Peroxisome Proliferator Activated Receptors

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Activation scheme of PPAR α and PPAR γ

Peroxisome proliferator-activated receptors ( PPARs for short ) are intracellular receptors that are activated via a physiological or pharmacological ligand and, as transcription factors, regulate the expression of a large number of genes . They belong to a group of receptors that are located in the cell nucleus .

So far, three PPAR subtypes (α, β / δ, γ) have been identified in the human organism. These differ not only in their local expression, but above all in terms of their gene expression pattern and the biological function of the genes whose transcription is influenced by them.

PPAR subtypes

PPAR α

PPAR α is expressed to a high degree in the liver as well as in the kidneys , the intestines and the heart . The activation of PPAR α primarily has effects on blood lipid levels : Among other things, it causes a reduction in circulating triglycerides , the synthesis of Apo A1, an increase in the absorption of free fatty acids , an increase in fatty acid oxidation and an increase in HDL with a simultaneous reduction in LDL concentration . In addition, the activation of PPAR α has anti-inflammatory effects.

PPAR β / δ

PPAR β (also referred to as PPAR δ ) can be detected in almost all tissues of the human organism. The β / δ receptor primarily regulates the expression of genes that affect lipid metabolism . In addition, PPAR β / δ has central functions in cell proliferation . In experiments on obese animals, the activation of PPAR β / δ brought about an improvement in various metabolic parameters and a reduction in body weight.

PPAR γ

PPAR γ is ubiquitously expressed. The activation of PPAR γ causes, in particular, an improvement in the glucose metabolism and insulin sensitivity . Furthermore, the activation of the PPAR γ receptor increases the uptake of free fatty acids and has an effect on the differentiation of adipocytes and macrophages . In addition, the activation of PPAR γ also has anti-inflammatory effects. Ultimately, an association between the activation of the PPAR γ receptor and a reduction in the risk of arteriosclerosis could be shown. Amorfrutins bind and activate PPAR γ .

Mechanism of action

Peroxisome Proliferator Activated Receptors (PPARs) can be activated by both physiological and pharmacological ligands. After activation, the PPARs bind to an activated retinoid X receptor (RXR). This complex then binds to a specific DNA sequence, the PPAR response element (PPRE), and thereby induces specific gene transcription patterns.

Clinical usability

Due to their influence on various metabolic processes in the human organism, interest in a therapeutic modulation of PPARs has risen sharply in recent years. Various substances that work by activating the PPARs are already in use or are in clinical studies. However, these so-called PPAR agonists differ significantly in the gene expression profiles induced by the activation, that is to say each PPAR agonist causes specific gene activation and gene deactivation patterns. A classification of PPAR agonists is only possible to a very limited extent due to this substance-specific action profile.

Fibrates

Fibrates are pharmacological ligands for PPAR α , which are primarily used as lipid-lowering agents for the therapy of lipid metabolism disorders (e.g. bezafibrate, gemfibrozil ). Fibrates cause, among other things, 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 substances that mainly activate PPAR γ . They increase insulin sensitivity and prevent hyperinsulinemia . The thiazolidinediones are also known as insulin sensitizers . Because of their effect, they are used to treat patients with diabetes mellitus (e.g. pioglitazone ).

Glitazars

Glitazars are dual PPAR agonists that interact with both the PPAR α and the PPAR γ receptors and thus potentially have a beneficial effect on a large number of metabolic processes: By activating PPAR γ , they increase the insulin sensitivity of the peripheral tissue. In addition, the activation of PPAR α brings about an improvement in various parameters of the lipid profile (e.g. increase in HDL cholesterol, reduction in LDL cholesterol). Due to this dual mode of action, PPAR α / γ agonists are considered to be very promising therapy options in cardiovascular risk prevention in patients with type 2 diabetes. However, the first representatives of the PPAR α / γ agonists Muraglitazar and Tesaglitazar could not meet the expectations placed in them and their development had to be stopped due to their side effect profile. With Aleglitazar, a PPAR α / γ agonist is currently in clinical studies that binds to PPAR α and PPAR γ receptors with almost the same affinity . Due to its balanced receptor affinity, aleglitazar causes a specific gene activation and deactivation pattern that is characteristic of this substance and which differs significantly from that of other glitazars. Clinical data from phase II confirm favorable effects on the glucose level, the lipid profile and other cardiovascular risk factors such as blood pressure and inflammation 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 endpoint study.

Individual evidence

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