In the field of molecular biology, the peroxisomeproliferator-activated receptors (PPARs) are a group of nuclear receptorproteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms.
Normal cellular energy metabolism is maintained through a delicate balance between energy intake and energy expenditure. When energy intake exceeds energy expenditure, the extra energy is stored in the form of fat. This energy imbalance is intimately linked to a cluster of metabolic diseases, including obesity, hyperlipidemia, and cardiovascular disease, as well as insulin resistance and type 2 diabetes. Our laboratory is interested in understanding the transcriptional control of fatty acid and glucose metabolism by the PPAR subfamily of nuclear receptors.
THE REGULATION of lipid and carbohydrate metabo-lism is central to energy homeostasis in higher multi-cellular organisms. It involves control systems that are sen-sitive to stimuli such as the availability of food, physicalactivity, stress, light, and temperature. The coordination ofthe responses to signals triggered by these stimulimust occuron several levels to ensure a well adapted energy balance,ranging from hypothalamic functions in the brain to thedirect control by lipids and carbohydrates of their own fate.
So far, three major types have been identiﬁed, namely PPAR-,PPAR-/ and PPAR-. PPAR- and PPAR- are crucial for lipid and glucose metabolism, respectively. Although limited information isavailable on PPAR- biological functions, recent studies have shown that PPAR- also regulates glucose metabolism and fatty acid oxidation.The discovery of PPAR- agonists such as ﬁbrates and PPAR- agonists such as thiozolidinediones enables recognition of the mechanismsinvolved in ameliorating the adverse effects of chronic disorders such as atherosclerosis and diabetes. In addition, PPARs are also involvedin the regulation of various types of tumours, inﬂammation, cardiovascular diseases and infertility. The importance of these transcriptionfactors in physiology and pathophysiology has instigated much research in this ﬁeld. In this article, structural features of PPARs, their genetranscription mechanisms and recent developments in the discovery of their biological functions are reviewed.
Crystallographic structure of a heterodimer of the nuclear receptors PPAR-γ (green) and RXR-α (cyan) complexed with double stranded DNA (magenta) and NCOA2coactivator peptide (red). The PPAR-γ GW9662 antagonist and RXR-α retinoic acid are depicted as space-filling models (carbon = grey, oxygen = red, nitrogen = blue, chlorine = green.
he CYP4A subclass ofcytochrome P450 enzymes catalyzes the -hydroxylation offatty acids . These mechanisms are beneﬁcial in reduc-ing the synthesis of triglycerides (TGs). In addition, PPAR- activation further decreases TG levels by amplifying theexpression of lipoprotein lipase (LPL)  and inhibitingapolipoprotein (apo) C-III in the liver
Fine tuning of metabolic processes is a hallmark of healthy organisms
PPARs• PPARs are transcriptional factors, regulating gene expression belonging to the ligand activated nuclear receptor superfamily.• PPARs play essential roles in the regulation of cellular differentiation, development and metabolism (carbohydrate, lipid, protein),• Activation by endogenously secreted prostaglandins, fatty acids and eicasanoids.• On activation, initiate transcription of an array of genes that are involved in energy homeostasis.
Gene transcription machinery• In addition to activation of PPARs by natural and synthetic ligands other factors such as RXR,PPRE and cofactors play a pivotal role in acheiving desired transcription.
RXR Vs RXR and heterodimerisation RAR. .• The LBD domain facilitates the heterodimerisation of PPARs with the RXR and the resultant heterodimer subsequently binds to PPRE with the recruitment of cofactors
PPREs• Structurally, PPREs consist of direct repeat (DR)-1 elements of two hexanucleotides with the AGGTCA sequence separated by a single nucleotide spacer.• The DR-1 pattern is speciﬁc for PPAR–RXR heterodimer, which distinguishes it from the DR- 3, DR-4 patterns of other nuclear receptor responsive element patterns.
Coactivators and Corepressors• Several proteins act as coactivators or corepressors that mediate the ability of nuclear receptors to initiate or suppress the transcription process.• Unliganded state – corepression – histone deacetylase activity• Liganded state – coactivation- histone acetylase activity• NCoR & SMRT• SRC-1 & PPAR-BP
PPAR -γCritical factor for adipogenesis and glucose metabolism
The PPAR-γ gene contains three promoters thatyield three isoforms, namely, PPAR-γ1, PPAR-γ2and PPAR-γ3.Tissue dependent expressionPPAR-γ1 is found in a broad range oftissues, whereas PPAR-γ2 is restricted to adiposetissue.PPAR-γ3 is abundant in macrophages, largeintestine and white adipose tissue.
PPAR-γ mediated gene transcription• The gene transcription mechanism is identical in all PPAR subtypes.• The process of transcription begins with the binding of ligands (endogenous or exogenous) to the PPAR-γ receptor.• Ligand-bound PPAR heterodimerises with RXR, this heterodimer binds to the promoter region of PPRE, with the recruitment of co-activators.• This results in the increase in transcription activities of various genes involved in diverse biological processes .
Major mechanisms ofPPAR-γ involved in the improvement of insulin resistance Lipid metabolism Glucose homeostasis Adipogenesis
Biological mechanisms of PPAR γ• Adipocyte differentiation Adipogenesis refers to the process of differentiation of the pre- adipocyte precursor cells into adipocytes that are capable of lipid ﬁlling, as well as the expression of hormones and cytokines. PPAR γ and C/EBP are important transcription factors involved in the process of cell growth and arrest, followed by progression into the fully differentiated adipocyte phenotype.
In addition to the stimulation of adipocyte differentiation, activation of PPAR-γ also promotes apoptosis in mature lipid-ﬁlled adipocytes. This ligand-induced apoptosis in mature cells causes the stimulation of adipogenesis from pre-adipocyte precursors, resulting in an increased number of small, relatively insulin-sensitive adipocytes.
Insulin SensitizationTissue necrosis factor alpha (TNF-α), a pro-inﬂammatorycytokine that is expressed by adipocytes, has been linked toinsulin resistance.In vivo investigations showed that PPAR- γ agonists improveinsulin resistance by opposing the effect of TNF-α in adipocytes.Expression of the glucose transporter protein GLUT4 by PPAR-γ agonists in adipocytes is also pivotal in the process of glucoseuptake..
Resistin, a hormone secreted by adipocytes that elevates bloodglucose levels, was inhibited by TZDs. Adipocyte-derived factors such as 11β-hydroxysteroiddehydrogenase 1 and adiponectin were inﬂuenced by PPAR-γactivation, improving insulin resistance and glucose homeostasis.
PPAR- α serves as a receptor for structurally diverseclass of compounds, including hypolipidemic ﬁbrates.PPAR- α is expressed in numerous tissues in rodentsand humans including liver, kidney, heart, skeletalmuscle and brown fat.
Biological mechanisms of PPAR α• The critical role of PPAR-α agonists in the regulation of β oxidation of fatty acids has been well documented.• They stimulate the cellular uptake of fatty acids by increasing the expression of the fatty acid transport protein (FATP) and fatty acid translocase (FAT).• Exogenous ligands of PPAR-α such as ﬁbrates and other peroxisome proliferator agents promote the expression of cytochrome P4504A (CYP4A).• In the heart, PPAR-α primarily supplies energy to the myocardium by regulating the genes responsible for fatty acid uptake and oxidation.• This is achieved by decreasing fatty acid oxidation and inhibiting lipoprotein lipase.
PPAR-α agonists have been reported to activatethe expression of apolipoprotein A-1.PPAR-α activation also inﬂuences the expressionof the cholesterol efﬂux “pump” known as ATPbinding cassette A1 (ABCA1) in macrophages, animportant component of the apolipoprotein A1-mediated RCT pathway.
PPAR β• Despite vigorous research on PPAR-γ and PPAR-α, the functional identity of PPAR-β remains unclear.• PPAR-β is expressed in a wide range of tissues and cells, with relatively higher levels in the brain, adipose tissue and skin.
CONCLUSION• PPARs are key transcriptional factors that catalyze and coordinate different biochemical events in order to achieve energy homeostasis.• To date, three main types of PPARs have been identiﬁed, namely α,β, and γ.• Each isoform varies in ligand speciﬁcity and tissue distribution and hence serve different biological purposes.
REFERENCES• B.Desvergne, et.al, Peroxisome Prolferator-Activated Receptor;Nuclear control of metabolism,Endocrine reviews:649-688:1999;20.• K.Bhavani , et . al, An overview of Biological Mechanisms of PPARs, Pharmacological research:51,85-94.