3. Fine tuning of metabolic processes is a
hallmark of healthy organisms
4. 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.
11. 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.
12. 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
13. 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.
14.
15. 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
18. The PPAR-γ gene contains three promoters that
yield three isoforms, namely, PPAR-γ1, PPAR-γ2
and PPAR-γ3.
Tissue dependent expression
PPAR-γ1 is found in a broad range of
tissues, whereas PPAR-γ2 is restricted to adipose
tissue.
PPAR-γ3 is abundant in macrophages, large
intestine and white adipose tissue.
19.
20. 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 .
21. Major mechanisms of
PPAR-γ involved in the improvement of insulin
resistance
Lipid
metabolism
Glucose
homeostasis
Adipogenesis
25. 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.
26. 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.
27. Insulin Sensitization
Tissue necrosis factor alpha (TNF-α), a pro-inflammatory
cytokine that is expressed by adipocytes, has been linked to
insulin resistance.
In vivo investigations showed that PPAR- γ agonists improve
insulin 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 glucose
uptake..
28. Resistin, a hormone secreted by adipocytes that elevates blood
glucose levels, was inhibited by TZDs.
Adipocyte-derived factors such as 11β-hydroxysteroid
dehydrogenase 1 and adiponectin were influenced by PPAR-γ
activation, improving insulin resistance and glucose homeostasis.
30. PPAR- α serves as a receptor for structurally diverse
class of compounds, including hypolipidemic fibrates.
PPAR- α is expressed in numerous tissues in rodents
and humans including liver, kidney, heart, skeletal
muscle and brown fat.
31. 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.
32. PPAR-α agonists have been reported to activate
the expression of apolipoprotein A-1.
PPAR-α activation also influences the expression
of the cholesterol efflux “pump” known as ATP
binding cassette A1 (ABCA1) in macrophages, an
important component of the apolipoprotein A1-
mediated RCT pathway.
33.
34. 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.
35. 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.
36. REFERENCES
• B.Desvergne, et.al, Peroxisome Prolferator-Activated
Receptor;Nuclear control of metabolism,Endocrine
reviews:649-688:1999;20[5].
• K.Bhavani , et . al, An overview of Biological Mechanisms of
PPARs, Pharmacological research:51[2005],85-94.
Hinweis der Redaktion
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.[1] PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis[2] 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.[1]
he CYP4A subclass ofcytochrome P450 enzymes catalyzes the -hydroxylation offatty acids [78]. 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) [79] and inhibitingapolipoprotein (apo) C-III in the liver