Andy, Here's a metabolic diseases meeting by the New York Academy of Sciences on PPARs. Notice how PPAR/RXR heterodimers are mentioned in several abstracts (and now should be in all):
Summary of The Biochemical Pharmacology Discussion Group Meeting on
PPARs and Other Activated Nuclear Receptor Targets for the Treatment of
Metabolic Diseases, April 29, 1997
Organizers: Dr. Janet Sredy (Institute for Diabetes Discovery, janet.sredy@diabetesdisc.com) &
Dr. Barbara Petrack (Drew University, bpetrack@drew.edu)
Abstract of the program
The nuclear receptor superfamily of ligand activated transcription factors includes the peroxisome
proliferator-activated receptors (PPARs). PPARs regulate the expression of a variety of genes
including those involved in lipid and glucose homeostasis. This symposium will focus on the latest
developments in this field and potential therapeutic targets.
"PPARs: A Family of Nuclear Fatty Acid and Eicosanoid Receptors"
The first speaker, Dr. Barry Forman (Salk Institute) presented a summary of the PPARs family of
nuclear receptors. Many are orphan receptors but fatty acid or prostanoid metabolites are likely
endogenous ligands. PPAR-alpha resides in the liver where it controls beta-oxidation of
long-chained fatty acids in peroxisomes. Although the in vivo ligands have not been identified, in
vitro studies suggest that 8,9-di-HETE is the endogenous ligand for PPAR-alpha receptors.
PPAR-gamma controls lipid storage by increasing adipocyte differentiation and these receptors also
control glucose homeostasis. The endogenous ligand of gamma receptors may be
15-deoxy-(delta12-14)-prostaglandin J2. The thiazolidinediones are ligands for PPAR-gamma; they
improve insulin resistance and have been shown to be novel drugs for treating Syndrome X
associated with Type II diabetes. Pioglitazone also lowers triglycerides in liposarcoma tumor cells
and pioglitazone is undergoing clinical evaluation since no good drugs are available for such cancers.
PPAR-delta is ubiquitous; its endogenous ligand is unknown but it seems to be a poly-unsaturated
fatty acid. Receptors for retinoids, thyroid hormone, vitamin D3 and PPARs bind to their response
elements as heterodimers with retinoid X receptors. The DNA response elements consist of core
motifs organized as direct or inverted repeats.
Dr. Barry Forman
Phone: 619-453-1550; Fax: 619-455-1349; Email: Forman@AXPI.Salk.edu
References: Genes and Development 10,974-984,1996; Cell: 83, 803-812,1995; Cell 81,
687-693, 1995.
"Two Mechanisms for Repression of Gene Expression by the Orphan Receptor SHP"
Dr. David Moore (Mass General Hospital) described a new orphan nuclear receptor, SHP, which
contains both ligand-binding and imerization domains but not the DNA-binding domain; it has no
zinc-finger. SHP interacts with retinoid, thyroid, glucocorticoid and estrogen receptors both in vitro
and in the yeast two-hybrid system. SHP blocks binding by RAR/RXR heterodimers; it inhibits
transactivation by direct protein interactions. SHP functions in the liver as a transcriptional repressor
of signaling pathways and it blocks DNA binding, suggesting that it may be a useful therapeutic
target when its ligand is identified.
Dr. David Moore
Phone: 617-726-5943; Fax: 617-726-6893; Email: Moore@Frodo.mgh.harvard.edu
References: Science: 272,1336-1339, 1996; J. Steroid Biochem. & Moo. Biol. 56, 23-30,1996.
"PPARs: Ligand Discovery and Development"
Dr. Timothy Willson (Glaxo-Wellcome) described the development of compounds for the treatment
of insulin-resistance from clofibrate, the first hypolipidemic agent that was found to activate
peroxisomal proliferation, to the more potent and PPAR receptor subtype specific
thiazolidinediones. The thiazolidinediones e.g., BRL-49653, bind PPAR-gamma, reduce plasma
glucose, increase white and brown fat and increase the level of uncoupling protein both in vitro
(HIB-B cells) and in vivo (Zucker obese rat model). UCP gene up- regulation is an important
therapeutic target for PPAR agonists. Selective ligands are available for binding both alpha
(8S-hydroxyeicosatetrenoic acid) and gamma (15d--PG J2) receptors. There is a structure activity
relationship with in vitro PPAR-gamma agonist activity and in vivo antihyperglycemic activity. A
further research goal is to find the most specific and potent
PPAR ligands and then to explore their relationship to diseases. Dr. Willson termed this strategy,
reverse endocrinology.
Dr. Timothy Willson
Phone: 919-483-9875; Fax: 919-315-5668, Email: willson tm@glaxo.com
References: J Med Chem 39, 665-668, 1996; Cell 83, 813-9, 1995; J Biol Chem
270,12953-6,1995
"Regulation of Adipocyte Differentiation by Nuclear Hormone Receptors"
Dr. Lazar ( U of Penn) reviewed his research on the 3T3 -L1 adipocyte cell model for
differentiation. In addition to the PPAR ligands playing a role in the initial differentiation process the
PPAR ligands appear to be important in maintaining the 3T3-L1 cells in a differentiated state. He
presented a number of cellular experiments suggesting that the induction of adipogenesis in the NIH
3T3 cell differs somewhat from that of the 3T3-L1 cells. Adipogenesis is associated with a
sequential induction of C/EBP beta, PPAR-gamma, C/EBPalpha and again PPAR-gamma, thus
providing a feedback loop that keeps the cells in a differentiated state. Prostaglandins and
compounds such as thiazolidinediones induce differentiation of the 3T3-L1 cell. Although the
thiazolidinediones induce differentiation, a paradoxical decrease in the expression of leptin occurs.
The nuclear receptor C terminal end is generally considered the activation domain although serine
phosphorylation of the N terminal domain of the estrogen receptor activates this receptor. However,
phosphorylation of a MAP kinase consensus site in the N terminal domain of the PPAR-gamma
receptor inhibits both ligand-dependent and ligand-independent transcriptional activation. Thus
phosphorylation may prove to be another route by which hormone/cytokine signaling cascades
could potentially regulate PPAR-gamma activity.
Dr. Mitchell A. Lazar
Phone: 215-898-0198, FAX: 215-898-5408, Email:lazar@mail.med.upenn.edu
References: J Biol Chem 272: 5128-32,1997; Mol & Cell Biol 17:1552-61,1997; Proc Nat Acad
Sci 93:5793-6,1996
"Troglitazone: Mechanism and Effects in Models of Insulin Resistance"
Dr. Randall Whitcomb (Parke-Davis) reviewed the clinical data of the PPAR agonist troglitazone
(Rezulin). This thiazolidinedione contains an alpha tocopherol tail. Troglitazone was recently
approved in the US for the treatment of NIDDM and is being considered for other insulin-resistant
disease states such as polycystic ovary syndrome (PCOS). Treatment with troglitazone improves
hyperglycemia, hyperinsulinemia, and insulin-mediated glucose disposal. Triglycerides are lowered,
HDL and LDL levels are elevated and diastolic blood pressure is lowered. All the mechanisms of
action of this agent are not well defined since with the major therapeutic effect is to enhance
peripheral glucose uptake. Women with PCOS treated with troglitazone show improved insulin
action and a decrease in the elevated levels of estrogen, LH and adrenal androgen. To date, no
significant side effects have been observed in humans.
Dr. Randall W. Whitcomb
Phone: 313-996-5762, FAX: 313-998-5819, Email: WHITCOR@AA.WL.COM
References: Diabetes 46:433-9,1997; J of Clin Endo & Metabol 81:3299-306, 1996; Exp Opin in
Invest Drugs 4:1299-09,1995 |
