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Center for Integrative Genomics, National Centre of Competence in Research Frontiers in Genetics, University of Lausanne, CH-1015 Lausanne, Switzerland
Address all correspondence and requests for reprints to: Beatrice Desvergne or Walter Wahli, Center for Integrative Genomics, University of Lausanne, Biology Building, CH-1015 Lausanne-Dorigny, Switzerland. E-mail: Beatrice.desvergne{at}cig.unil.ch or walter.wahli{at}cig.unil.ch.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPPARs IN THE HEALTHY...PPARs IN DISEASE: THE...CONCLUSIONSREFERENCES |
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in fatty oxidation and of PPAR
in adipocyte differentiation and lipid storage. Today, the molecular bases of the functional links between glucose, lipid, and protein metabolism, under the important but nonexclusive control of PPAR and PPAR, are starting to be uncovered. In addition, in the last couple of years evidence has been provided for an important role of PPARß (
) in lipid metabolism. Inevitably, such actors of metabolic homeostasis are implicated in the physiopathology of complex metabolic disorders, such as those constituting the metabolic syndrome, resulting in atherosclerosis and cardiovascular diseases. This review presents a summary of the recent findings on their dual involvement in health and disease. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPPARs IN THE HEALTHY...PPARs IN DISEASE: THE...CONCLUSIONSREFERENCES |
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Although there is still an important gap in knowledge, it clearly appears that a strict energy balance is required for the harmonious growth and health of multicellular organisms. This balance depends on very well-tuned machinery involving control of appetite, nutrient identification and absorption, neuroendocrine and gastrointestinal factors, and energy storage and expenditure. It is now commonly accepted that this machinery is regulated by allosteric controls and posttranslational modifications, which can activate an enzyme within seconds or affect protein stability. However, transcriptional regulation is the most effective mechanism on a longer time scale, as it affects the levels of expression of key proteins.
Transcriptional control requires specific signals to be transduced to the cell nucleus in which defined sets of genes are targeted. Virtually all transcription factor families participate in metabolic regulation; however, a few of them have a clear predominant role. Among these transcription factors, the sterol response element binding proteins (SREBPs) play a major role in lipid and cholesterol metabolism. The heterogenous family of proteins initially grouped under the name of liver-enriched transcription factors and which comprises the CAAT enhancer binding proteins is also of importance for metabolic control. Last, but certainly not least, are the members of the nuclear receptor family, such as the peroxisome proliferator-activated receptor (PPAR), the liver X receptor (LXR), and the farnesol X receptor (FXR), which all heterodimerize with the retinoid X-receptor (RXR) and act as "sensor" receptors. These metabolic sensors bind a broad range of molecules that are implicated in metabolic pathways, such as fatty acids, eicosanoids, and oxysterols, and which can act as substrates, intermediates, or end-products. Upon activation by dietary signals and/or metabolites generated by the organism, these receptors modulate the expression of their target genes and are thus responsible for metabolic adaptations at the cellular, organ, and whole-organism level. They are therefore important in the healthy organism but are also of particular interest as public health epidemics advance in the context of the metabolic syndrome (mentioned above).
The identification of PPARs as sensors for fatty acids, rather than classic hormone receptors, suggested a major function of these transcription factors in the molecular control of important metabolic pathways. Indeed, they have been implicated in the control of energy homeostasis and obesity-related metabolic diseases (reviewed in Ref.1). They are bona fide members of the nuclear receptor family, which are encoded by 48 genes in human. Once activated by a ligand, they control a variety of genes in several pathways of intermediary metabolism (reviewed in Ref.2). Thus, the effector functions of PPARs allow to adjust the gene expression program according to the levels of fatty acids and eicosanoids that reflect diverse physiological conditions. There are three PPAR isotypes, PPAR (NR1C1), PPARß (NR1C2; also called , NUCI, and FAAR), and PPAR (NR1C3), all of which bind to DNA as heterodimers with RXR (NR2B) (3, 4, 5, 6). In the process of transcriptional regulation, the ligand-activated heterodimers recruit coactivators (7), possibly in an isotype-selective manner to ensure the specificity of target gene activation. In addition, PPARs can also be activated by phosphorylation of the A/B domain, and the PPAR:RXR heterodimer can be activated by RXR ligands as well. These different activation mechanisms, which can act concomitantly, illustrate the capacity of fine-tuning that may be orchestrated by PPAR actions.
The first molecules recognized as PPAR activators, and later characterized as ligands, belong to a group of molecules that induce peroxisome proliferation in rodents, thus giving rise to the name of PPAR. In addition to being activated by these compounds as well as fatty acids, PPAR responds to fibrates, a class of hypolipidemic drugs, and PPAR binds insulin-sensitizing thiazolidinediones. These findings have shed light on the role of these receptors and simultaneously revealed their potential as drug targets.
As could be suspected from sensors of fatty acids and their derivatives, PPARs regulate most of the pathways linked to lipid metabolism. Most fascinating is the observation of balanced regulatory actions between fatty acid oxidation in the liver and other organs via PPAR, and fatty acid storage in the adipose tissue via PPAR, both of which can be modulated by the less well known PPARß isotype (reviewed in Ref.8). In addition, it appears more and more clearly today that PPARs are involved in all three main branches of intermediary metabolism, i.e. lipid, protein, and carbohydrate metabolism.
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PPARs IN THE HEALTHY ORGANISM |
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TOPABSTRACTINTRODUCTIONPPARs IN THE HEALTHY...PPARs IN DISEASE: THE...CONCLUSIONSREFERENCES |
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Is the Key Transcriptional Regulator of Fatty Acid Oxidation. is highly expressed in tissues with high fatty acid oxidation, in which it controls a comprehensive set of genes that regulate most aspects of lipid catabolism (reviewed in Ref.1). The role of PPAR in liver fatty acid oxidation is vital during fasting. In this situation, an enhanced release of fatty acids from the adipose tissue is used as an energy source. Food deprivation increases the hepatic expression and activity of PPAR, which in turn stimulates ß-oxidation of the fatty acids released from adipose tissue. PPAR-null mice, which exhibit only subtle abnormalities in lipid metabolism when kept under normal laboratory confinement and diet (9, 10), cannot sustain fasting. Their inability to enhance liver fatty acid oxidation in the absence of PPAR results in hypoketonemia, associated with severe hypothermia and hypoglycemia (11, 12). Thus, at least in rodents, PPAR is crucial for the organism to adapt to an increased demand in fatty acid oxidation.
Quantitatively, the major site of fatty acid oxidation at rest and during exercise is the skeletal muscle (reviewed in Ref.13). This tissue expresses PPAR, and, interestingly, a clinical study in lean women demonstrated that endurance training up-regulates PPAR expression and increases muscle oxidative capacity (14). During physical exercise, PPAR-null mice have a relatively mild phenotype, which is characterized by a precocious exhaustion (15). In contrast, fasting does not significantly increase PPAR in skeletal muscle (16, 17), and the fatty acid oxidative capacity of PPAR-null mice muscle is reduced by only 30%, suggesting that other factors are important for the regulation of this pathway (15). The importance of these yet unidentified factors is supported by the induction of many genes involved in fatty acid oxidation in muscle of streptozotocin-induced diabetic mice, despite a paradoxical decreased expression of PPAR (18).
The cardiac muscle also mainly relies on fatty acid oxidation as energy source. During development, PPAR is increased at the time of the transition from fetal to adult cardiomyocytes. This step corresponds to a switch in the source of energy from glucose and lactate to fatty acids and is accompanied by an increase in the expression of PPAR target genes involved in fatty acid oxidation. In parallel, the expression of the PPAR coactivator-1 (PGC-1), which has an important role in mitochondrial biogenesis and thus in the cellular oxidative capacity (19), is stimulated and may cooperate with PPAR for the induction of the fatty acid oxidation pathway (20). In pathological cardiac hypertrophy, the expression of PPAR is down-regulated. Consequently, the utilization of fatty acids as energy substrate is decreased, and the genes implicated in the utilization of glucose as the main energy source are reinduced (21). Whether this is a cause or a consequence of the pathology is presently unclear. Therefore, it is still uncertain whether PPAR ligands would be beneficial or detrimental in this condition (Ref.22 and reviewed in Ref.23).
Another consequence of impaired energy homeostasis in starved PPAR-null mice is found in the kidney proximal tubules. Upon starvation, and as a consequence of low glucose availability, renal ATP production depends on fatty acid metabolism, the impairment of which in PPAR-null mice results in an acute ATP insufficiency (24). This provokes a dysfunction of the lysosomal digestion ability with appearance of giant lysosomes in the proximal tubule cells. These alterations in turn likely account for the observed increase in daily urinary albumin secretion in PPAR-null mice (24).
PPAR, Adipogenesis, and Fatty Acid Storage.
The adipose tissue is believed to be a lifelong reservoir of preadipocytes that can be triggered to differentiate into adipocytes if fat has to be stored. This tissue sustains efficient lipogenesis, triglyceride synthesis, and storage and, on demand, can release fatty acids and glycerol into circulation via lipolysis. It also secretes many endocrine signals, collectively named adipokines, that are presently under intense scrutiny in the context of whole-body energy metabolism (reviewed in Ref.25).
PPAR is a late marker of adipocyte differentiation and its ectopic expression suffices to force fibroblasts into the adipogenic program. Although PPAR-null mice are not viable, due to defects in placenta formation (26), the lack of PPAR–/– adipocytes in chimeric PPAR+/+:PPAR–/– mice has revealed the necessity of PPAR for adipocyte differentiation in vivo (Ref.27 and reviewed in Ref.28). The role of PPAR in the mature adipose tissue has long remained unclear. The adipocyte hypertrophy observed in the adult mouse on a high-fat diet requires both PPAR alleles to be functional. Indeed, PPAR heterozygous mice are protected from this adipocyte enlargement (29). In obese Zucker rats, treatment with synthetic PPAR agonists mainly increases the number of adipocytes, likely as a result of accelerated adipocyte differentiation (30). Reciprocally, feeding the ob/ob mice with a PPAR antagonist results in reduced white and brown adipose tissues, albeit the main reason seems to be a decrease in average adipocyte volume (31). Altogether these results highlight the subtle balance that PPAR activity exerts on adipogenesis and fat storage. This is further emphasized experimentally in adipose tissue carrying a tissue-specific deletion of PPAR, by the decreased number of mature adipocytes with small and likely preadipocytes becoming more abundant. These observations imply that PPAR is essential for the survival of mature adipocytes in the adult (32, 33).
Lipid accumulation, via PPAR activation, may occur in tissues other than the adipose tissue. A forced expression of PPAR in hepatocytes induces the classic pattern of PPAR-mediated gene activation and results in steatosis (34). A similar phenotype is also observed in the liver of murine models of diabetes or obesity, characterized by elevated hepatic levels of PPAR (35). Consistently, PPAR heterozygous mice challenged by a high-fat diet are less prone to steatosis than their wild-type counterparts (36). However, a liver-specific deletion of the PPAR gene has no obvious effect unless this deletion is performed in a murine model with significant steatosis, such as the leptin-deficient ob/ob mice (35), restricting the contribution of PPAR activity in liver functions to the context of an unbalanced metabolic status. The phenotype of mice carrying a specific deletion of PPAR in skeletal muscle, which comprises increased serum lipids, insulin resistance, and increased adiposity, only appears upon high fat diet (37, 38). Finally, PPAR-dependent lipid accumulation might also occur in smooth muscle cells and activated macrophages. However, PPAR has also been implicated in cholesterol export from macrophages and is possibly involved in counterbalancing the detrimental effects of lipid loading in these cells (reviewed in Ref.39).
Intricate Functions of PPARß.
Like PPAR and PPAR, PPARß binds fatty acids (reviewed in Ref.8). In preadipocytes, PPARß mediates long-chain fatty acid effects on the expression of adipose-related genes (40). In these cells, together with the two transcription factors CCAAT/enhancer-binding protein (C/EBP)ß and C/EBP, PPARß appears to be implicated in the induction of PPAR expression (41, 42). In turn, PPAR and C/EBP establish and maintain the terminal adipocyte differentiation program. According to this scheme, activation of PPARß by dietary lipids in preadipocytes would contribute to the expansion of the adipose tissue. Consistent with this hypothesis, the amount of brown and white adipose tissues is decreased in the PPARß-null mice (43, 44), and overexpression of PPARß in C2C12 myoblasts participates in their transdifferentiation into adipocytes (42). Yet unexpectedly, adipose tissue-specific deletion of the PPARß gene does not alter fat mass (44). Just as surprising, overexpression of a constitutively active PPARß-VP16 fusion protein in the white adipose tissue triggers fatty acid mobilization and oxidation leading to fat mass reduction (45). However, it is presently unclear how much this fusion protein specifically mimics the roles of PPARß in physiological conditions. In muscle cells, agonists of PPARß induce fatty acid oxidation (17, 46). Consistently, in vivo overexpression of PPARß in skeletal muscle provokes a shift toward more oxidative fibers and promotes a general decrease of body fat content (47).
These observations emphasize some apparently contradictory functions of PPARß in lipid metabolism and its roles in connection with those of PPAR and PPAR await further careful dissection.
PPARs and Lipid Transport.
Lipoproteins are complex particles allowing the transport of lipids in the vascular system. These lipids can be phospholipids, free or esterified cholesterol, as well as triglycerides. Both PPAR and PPAR modulate the lipoprotein serum profile via increased expression of lipoprotein lipase (LPL) (reviewed in Ref.48) and decreased expression of apolipoprotein (apo)CIII, an inhibitor of LPL activity. These joint effects lower serum triglyceride levels and increase the delivery of free fatty acids to peripheral tissues such as muscle and adipose tissue. PPAR also up-regulates the expression of the cholesterol acceptors apoAI and apoAII, thus increasing the reverse cholesterol transport. These two proteins participate in the formation of high-density lipoprotein (HDL) particles, which carry to the liver the cholesterol either released by peripheral tissues or transferred from chylomicron and very low-density lipoprotein (VLDL) surface remnants. In this process, PPAR increases the expression of the scavenger receptor BI (SR-BI)/CLA-1, thereby increasing the selective up-take of HDL cholesteryl esters from the circulation by hepatocytes (reviewed in Ref.1). A role of PPARß in regulating lipid transport through the lipoproteins has been revealed in obese rhesus monkeys, an animal model for human obesity and associated metabolic disorders. Treatment of these animals with a selective PPARß agonist caused a beneficial increase in serum HDL cholesterol and a decrease in small, dense LDL, fasting triglycerides, and fasting insulin (49). Similarly, the administration of a PPARß synthetic agonist to obese and diabetic db/db mice raised total plasma cholesterol levels primarily associated with HDL particles and decreased expression of LPL in white adipose tissue (50). Conversely, PPARß-deficient mice exhibit LDL hypertriglyceridemia, due to increased hepatic production of VLDL and decreased LPL-mediated catabolism (51). However, the contribution of PPARß to lipoprotein metabolism in healthy animals remains to be further studied, especially in the context of different diets or levels of physical exercise.
PPARs and Protein Metabolism: Transcriptional Regulation of Urea and Ammonia Homeostasis
Urea production in the liver, via the activity of the five enzymes of the urea cycle—carbamoyl phosphate synthetase I (CPSI), ornithine transcarbamoylase (OTC), argininosuccinate synthase (ASS), argininosuccinate lyase (ASL), and arginase—is the main pathway for ammonia detoxification. The two main sources of ammonia production in the body are the catabolism of diet proteins and the degradation of endogenous proteins, which occurs after prolonged food deprivation. Whereas fasted wild-type mice exhibit a drop in plasma urea concentration, urea concentration in PPAR-null mice remains high. PPAR indeed acts as a negative regulator of the urea cycle, via down-regulation of the expression of CPSI, OTC, ASS, and ASL (52). Although the mechanism by which PPAR exerts this coordinated down-regulation of urea enzyme gene expression is not known, the benefit for the organism during fasting is the use of lipids as the first energy source rather than muscle proteins, to prevent rapid weakening of the organism. As revealed by the severe hyperammonemia and hypouremia observed in mice with liver-specific deletion of hepatocyte nuclear factor (HNF)4 (53), which dramatically reduces the expression of the OTC gene, HNF4 is an important positive regulator of the urea cycle. It has been proposed that HNF4 up-regulates PPAR gene expression (54). This regulation could explain the relatively low levels of PPAR in HNF4-null mice (55) and thus the normal or higher levels of CPSI, ASS, and ASL enzymes in these mice. Although the direct positive regulation of PPAR expression in the liver by HNF4 remains to be ascertained, the balance between activation (HNF4) and inhibition (PPAR) of urea cycle activity illustrates a general mode of regulation that might be very important in metabolism in which homeostasis is obtained via the simultaneous opposite control of the same pathway. In the same line of thought, C/EBP is an important positive regulator of the urea cycle, and its increased expression by glucocorticoids is accompanied by increased levels of PPAR, an inhibitor of the same cycle.
Roles of PPARs in Glucose Metabolism
The crucial importance of the tight control of glucose plasma levels is illustrated by the deleterious consequences of hypoglycemia and hyperglycemia. Prolonged hypoglycemia causes acute brain damage and, as seen in diabetes, chronic hyperglycemia is a major risk factor for neuropathy and vasculopathy. PPAR, in addition to its role in lipid metabolism, is involved in liver glucose metabolism, an essential element of glucose homeostasis. PPAR-null mice are more insulin sensitive and are protected from insulin resistance when on a high-fat diet (56). However, when fasted, these animals suffer from severe hypoglycemia, in addition to lipid accumulation in the liver, elevated free fatty acid plasma levels, and hypoketonemia (11). Under healthy physiological conditions, the liver contributes to improve hypoglycemia by increasing glycogenolysis, gluconeogenesis, and the release of glucose into the bloodstream. PPAR exerts a direct role in the regulation of gluconeogenesis via stimulation of the expression of pyruvate dehydrogenase kinase 4 (PDK4) (57). This enzyme inactivates the pyruvate dehydrogenase complex via phosphorylation, thus guiding the utilization of pyruvate to gluconeogenesis rather than fatty acid synthesis. In fasted PPAR-null mice, glucose synthesis from lactate and lactate production itself is strongly reduced, showing that PPAR also influences substrate utilization for glucose production in the liver. However, hepatic glucose production was surprisingly higher in the PPAR-null mice than in the wild-type animals at the end of a fasting period (58), due to increased glucose production from glycerol in these animals. These data reveal that the severe hypoglycemia observed in the PPAR–/– mutant mice during fasting is not due to reduced glucose production but to increased glucose disposal. Thus, together these observations emphasize the importance of PPAR in the regulation of both glucose production and disposal. Consistent with these roles of PPAR, synthetic PPAR agonists improve glucose homeostasis in several rodent models of diabetes, by affecting liver, skeletal muscle, and pancreas functions (59, 60).
Given the beneficial effects of PPAR ligands in therapies aimed at lowering glucose levels in type 2 diabetes, a role of PPAR in glucose metabolism has been explored. However, the reports so far mainly focus on the role of PPAR in glucose metabolism during metabolic disorders, as is described in the next section, rather than in healthy organisms.
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PPARs IN DISEASE: THE METABOLIC SYNDROME |
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TOPABSTRACTINTRODUCTIONPPARs IN THE HEALTHY...PPARs IN DISEASE: THE...CONCLUSIONSREFERENCES |
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). As a cause and/or consequence, high circulating levels of fatty acids appear to be central in the development of insulin resistance. Even in absence of overt metabolic abnormalities, obesity is accompanied by elevated circulating levels of free fatty acids, which increase proportionally to fat mass. In these conditions, enlargement of the visceral fat depot contributes to the development of insulin resistance, as this fat pad is in particular less sensitive to the antilipolytic action of insulin. Once insulin resistance is established in obese patients, lipolysis becomes even more important, affecting all fat depots and leading to a further increase in the flux of free fatty acids toward the liver. This in turn augments VLDL production and reinforces the pool of blood triglycerides. In parallel, the liver maintains a high glucose production, aggravating hyperglycemia. In muscle, increased free fatty acids also negatively interfere with the insulin signaling cascade via unknown mechanisms. An impaired Glut 4 gene expression and protein translocation seem to be responsible for the defect of glucose transport and metabolism in this tissue (reviewed in Ref.61).
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, was one major step in the search for the molecular mechanisms responsible for the development of the metabolic syndrome. Glitazones decrease plasma free fatty acid concentrations and fasting hyperglycemia via an insulin-sensitizing effect (62, 63). They also lower hypertension and improve the overall lipoprotein profile, thereby reducing the risk of atherosclerosis. However, and not surprisingly, because they are potent and high-affinity ligands for PPAR, glitazones enhance adipocyte differentiation, thus contributing to the weight gain often observed in patients under treatment (64, 65). Other side effects of some of these compounds include edema and an idiosyncratic acute hepatotoxicity. The link between the promotion of adipocyte differentiation and lipid storage by PPAR on the one hand, and the antidiabetic effects of glitazones on the other, is still unclear. Several hypotheses based on a wealth of experiments have been proposed.
One of these is that PPAR allows retrieval of lipids that had unduly accumulated in nonadipose tissues by increasing the ability of the adipose tissue to store excess circulating fat. Thereby, fat accumulated in muscle, liver, and pancreas is redistributed toward fat tissues, and more particularly to sc fat, which is more sensitive to insulin than visceral fat (66, 67). This is consistent with reduced adipogenesis in muscle and liver in patients treated with glitazones. Thus, the deleterious effects of an increase in adiposity are counterbalanced by a redistribution of these lipids that prevents excessive fat accumulation in peripheral organs including visceral fat, thus improving insulin sensitivity of the organism (reviewed in Ref.68).
Beside fat redistribution, glitazones may also stimulate cytokine production by the adipose tissue. Indeed, adiponectin might be a crucial link between PPAR activation in the adipose tissue and the metabolic response of peripheral organs (67). Leptin may also be a potential effector of glitazones, but consistent clinical data are difficult to assemble and results obtained in rodent models are controversial. PPAR might also directly regulate TNF expression. A global analysis by DNA microarray of PPAR target genes suggested an interesting mechanism by which PPAR activation inhibits nuclear factor 
B, thereby blocking the TNF-mediated inhibition of adipogenesis (69).
The action of glitazones remains difficult to understand, mainly because different in vivo observations appear difficult to reconcile. Lipodystrophic rodents with associated insulin resistance also benefit from thiazolidinedione treatment, suggesting an adipose-tissue independent mechanism (70). Along the same line, selective deletion of PPAR in the adipose tissue only causes insulin resistance in the adipose tissue itself but not in the muscle (32). Because its expression is rather low in skeletal muscle, a direct action of PPAR on this tissue appears unlikely at first sight. However, muscle-specific deletion of PPAR is reported to increase adiposity and insulin resistance via an unknown mechanism. The beneficial effect of glitazones in these mice is unclear because two independent reports describe opposite results, with either the persistence (37) or the loss (38) of a thiazolidinedione-induced response in animals lacking PPAR in muscle. Although these discrepancies are likely due to small but significant differences in the experimental design and methodology, they underline the urgent need for further mechanistic explorations. Mice in which PPAR has been specifically deleted in the liver do not exhibit any phenotype unless they carry an additional mutation with deleterious metabolic effects [ob/ob mice and lipodystrophic A-ZIP/F-1 mice (35, 71)]. This situation probably reflects the hepatic expression level of PPAR, which is low in normal liver and is increased in pathological situations, most notably in steatosis that may occur in the metabolic syndrome.
Adding to this complexity, a diminished PPAR activity protects from the development of insulin resistance. Reduced PPAR activity can be obtained by PPAR antagonists. One of them, SR-202 [dimethyl -(dimethoxyphosphinyl)-p-chlorobenzyl phosphate], which partially prevents adipocyte differentiation in cell culture, has been tested in mice. In vivo, it partially blocks PPAR activity, decreases fat depots, and increases insulin sensitivity, setting most of the metabolic parameters at the levels of those seen in PPAR+/– mice (31). Indeed, PPAR+/– heterozygous mice, rather than being prone to insulin resistance, are partially protected from high-fat-diet- or monosodiumglutamate-induced weight gain and insulin resistance, when compared with their wild-type littermates (36, 72). Treating these mice with glitazones does not further enhance insulin sensitivity but restores a "wild-type"-like phenotype (73). In this situation, glitazones appear as correctors of insulin sensitivity. Although they do not affect insulin sensitivity in healthy humans and animals, they improve insulin sensitivity in human and rodent models with insulin resistance but diminish insulin sensitivity in abnormally sensitive rodents. PPAR+/– mice have smaller adipocytes and smaller fat depots. In these mice, glitazone treatment would simply help in restoring a normal fat mass, and thus would make them equal to wild-type mice in the face of a metabolic challenge, such as a high-fat diet. In contrast, a PPAR antagonist would inhibit triglyceride accumulation in fat tissue and, like in PPAR+/– animals, would not allow fat accumulation to unduly occur in muscle, thus preserving insulin sensitivity. This strongly suggests that PPAR antagonists might represent a better treatment of obesity and type 2 diabetes than glitazones. However, although these animal data are promising, the demonstration that PPAR antagonists can act similarly in obese diabetic humans is still lacking.
Several mutations in the human PPAR gene have been reported. However, their consequences on obesity and metabolic disorders are still debated. This has been recently reviewed and will therefore not be discussed further herein (67, 74). Finally, to close this discussion on PPAR and glitazones, it should be kept in mind that not all glitazone effects are PPAR dependent (reviewed in Ref.75).
Are PPAR and PPARß Involved in the Metabolic Syndrome?
If circulating fatty acid levels are important determinants in inducing or nourishing insulin resistance, improvement by increased fatty acid oxidation in the liver should be predicted. Indeed, hepatic overexpression of malonyl-CoA decarboxylase, an enzyme that promotes fat oxidation and decreases lipid esterification, reverses muscle, liver, and whole-animal insulin resistance in obese rats (76). Thus, because of its role in fatty acid oxidation, PPAR could be an interesting target for restoring insulin sensitivity in patients suffering from dyslipidemia. However, there is little support so far for a fibrate action on insulin sensitivity. Studies aimed at exploring this possibility showed that the experimental synthetic PPAR ligand Wy-14643, as well as fenofibrate and ciprofibate, are able to improve insulin sensitivity in rodent models of insulin resistance (77, 78). The PPAR-dependent increase in insulin sensitivity would be mediated via an increased oxidation of fatty acids in skeletal muscle, thereby decreasing fat accumulation in this tissue. In opposition to this observation, PPAR-null mice are protected from developing insulin resistance under a high-fat diet or more simply during aging (56). Despite these apparent contradictions and difficulties, numerous pharmaceutical companies are currently developing dual agonist compounds that associate PPAR and PPAR ligand properties. However, the development of Ragaglitazar (DRF 2725; Dr. Reddy’s Laboratories, Hyderabad, India), one of the first clinically tested dual agonists, was interrupted by the persistence of side effects already mentioned for glitazones, e.g. peripheral edema and anemia (79). In addition, a word of caution with respect to species differences must be given. If mice have a robust response to PPAR ligands, humans are less responsive. Thus, species differences in terms of PPAR-mediated transcriptional response need to be assessed when investigating human and rodent physiology.
The previously mentioned effect of a PPARß ligand on HDL-cholesterol levels in obese monkeys and the decreased adiposity of PPARß–/– mice suggest that PPARß may play a role in the context of obesity, diabetes, and dyslipidemia (43, 44). However, this function is not clear yet, because in vivo data are sometimes contradictory and remain difficult to integrate in a general physiological scheme. PPARß–/– mice fed on a chow diet have a reduced total body weight compared with wild-type mice. Exposure of PPARß–/– mice to a high-fat diet results in either the same growth pattern as the wild-type mice, i.e. the weight difference is maintained unchanged between the two genotypes (51), or in a remarkable increased weight gain in null animals, overreaching the weight of wild-type mice (45). A tissue-specific gene deletion of PPARß in the white adipose tissue does not alter the fat mass, whereas a transgenic animal artificially overexpressing an overactive PPARß in white adipose tissue had increased fatty acid oxidation and energy dissipation, which reduce adiposity and improve the lipid profile (45). This latter observation is consistent with a proposed participation of PPARß in muscle fatty acid oxidation (15, 46). Altogether, these observations emphasize the difficulties in addressing the complexity of the mechanisms involved in metabolic diseases and the caution that should be applied when interpreting in vivo observations. These demonstrations also demonstrate that further investigation is needed to clarify the therapeutic potential of PPARß for the treatment of the metabolic syndrome and diabetes.
PPARs in Atherosclerosis
The correlation between a proline-to-alanine substitution in the human PPAR gene and a decreased risk of incident myocardial infarction emphasizes the potential involvement of PPAR in atherosclerosis (80). Internalization of atherogenic lipoproteins by the macrophages of arterial intima results in the formation of cholesteryl ester depots characteristic of foam cells and in the intracellular delivery of PPAR ligands. A proatherogenic property of PPAR is revealed by the stimulation of expression of the scavenger receptor CD36 by activated PPAR, which further promotes oxidized LDL uptake and foam cell formation (81, 82). However, PPAR also has opposite effects. It enhances the transcription of LXR, which is activated by oxysterols. Activated LXR increases the expression of the ATP-binding cassette transporter A1 (ABCA1), thereby promoting cholesterol efflux in macrophages (83, 84, 85). Additional antiatherosclerotic effects might result from reducing the macrophage production of inflammatory cytokines and the expression of scavenger receptor type AI/II (86, 87, 88). Thus, the beneficial effects of PPAR ligands seen in atherosclerosis in mice and humans can be attributed to both increased cholesterol efflux and reduced inflammation (85, 89, 90, 91, 92, 93, 94).
PPAR was also shown to promote cholesterol efflux by stimulating ABCA1 expression (95) and to have antiinflammatory functions (96, 97, 98). Exposure of human macrophages and foam cells in culture to fibrates results in a PPAR-dependent reduction in the cholesteryl ester to free cholesterol ratio that may contribute to an enhanced availability of free cholesterol for efflux through the ABCA1 pathway (95). As discussed above, PPAR activation also has a beneficial effect on lipoprotein profile, which, associated to the PPAR-dependent stimulation of fatty acid oxidation, would counteract highly atherogenic situations characterized by high levels of circulating triglycerides and low levels of HDL. Together, these observations unveil that fibrates possibly act at two different levels to counteract the development of atherosclerosis: at a systemic level via their hypolipidemic properties that are very useful for the treatment of human lipid disorders and at the level of the atherosclerotic lesion itself via its action on macrophages and inflammation.
PPARß might also be involved in the evolution of atherosclerosis. First, as discussed above, activated PPARß acts on lipoprotein metabolism by increasing the HDL levels in obese rhesus monkeys (49), whereas loss of PPARß leads to VLDL hypertriglyceridemia (51). In addition, an in vivo model in which macrophages and foam cells were derived from PPARß–/– cells exhibits a 50% reduction of the atherosclerotic lesion. The mechanism proposed here is an unconventional ligand-dependent transcriptional pathway in which PPARß controls an inflammatory switch through its association with and dissociation from transcriptional repressors (99). How this can be linked to the PPARß-mediated transcriptional response of macrophages to VLDL exposure, which consists in inhibiting the expression of the VLDL receptor (100), is so far unclear.
Together, these findings suggest that dysfunctions in the response of macrophages to VLDL or in the balance between oxidized LDL uptake, cholesterol afflux, and stimulation of the innate immune response, may promote atherosclerosis. In this situation, all three PPAR isotypes may serve as therapeutic targets to attenuate inflammation and to slow down the progression of atherosclerosis.
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CONCLUSIONS |
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As mentioned in the introduction, technological, cultural, as well as lifestyle habit changes, especially in the past 50 yr, have considerably challenged the well-tuned but relatively fragile machinery that regulates energy homeostasis at all levels of its ramifications. Thereby, these changes are contributing to the rapid development of lifestyle-induced diseases that are becoming the major cause of death and morbidity in developed countries. Excess food and sedentary and other deleterious lifestyle habits disturb an adaptive system resulting from the life history of multicellular organisms, which is definitively more suited for scarcity rather than plenty of food. In addition to exercise and weight loss, which are the obvious first steps in the treatment of the metabolic syndrome, the development of drugs modulating the activity of PPARs and other energy metabolism-associated receptors will contribute to therapies tailored to a patient’s specific risk factors and comorbid conditions.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: ABCA1, ATP-binding cassette transporter A1; apo, apolipoprotein; ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; C/EBP, CCAAT/enhancer-binding protein; CPSI, carbamoyl phosphate synthetase I; HDL, high-density lipoprotein; HNF, hepatocyte nuclear factor; LPL, lipoprotein lipase; LXR, liver X receptor; OTC, ornithine transcarbamoylase; RXR, retinoid X receptor; PPAR, peroxisome proliferator-activated receptor; VLDL, very low-density lipoprotein.
Received for publication March 2, 2004. Accepted for publication April 6, 2004.
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