metabolic disorders

1. PPARs
Peroxisome Proliferator Activated Receptors

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.

6. Overview of metabolic roles of 3 PPAR isoforms

8. Structural features of PPARs

10. Molecular mechanisms of PPARs

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.

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

17. PPAR -γ
Critical factor for adipogenesis and glucose metabolism

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.

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

22. Important biological effects of PPAR-γ

23. PPAR γ ligands
• Exogenous Vs Endogenous. . . .

24. PPAR γ agonists from natural product
library
Saururus chinensis Glycyrrhiza uralensis

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.

29. PPAR α

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.

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.