Peroxisome proliferator-activated receptor
Peroxisome proliferator- activated receptors (short: PPARs ) are intracellular receptors that are activated by a physiological or pharmacological ligands and regulate the transcription factors, the expression of a variety of genes. They belong to a group of receptors that are located in the nucleus.
In the human organism have so far three PPAR subtypes ( α, β / δ, γ ) are identified. They differ not only in their local expression, but also in terms of their gene expression pattern and the biological function of the genes whose transcription is influenced by it.
- 3.1 fibrates
- 3.2 thiazolidinediones / glitazones
- 3.3 Glitazare
PPAR subtypes
PPARa
PPARa is highly expressed in the liver and in the kidney, intestine and heart. , The activation of PPARa primarily effects on Bluttfettwerte: It causes inter alia a reduction of the circulating triglycerides, the synthesis of apo A1, an increase in the uptake of free fatty acids, an increase in fatty acid oxidation and an HDL - increasing while reducing LDL concentration. In addition, the activation of PPAR has anti-inflammatory effects.
PPARβ / δ
PPARβ (also referred to as PPAR delta ) is in almost all tissues of the human body detected. The β / δ receptor regulates primarily the expression of genes with effects on lipid metabolism. In addition, owns PPARβ / δ central functions in cell proliferation. In experiments in obese animals the activation of PPARβ / δ an improvement of various metabolic parameters as well as a reduction in body weight caused.
PPAR
PPAR is ubiquitously expressed. The activation of PPAR in particular brings an improvement of glucose metabolism and insulin sensitivity. Furthermore, the activation of the PPAR receptor, increases the uptake of free fatty acids, and effect on the differentiation of adipocytes and macrophages. In addition, activation of PPAR has anti-inflammatory effects. Ultimately was an association between the activation of the PPAR receptor, and a reduction in the risk of atherosclerosis are illustrated.
Mechanism of Action
Peroxisome proliferator- activated receptors ( PPARs ) can be activated by both physiological and pharmacological ligands. After the activation of the PPAR binding occurs at a similarly activated retinoid X receptor ( RXR). Next, this complex binds to a specific DNA sequence, the PPAR response element ( PPRE ) and thereby induces specific Gentranskriptionsmuster.
Clinical usefulness
Due to their influence on various metabolic processes in the human organism, the interest in therapeutic modulation of PPARs in recent years has risen sharply. Various substances that act via activation of PPARs, are already being used or are in clinical trials. These so-called PPAR - agonists, however, differ significantly in the induced by the activation of gene expression profiles, ie, each PPAR agonist causes specific gene activation and gendering activation patterns. A classification of PPAR agonists is extremely limited due to this substance-specific effect profile possible.
Fibrates
Fibrates are pharmacological ligands for PPAR, as lipid-lowering agents for the treatment of lipid disorders for use that come in the first place (eg bezafibrate, gemfibrozil ). Fibrates produce, inter alia, a marked reduction in the concentration of triglycerides in the blood, and a slight increase in HDL cholesterol.
Thiazolidinediones / glitazones
Thiazolidinediones or glitazones are pharmacological agents that activate predominantly PPAR. They increase insulin sensitivity and prevents hyperinsulinemia. The thiazolidinediones also referred to as insulin sensitizers. Because of their action, they are used to treat patients with diabetes mellitus used (eg, pioglitazone ).
Glitazare
Glitazare are dual PPAR agonists that interact with both the PPARa and the PPAR receptor and thus potentially can affect a variety of metabolic processes favorable: About the activation of PPAR they increase the insulin sensitivity of the peripheral tissue. In addition, the activation of PPARa results in an improvement of different parameters in the lipid profile (for example, increase of HDL cholesterol, reducing LDL-cholesterol ). Because of this dual mode of action PPARa / γ agonists are considered as promising treatment options in cardiovascular risk prevention in patients with type 2 diabetes. However, the first representatives of the PPARa / γ agonists muraglitazar and tesaglitazar could not meet the expectations set for them, and had due to their side effect profile are stopped in their development. Currently located with Aleglitazar a PPARa / γ agonist in clinical trials, which binds with similar affinity to PPAR - and PPAR receptors. Due to its balanced receptor affinity Aleglitazar causes a specific and characteristic for this substance gene activation and gendering activation pattern that differs significantly from that of other Glitazare. Clinical data from Phase II demonstrate beneficial effects on glucose levels, lipid profile and other cardiovascular risk factors such as blood pressure and inflammatory markers. The data suggest that Aleglitazar has the potential to reduce cardiovascular risk in patients with type 2 diabetes. This hypothesis is currently being investigated in a Phase III study endpoint.