cytokines, suppressors of hepatic glucose production, and involved in different cell-signaling pathways. LXR{alpha} is a target gene of the peroxisome proliferator-activated receptor-{gamma}, a target of drugs used in treating elevated levels of glucose seen in diabetes. Furthermore, insulin induces LXR{alpha} in hepatocytes, resulting in increased expression of lipogenic enzymes and suppression of key enzymes in gluconeogenesis, including PEPCK. LXR seems to have an important role in the regulation of glucocorticoid action and a role in the overall energy homeostasis suggested by its putative regulatory effect on leptin and uncoupling protein 1. The physiological roles of LXR indicate that it is an interesting potential target for drug treatment of diabetes.

Type 2 diabetes accounts for >90% of the cases of diabetes and is caused by defective insulin secretion and insulin resistance. Type 2 diabetes is often of polygenic origin, but the molecular defects are still not fully known. However, the genetic background of maturity-onset type diabetes of the young is known.

A class of nuclear receptors has recently become the focus for its important role in cholesterol, lipid, and carbohydrate metabolism, namely the liver X receptor (LXR). A number of recent studies have shown that LXR is a key player in these biological functions. The main target tissues for LXR action are liver and adipose tissue, where its function has been carefully studied, but LXR has recently been suggested to be involved in lipid and carbohydrate metabolism in muscle as well. Important target tissues of insulin action are also liver, muscle, and adipose tissue, where insulin stimulates the uptake of excess glucose from blood and inhibits hepatic glucose production. A salient feature of type 2 diabetes is insulin resistance in these tissues, which leads to hyperglycemia and hyperlipidemia, both pathological conditions where, based on recent studies, LXR may be a key player. The LXR subfamily consists of two members, LXR{alpha} and LXRß, which are activated by oxysterols. Whereas LXRß is ubiquitously expressed, high expression of LXR{alpha} is restricted to liver, adipose tissue, small intestine, and macrophages. LXR target genes have been shown to be involved in lipid and cholesterol metabolism, glucose homeostasis, and inflammatory response (Table 1). This review will focus on physiological roles of LXR and highlight why LXR could be an important potential target for drug treatment of lipid and carbohydrate disorders.


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  		TABLE 1 LXR target genes

 

   LXR IN CHOLESTEROL AND LIPID METABOLISM
TOP
 ABSTRACT
 LXR IN CHOLESTEROL AND...
LXR IN CARBOHYDRATE METABOLISM
 OTHER METABOLIC EFFECTS OF...
 INFLAMMATORY RESPONSE AND LXR
 SIGNAL TRANSDUCTION AND LXR
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
The phenotypes of LXR knockout mice generated in our laboratory and by Mangelsdorf and colleagues have shown that LXR is important for cholesterol and lipid metabolism (1,2). These were the first of many articles reporting LXR as a sensor for metabolites of lipid and cholesterol metabolism. Thus, Mangelsdorf and colleagues reported impaired expression of hepatic genes involved in cholesterol and fatty acid metabolism, such as cholesterol 7{alpha}-hydroxylase, hydroxymethyl glutaryl (HMG)-CoA synthase/reductase, farnesyl diphosphate synthase, squalene synthase, sterol response element-binding protein (SREBP), stearoyl CoA desaturase (SCD)-1, and fatty acid synthase in LXR{alpha}-/- knockout mice. Our study showed a similar phenotype in LXR{alpha}-/- knockout mice. In addition, we investigated the LXRß-/- knockout mice as well, but these mice failed to show the phenotype observed in LXR{alpha}-/- knockout mice. This suggests a more prominent role of LXR{alpha} than LXRß as a regulator of these enzymes. Several of these genes have been shown to be under direct transcriptional control of LXR by its cognate response element in their respective promoters (Table 1). Of particular interest is the regulation of SCD-1. Recent experiments in our group have shown that both SCD-1 and SCD-2 are highly induced in several tissues upon feeding of mice with an LXR agonist (36; K.R.S., S.Y. Neo, T.M. Stulnig, V.B. Vega, S.S. Rahman, G. Schuster, J.-Å.G., and E.T. Liu, unpublished data). SCD is the rate-limiting enzyme in the cellular synthesis of monounsaturated fatty acids from saturated fatty acids—an important step in the generation of triglycerides for transport and storage as well as maintaining cellular membrane fluidity. Altered SCD activity has been linked to several diseases including cardiovascular disease and obesity. Increased SCD activity in liver generates monounsaturated fatty acids, leading to synthesis of triglycerides and esterification of cholesterol for transport out of the liver. It is suggested that this increase in plasma lipids leads to cardiovascular disease. Obese hyperglycemic mice (ob/ob mice) were shown to have an elevated activity of SCD and, in addition, higher depositions of body fat than their lean counterparts. In type 2 diabetes, SCD activity is increased, probably in response to increased levels of insulin (3). SCD might therefore contribute to the hyperlipidemia seen in type 2 diabetes. A causal relationship between SCD activity and the various diseases is still unclear, but these results suggest that the LXRs could be involved in diseases caused by altered SCD activity.

Nebb and colleagues showed that LXR{alpha} expression, but not LXRß expression, was induced by fatty acids in rat hepatoma cells and primary rat hepatocytes (4). A mechanistic explanation for this observation was given when peroxisome proliferator-activated receptor (PPAR) was shown to induce LXR{alpha} expression (5). In this study, Chawla et al. showed that cholesterol efflux from macrophages due to PPAR-{gamma} activation was mediated by LXR{alpha}, and investigation of the LXR{alpha} promoter revealed a response element for PPAR. Furthermore, they showed that LXR induced expression of a transmembrane transporter, ABCA1—one of several ABC transporters later found to be regulated by LXR (6–10), which mediates cholesterol efflux from cells. This LXR-mediated cholesterol efflux from peripheral tissues, termed "reverse cholesterol transport," also involves apolipoproteins, another class of proteins regulated by LXR (11,12). These studies indicate that LXR{alpha} can mediate effects of PPAR-{gamma}, a target for drug therapy in diabetes because of its hypoglycemic effects.

The pivotal role of LXR in lipid biosynthesis was established when Mangelsdorf and colleagues (13) and others (14) found that LXR induces SREBP1c expression via an LXR response element in its promoter. SREBP1c in turn induces lipogenic enzymes, thereby promoting lipid biosynthesis. Several LXR target genes such as SCD and SREBP1c are regulated by insulin signaling as well (Fig. 1), and in a collaborative effort with Nebb and colleagues, we showed that LXR{alpha} expression was induced by insulin in hepatocytes (15). This finding led us to believe that LXR is a mediator of insulin action and suggested novel biological functions for LXR. SREBP1c has a distinct function in mediating insulin signaling, where it stimulates expression of several enzymes involved in lipogenesis, such as fatty acid synthase and acetyl CoA carboxylase. Both fatty acid synthase (16) and acetyl CoA carboxylase (17) are direct as well as indirect targets of LXR (Fig. 1). A recent report also showed that overexpression of SREBP1c in ß-cells of the islets of the pancreas leads to lipid accumulation and eventually apoptosis of these cells, a known feature of diabetes (18). This finding suggests an important role of LXR in the biosynthesis of lipids and lipid accumulation, where LXR might mediate some of the effects of insulin on SREBP1c.



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  		FIG. 1. Interplay of metabolic effects of insulin and LXR. The green areas indicate LXR target genes, blue arrows indicate activating effect, and the red arrow indicates inhibitory effects. Activation of LXR leads to increased glucose uptake in muscle and adipose tissue via the GLUT transporters. In liver and adipose tissue, LXR promotes lipid biosynthesis by inducing expression of lipogeneic enzymes. Furthermore, LXR suppresses gluconeogenesis in the liver by inhibiting vital gluconeogenetic enzymes. These are also known effects of insulin. Insulin induces expression of LXR{alpha}, indicating a pivotal role of LXR as a mediator of insulin signaling. Insulin exerts its effect via the insulin receptor that becomes autophosphorylated and further phosphorylates the insulin receptor substrates. This leads to activation of several downstream signaling pathways including phosphatidylinositol 3-kinase, pyruvate dehydrogenase kinase, protein kinase B, and variants of protein kinase C. The molecular mechanism behind the induction of LXR{alpha} by insulin is still unknown. Knowing what part of the insulin-signaling pathway induces LXR{alpha} expression would help to better understand the interplay between insulin and LXR on lipid and carbohydrate metabolism. ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; Fbp1, fructose biphosphatase 1; G6Pase, glucose-6-phosphatase.

 
Detailed studies within our group have been performed to elucidate the physiological relevance of LXR in lipid metabolism and to characterize lipid profiles in LXR-deleted mice (19). We found an increase in LDL cholesterol content and a decrease in HDL cholesterol content in LXR{alpha}-/- and LXR{alpha}-/-ß-/-, but not LXRß-/-, mice and a decrease in triglyceride levels in serum and VLDL in LXR{alpha}-/-ß-/-, but not LXR{alpha}-/- or LXRß-/-, mice. We did not observe any changes in serum cholesterol levels. Similar findings have also been reported by others (20). Interestingly, LXR was found to upregulate angiopoietin-like protein 3 (Angptl3), a member of the family of vascular endothelial growth factors that is also a key regulator of lipid metabolism (21). The KK/San mouse strain has low levels of plasma triglycerides, total cholesterol, and nonesterified fatty acids because of a mutation in the Angptl3 gene. A study in this mice strain showed that overexpression of Angptl3 leads to increased circulating level of plasma cholesterol triglycerides and nonesterified fatty acids (22). This finding speaks in favor of a novel mechanism for LXR in regulation of lipid homeostasis. No studies have fully addressed the functional role of LXR in skeletal muscle, another main target organ of insulin signaling. However, expression of both LXR{alpha} and LXRß has been detected in quadriceps from mice, and it was shown that treatment of a myoblast cell line (C2C12) with an LXR agonist induced genes involved in lipid and cholesterol metabolism (23).

In summary, LXR induces reverse cholesterol transport from peripheral tissue to liver via HDL by stimulating the production of apolipoproteins and ABC transporters, a positive effect of LXR in terms of counteracting atherosclerosis. LXR, however, also induces fatty acid production and serum triglycerides by stimulating expression of SREBP1c and Angptl3, leading to an increased risk of developing metabolic diseases such as type 2 diabetes.


   LXR IN CARBOHYDRATE METABOLISM
TOP
 ABSTRACT
 LXR IN CHOLESTEROL AND...
 LXR IN CARBOHYDRATE METABOLISM
OTHER METABOLIC EFFECTS OF...
 INFLAMMATORY RESPONSE AND LXR
 SIGNAL TRANSDUCTION AND LXR
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
Although the first reports about LXR placed the nuclear receptor as a sensor of cholesterol and lipid metabolism, new data indicate another physiological function of LXR. Published and ongoing studies in our laboratory indicate that LXR is a key regulator of carbohydrate metabolism. In two articles by Stulnig et al. (24,25), we report that feeding mice an LXR agonist significantly inhibits expression of gluconeogenic enzymes. In liver, treatment of an LXR agonist significantly inhibits expression of gluconeogenetic enzymes such as PEPCK, the rate-limiting enzyme in gluconeogenesis, fructose biphosphatase 1, and glucose-6-phosphatase (24,25). A study by Cao et al. (26) supports our findings; they treated diabetic rodents with an LXR agonist and showed a dramatic reduction of plasma glucose. Furthermore, they showed that an LXR agonist increased insulin sensitivity in insulin-resistant Zucker rats and that gluconeogenic genes were suppressed, leading to decreased hepatic glucose output.

MacDougald and colleagues showed that LXR{alpha} increased basal uptake of glucose in adipocytes (27). This is mediated mainly through the GLUT1 transporter, and an LXR agonist was shown to induce expression of GLUT1 mRNA as well as protein levels. We have also reported increased expression of GLUT4 mRNA in white adipose tissue (WAT) in response to an LXR agonist (24). GLUT4 expression is known to be highly upregulated in response to insulin in adipose tissue. Our findings suggest that this increase in GLUT4 expression might, at least partially, be mediated by LXR. Furthermore, MacDougald and colleagues showed that activation of ectopically expressed LXR{alpha} in adipocytes resulted in increased synthesis of glycogen and cholesterol in adipose tissue and elevated levels of glycerol and nonesterified fatty acids in serum. The authors suggest that LXR is involved in lipolysis in adipocytes as well as in several aspects of carbohydrate metabolism by stimulating glucose uptake and glycogen synthesis.

We have also found the LXR agonist to inhibit expression of enzymes involved in glycolysis. In WAT and brown adipose tissue, enzymes promoting glycolysis, including 6-phosphofructo-2-kinase 3, were suppressed. This enzyme is the most potent activator of 6-phosphofructo-1 kinase, the rate-limiting enzyme in glycolysis. Pyruvate dehydrogenase kinase 4, a negative regulator of glycolysis, was induced by an LXR agonist. Inhibition of glycolytic enzymes is also seen in other tissues (K.R.S., S.Y. Neo, T.M. Stulnig, V.G. Vega, S.S. Rahman, G. Schuster, J.-Å.G., and E.T. Liu, unpublished data). Additional studies are needed to elucidate this effect, and a careful study of LXR action on glycolytic enzymes in muscle would provide vital information about the physiological relevance of the observed regulatory effects on these enzymes.

While the effect of LXR on glycolysis needs further investigation, these results show that treatment of LXR agonists in mice leads to decreased plasma glucose levels and decreased hepatic glucose production by inhibiting key enzymes that promote gluconeogenesis.


   OTHER METABOLIC EFFECTS OF LXR
TOP
 ABSTRACT
 LXR IN CHOLESTEROL AND...
 LXR IN CARBOHYDRATE METABOLISM
 OTHER METABOLIC EFFECTS OF...
INFLAMMATORY RESPONSE AND LXR
 SIGNAL TRANSDUCTION AND LXR
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
Many health problems in the Western world have been linked to obesity. Leptin is part of a biological mechanism that controls the nutritional status of the body. Although the effect of leptin is mostly studied in rodents, it is suggested that impaired function of this hormone, or lack of response to the hormone, results in obesity in humans as well (28). Obesity also occurs when energy intake exceeds energy expenditure or when energy balance is impaired in other ways. The uncoupling proteins (UCPs) represent a class of proteins that is involved in energy expenditure (29). They use the proton gradient generated by the electron transport chain to transport protons across the mitochondrial membrane to generate heat. Energy is thereby used to produce heat instead of generation of ATP. Recent reports connect LXR to both control of nutritional status and energy metabolism, where studies within our group have identified both leptin and UCP-1 as target genes of LXR (Fig. 2). Leptin expression was downregulated in WAT in mice fed an LXR agonist (24). The same study, as well as unpublished data (K.R.S., S.Y. Neo, T.M. Stulnig, V.B. Vega, S.S. Rahman, G. Schuster, J.-Å.G., and E.T. Liu), also showed a drastic downregulation of UCP-1 expression after administration of an LXR agonist. Decreased leptin levels would eventually lead to increased energy intake, and decreased UCP-1 leads to decreased energy expenditure—both unwanted effects in terms of developing obesity. Although careful investigations are needed to elucidate these findings, this suggests a putative role of LXR in several aspects of metabolism.



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  		FIG. 2. Metabolic effects of LXR. The figure shows a simplified model of potential regulatory mechanisms of LXR. See text for details. Blue arrows indicate stimulatory effects, whereas red arrows indicate inhibitory effects. LXR induces lipogenesis and inhibits hepatic gluconeogenesis. LXR reduces leptin expression in adipocytes, promoting increased energy uptake, and suppresses glucocorticoid action by inhibiting 11ß-HSD1 expression. The downregulation of UCP-1 expression seen by LXR probably leads to lower production of heat in the mitochondria. FFA, free fatty acid; TG, triglycerides.

 
Increased visceral adipose deposit increases the release of free fatty acids, and lipolysis is further enhanced by norepinephrine and glucocorticoids. Chronically high levels of free fatty acids eventually lead to increased hepatic gluconeogenesis and insulin resistance in liver, adipose tissue, and skeletal muscle. In particular, a visceral deposit of adipose tissue is associated with developing type 2 diabetes (30). Although the role of glucocorticoids in obesity is poorly understood, several findings suggest that they are important in this context. In Cushing’s syndrome, elevated production of glucocorticoids and activation of the glucocorticoid receptor results in insulin resistance and obesity. In addition, glucocorticoid receptor antagonists have been shown to prevent obesity in rodents (31). 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is an enzyme that reactivates inactive glucocorticoids (cortisone) to active glucocorticoids (cortisol) in humans. Enhanced 11ß-HSD1 activity has been reported to promote obesity (32), and inhibition of this activity in liver improved the lipid profile in Zucker obese rats (33). The activity of the enzyme in adipose tissue has also been suggested to affect glucose uptake in adipocytes.

Studies within our group have shown that both a synthetic and a natural LXR agonist decreased 11ß-HSD1 mRNA expression and activity by 50% in adipocytes generated from the 3T3-L1 cell line as well as in primary adipocytes in culture (25). The inhibitory effect depended on ongoing protein synthesis. That suggests an indirect effect of LXR on 11ß-HSD1 expression, probably by stimulating expression of an inhibitor or by inhibiting expression of an activator of 11ß-HSD1. Moreover, long-term treatment of mice with a synthetic LXR agonist downregulated 11ß-HSD1 mRNA expression in both brown adipose tissue and liver of wild-type mice but not in LXR{alpha}-/-ß-/- mice. The inhibition of 11ß-HSD1 indicates that LXR might be involved in suppressing glucocorticoid effects, which might lead to reduced development of obesity and improved insulin sensitivity linked with glucocorticoid activity. Furthermore, LXR could decrease gluconeogenesis in liver by a direct inhibitory effect on PEPCK expression, as previously described, and indirectly by inhibiting glucocorticoid stimulatory effects on PEPCK expression. Taken together, these findings indicate a possible role of LXR in the hormonal regulation of overall energy metabolism (Fig. 2).


   INFLAMMATORY RESPONSE AND LXR
TOP
 ABSTRACT
 LXR IN CHOLESTEROL AND...
 LXR IN CARBOHYDRATE METABOLISM
 OTHER METABOLIC EFFECTS OF...
 INFLAMMATORY RESPONSE AND LXR
SIGNAL TRANSDUCTION AND LXR
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
Type 1 diabetes is an autoimmune disease where proinflammatory cytokines including {gamma}-interferon, tumor necrosis factor (TNF)-{alpha}, and interleukin (IL)-4 play important roles. Inflammatory responses, particularly by TNF-{alpha}, have been linked to increased insulin resistance, and several studies in rodent models have revealed that manipulation of the cytokine network can delay or prevent diabetes. There are also indications that chronic inflammation leads to a condition of insulin insensitivity where TNF-{alpha} has a central role of mediating insulin resistance (34,35). Mechanistically, it has been suggested that TNF-{alpha} may downregulate genes required for insulin action. Recently, two articles were published linking LXR to inflammatory responses. Fowler et al. (54) showed that LXR had anti-inflammatory effects in contact dermatitis models in rodents. Using immunohistochemistry on the LXR-treated foci of the skin, they showed that LXR inhibits production of TNF-{alpha} and IL-1{alpha}. Landis et al. (36) have shown that an LXR agonist induced TNF-{alpha} in macrophages and primary monocytes so the effect of LXR on TNF-{alpha} is not fully understood yet. In a transcriptional profiling study of lipopolysaccharide-induced macrophages carried out by Joseph et al. (37), an LXR-dependent downregulation of the expression of inflammatory mediators such as cyclooxygenase-2, inducible nitric oxide synthase, and IL-6 was demonstrated, suggesting a link between lipid metabolism and inflammation mediated by LXR. Furthermore, obesity may induce a cycle of inflammation leading to increased insulin insensitivity via adipocyte-derived TNF-{alpha}. Thus, LXR may work as a key player in responses to inflammation, and because it has been shown to be important in lipid metabolism, LXR might be involved in obesity-induced inflammatory responses as well.


   SIGNAL TRANSDUCTION AND LXR
TOP
 ABSTRACT
 LXR IN CHOLESTEROL AND...
 LXR IN CARBOHYDRATE METABOLISM
 OTHER METABOLIC EFFECTS OF...
 INFLAMMATORY RESPONSE AND LXR
 SIGNAL TRANSDUCTION AND LXR
CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
The involvement in various signaling pathways seems to be yet another novel function of LXR. Dexras1, the murine homolog of human activator of G-protein signaling, is involved in nitric oxide signaling and has been linked to the pathogenesis of insulin resistance (38). Gene expression profiling studies have shown Dexras1 to be downregulated by LXR in WAT, a finding that was confirmed by quantitative PCR. Furthermore, LXR{alpha} seems to be a cAMP-responsive modulator for a widespread number of genes including renin and c-myc via a CNRE (an overlapping cAMP response element and a negative response element). This response element has previously been shown to bind both a cAMP-induced transcription factor and a repressor of transcription (39). This is a unique LXR response element where LXR binds as a monomer (40). LXRß has also been shown to interact with the transforming growth factor-ß, called ALK-1, modulating signaling from the growth factor receptor (41). Thus, LXR appears to be a target and mediator of both cAMP and growth factor signaling pathways in addition to its previously demonstrated role in the insulin-signaling pathways. Further effort is indeed needed to unravel the role of LXR and its physiological relevance in different signaling pathways.


   CONCLUSIONS AND PERSPECTIVES
TOP
 ABSTRACT
 LXR IN CHOLESTEROL AND...
 LXR IN CARBOHYDRATE METABOLISM
 OTHER METABOLIC EFFECTS OF...
 INFLAMMATORY RESPONSE AND LXR
 SIGNAL TRANSDUCTION AND LXR
 CONCLUSIONS AND PERSPECTIVES
REFERENCES
 
Over the recent few years, much insight has been gained regarding the physiological functions of LXR. Although the first reports showed the involvement of LXR as a regulator of cholesterol metabolism, new findings suggest a role of LXR in lipogenesis, carbohydrate metabolism, inflammation, and various cellular signaling pathways. Interestingly, these biological mechanisms where LXR seems to play an important role are often linked to an increased risk of developing diabetes when they are dysfunctional. This makes LXR a highly interesting target for drug development for treating diabetes.

Whereas suppression of proinflammatory cytokines, limiting effects of glucocorticoids, inhibition of hepatic gluconeogenesis, and lowering serum glucose levels might be favorable features of a potential drug against diabetes, the increase in circulating lipids and triglycerides is not. Hence, the former effects need to be promoted by such a drug and the latter effect antagonized. The search for agonists and antagonists to LXR is prioritized in several pharmaceutical companies today. Generation of agonists and antagonists specific for LXR{alpha} and LXRß, respectively, will help to elucidate isoform-specific functions of LXR. Clearly, we are yet only at the beginning of what promises to be an extremely interesting period of continuous revelations of new functions of the two LXR isoforms, and it is likely that novel approaches to treat diabetes will become apparent as a result of this new knowledge.


   FOOTNOTES
 
This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Les Laboratoires Servier.

J.-Å.G. serves on an advisory panel for, holds stock in, and has received honoraria and grant support from KaroBio AB.

Address correspondence and reprint requests to Jan-Åke Gustafsson, Department of Medical Nutrition and Biosciences, Karolinska Institutet, S-14157 Huddinge, Sweden. E-mail: jan-ake.gustafsson{at}mednut.ki.se

Received for publication March 14, 2003 and accepted in revised form May 20, 2003

Key Words: 11ß-HSD1, 11ß-hydroxysteroid dehydrogenase type 1 • Angptl3, angiopoietin-like protein 3 • IL, interleukin • LXR, liver X receptor • PPAR, peroxisome proliferator-activated receptor • SCD, stearoyl CoA desaturase • SREBP, sterol response element-binding protein • TNF, tumor necrosis factor • WAT, white adipose tissue


   REFERENCES
TOP
 ABSTRACT
 LXR IN CHOLESTEROL AND...
 LXR IN CARBOHYDRATE METABOLISM
 OTHER METABOLIC EFFECTS OF...
 INFLAMMATORY RESPONSE AND LXR
 SIGNAL TRANSDUCTION AND LXR
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 

  1. Alberti S, Schuster G, Parini P, Feltkamp D, Diczfalusy U, Rudling M, Angelin B, Bjorkhem I, Pettersson S, Gustafsson JÅ: Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRbeta-deficient mice. J Clin Invest107 :565 –573,2001[Medline]
  2. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ: Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell93 :693 –704,1998[Medline]
  3. Ntambi JM: Regulation of stearoyl-CoA desaturase by polyunsaturated fatty acids and cholesterol. J Lipid Res40 :1549 –1558,1999[Abstract/Free Full Text]
  4. Tobin KA, Steineger HH, Alberti S, Spydevold O, Auwerx J, Gustafsson JÅ, Nebb HI: Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-alpha. Mol Endocrinol14 :741 –752,2000[Abstract/Free Full Text]
  5. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P: A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell7 :161 –171,2001[Medline]
  6. Schwartz K, Lawn RM, Wade DP: ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR. Biochem Biophys Res Commun274 :794 –802,2000[Medline]
  7. Costet P, Luo Y, Wang N, Tall AR: Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem275 :28240 –28245,2000[Abstract/Free Full Text]
  8. Kennedy MA, Venkateswaran A, Tarr PT, Xenarios I, Kudoh J, Shimizu N, Edwards PA: Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J Biol Chem276 :39438 –39447,2001[Abstract/Free Full Text]
  9. Engel T, Lorkowski S, Lueken A, Rust S, Schluter B, Berger G, Cullen P, Assmann G: The human ABCG4 gene is regulated by oxysterols and retinoids in monocyte-derived macrophages. Biochem Biophys Res Commun288 :483 –488,2001[Medline]
  10. Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, Mangelsdorf DJ: Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J Biol Chem277 :18793 –18800,2002[Abstract/Free Full Text]
  11. Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P: LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci U S A98 :507 –512,2001[Abstract/Free Full Text]
  12. Mak PA, Laffitte BA, Desrumaux C, Joseph SB, Curtiss LK, Mangelsdorf DJ, Tontonoz P, Edwards PA: Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages: a critical role for nuclear liver X receptors alpha and beta. J Biol Chem277 :31900 –31908,2002[Abstract/Free Full Text]
  13. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ: Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev14 :2819 –2830,2000[Abstract/Free Full Text]
  14. Yoshikawa T, Shimano H, Amemiya-Kudo M, Yahagi N, Hasty AH, Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Kimura S, Ishibashi S, Yamada N: Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol21 :2991 –3000,2001[Abstract/Free Full Text]
  15. Tobin KA, Ulven SM, Schuster GU, Steineger HH, Andresen SM, Gustafsson JÅ, Nebb HI: Liver X receptors as insulin-mediating factors in fatty acid and cholesterol biosynthesis. J Biol Chem277 :10691 –10697,2002[Abstract/Free Full Text]
  16. Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, Tontonoz P: Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem277 :11019 –11025,2002[Abstract/Free Full Text]
  17. Zhang Y, Yin L, Hillgartner FB: Thyroid hormone stimulates acetyl-coA carboxylase-alpha transcription in hepatocytes by modulating the composition of nuclear receptor complexes bound to a thyroid hormone response element. J Biol Chem276 :974 –983,2001[Abstract/Free Full Text]
  18. Wang H, Maechler P, Antinozzi PA, Herrero L, Hagenfeldt-Johansson KA, Bjorklund A, Wollheim CB: The transcription factor SREBP-1c is instrumental in the development of beta-cell dysfunction. J Biol Chem278 :16622 –16629,2003[Abstract/Free Full Text]
  19. Schuster GU, Parini P, Wang L, Alberti S, Steffensen KR, Hansson GK, Angelin B, Gustafsson JÅ: Accumulation of foam cells in liver X receptor-deficient mice. Circulation106 :1147 –1153,2002[Abstract/Free Full Text]
  20. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B: Role of LXRs in control of lipogenesis. Genes Dev14 :2831 –2838,2000[Abstract/Free Full Text]
  21. Kaplan R, Zhang T, Hernandez M, Gan FX, Wright SD, Waters MG, Cai TQ: Regulation of the angiopoietin-like protein 3 gene by LXR. J Lipid Res44 :136 –143,2003[Abstract/Free Full Text]
  22. Koishi R, Ando Y, Ono M, Shimamura M, Yasumo H, Fujiwara T, Horikoshi H, Furukawa H: Angptl3 regulates lipid metabolism in mice. Nat Genet30 :151 –157,2002[Medline]
  23. Muscat GE, Wagner BL, Hou J, Tangirala RK, Bischoff ED, Rohde P, Petrowski M, Li J, Shao G, Macondray G, Schulman IG: Regulation of cholesterol homeostasis and lipid metabolism in skeletal muscle by liver X receptors. J Biol Chem277 :40722 –40728,2002[Abstract/Free Full Text]
  24. Stulnig TM, Steffensen KR, Gao H, Reimers M, Dahlman-Wright K, Schuster GU, Gustafsson JÅ: Novel roles of liver X receptors exposed by gene expression profiling in liver and adipose tissue. Mol Pharmacol62 :1299 –1305,2002[Abstract/Free Full Text]
  25. Stulnig TM, Oppermann U, Steffensen KR, Schuster GU, Gustafsson JÅ: Liver X receptors downregulate 11beta-hydroxysteroid dehydrogenase type 1 expression and activity. Diabetes51 :2426 –2433,2002[Abstract/Free Full Text]
  26. Cao G, Liang Y, Broderick CL, Oldham BA, Beyer TP, Schmidt RJ, Zhang Y, Stayrook KR, Suen C, Otto KA, Miller AR, Dai J, Foxworthy P, Gao H, Ryan TP, Jiang XC, Burris TP, Eacho PI, Etgen GJ: Antidiabetic action of a liver x receptor agonist mediated by inhibition of hepatic gluconeogenesis. J Biol Chem278 :1131 –1136,2003[Abstract/Free Full Text]
  27. Ross SE, Erickson RL, Gerin I, DeRose PM, Bajnok L, Longo KA, Misek DE, Kuick R, Hanash SM, Atkins KB, Andresen SM, Nebb HI, Madsen L, Kristiansen K, MacDougald OA: Microarray analyses during adipogenesis: understanding the effects of Wnt signaling on adipogenesis and the roles of liver X receptor alpha in adipocyte metabolism. Mol Cell Biol22 :5989 –5999,2002[Abstract/Free Full Text]
  28. Friedman JM: Obesity in the new millennium. Nature404 :632 –634,2000[Medline]
  29. Lowell BB, Spiegelman BM: Towards a molecular understanding of adaptive thermogenesis. Nature404 :652 –660,2000[Medline]
  30. Kopelman PG: Obesity as a medical problem. Nature404 :635 –643,2000[Medline]
  31. Friedman JE, Yun JS, Patel YM, McGrane MM, Hanson RW: Glucocorticoids regulate the induction of phosphoenolpyruvate carboxykinase (GTP) gene transcription during diabetes. J Biol Chem268 :12952 –12957,1993[Abstract/Free Full Text]
  32. Livingstone DE, Jones GC, Smith K, Jamieson PM, Andrew R, Kenyon CJ, Walker BR: Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology141 :560 –563,2000[Abstract/Free Full Text]
  33. Livingstone DE, Walker BR: Is 11beta-hydroxysteroid dehydrogenase type 1 a therapeutic target? Effects of carbenoxolone in lean and obese Zucker rats. J Pharmacol Exp Ther305 :167 –172,2003[Abstract/Free Full Text]
  34. Tisch R, McDevitt H: Insulin-dependent diabetes mellitus. Cell85 :291 –297,1996[Medline]
  35. Grimble RF: Inflammatory status and insulin resistance. Curr Opin Clin Nutr Metab Care5 :551 –559,2002[Medline]
  36. Landis MS, Patel HV, Capone JP: Oxysterol activators of liver X receptor and 9-cis-retinoic acid promote sequential steps in the synthesis and secretion of tumor necrosis factor-alpha from human monocytes. J Biol Chem277 :4713 –4721,2002[Abstract/Free Full Text]
  37. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P: Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med9 :213 –219,2003[Medline]
  38. Pilon G, Penfornis P, Marette A: Nitric oxide production by adipocytes: a role in the pathogenesis of insulin resistance? Horm Metab Res32 :480 –484,2000[Medline]
  39. Tamura K, Chen YE, Horiuchi M, Chen Q, Daviet L, Yang Z, Lopez-Ilasaca M, Mu H, Pratt RE, Dzau VJ: LXRalpha functions as a cAMP-responsive transcriptional regulator of gene expression. Proc Natl Acad Sci U S A97 :8513 –8518,2000[Abstract/Free Full Text]
  40. Anderson LM, Choe SE, Yukhananov RY, Hopfner RL, Church GM, Pratt RE, Dzau VJ: Identification of a novel set of genes regulated by a unique liver X receptor-alpha-mediated transcription mechanism. J Biol Chem278 :15252 –15260,2003[Abstract/Free Full Text]
  41. Mo J, Fang SJ, Chen W, Blobe GC: Regulation of ALK-1 signaling by the nuclear receptor LXRbeta. J Biol Chem277 :50788 –50794,2002[Abstract/Free Full Text]
  42. Goodwin B, Watson MA, Kim H, Miao J, Kemper JK, Kliewer SA: Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-{alpha}. Mol Endocrinol17 :386 –394,2003[Abstract/Free Full Text]
  43. Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM: Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem272 :3137 –3140,1997[Abstract/Free Full Text]
  44. Luo Y, Tall AR: Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Invest105 :513 –520,2000[Medline]
  45. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ: Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science289 :1524 –1529,2000[Abstract/Free Full Text]
  46. Venkateswaran A, Laffitte BA, Joseph SB, Mak PA, Wilpitz DC, Edwards PA, Tontonoz P: Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci U S A97 :12097 –12102,2000[Abstract/Free Full Text]
  47. Yu L, York J, Bergmann Kv K, Lutjohann D, Cohen JC, Hobbs HH: Stimulation of cholesterol excretion by LXR agonist requires ATP-binding cassette transporters G5 and G8. J Biol Chem278 :15565 –15570,2003[Abstract/Free Full Text]
  48. DeBose-Boyd RA, Ou J, Goldstein JL, Brown MS: Expression of sterol regulatory element-binding protein 1c (SREBP-1c) mRNA in rat hepatoma cells requires endogenous LXR ligands. Proc Natl Acad Sci U S A98 :1477 –1482,2001[Abstract/Free Full Text]
  49. Whitney KD, Watson MA, Goodwin B, Galardi CM, Maglich JM, Wilson JG, Willson TM, Collins JL, Kliewer SA: Liver X receptor (LXR) regulation of the LXRalpha gene in human macrophages. J Biol Chem276 :43509 –43515,2001[Abstract/Free Full Text]
  50. Li Y, Bolten C, Bhat BG, Woodring-Dietz J, Li S, Prayaga SK, Xia C, Lala DS: Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism. Mol Endocrinol16 :506 –514,2002[Abstract/Free Full Text]
  51. Zhang Y, Repa JJ, Gauthier K, Mangelsdorf DJ: Regulation of lipoprotein lipase by the oxysterol receptors, LXRalpha and LXRbeta. J Biol Chem276 :43018 –43024,2001[Abstract/Free Full Text]
  52. Cao G, Beyer TP, Yang XP, Schmidt RJ, Zhang Y, Bensch WR, Kauffman RF, Gao H, Ryan TP, Liang Y, Eacho PI, Jiang XC: Phospholipid transfer protein is regulated by liver X receptors in vivo. J Biol Chem277 :39561 –39565,2002[Abstract/Free Full Text]
  53. Malerod L, Juvet LK, Hanssen-Bauer A, Eskild W, Berg T: Oxysterol-activated LXRalpha/RXR induces hSR-BI-promoter activity in hepatoma cells and preadipocytes. Biochem Biophys Res Commun299 :916 –923,2002[Medline]
  54. Fowler AJ, Sheu MY, Schmuth M, Kao J, Fluhr JW, Rhein L, Collins JL, Willson TM, Mangelsdorf DJ, Elias PM, Feingold KR: Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: liver-X-receptor-specific inhibition of inflammation and primary cytokine production. J Invest Dermatol120 :246 –255,2003[Medline]

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