Peroxisome proliferator activated receptor alpha (PPARα) ameliorates toxic mediated liver fibrosis

Palmitoylethanolamide is a natural, endogenous Peroxisome proliferator activated receptor alpha (PPARα) agonist. Since a decade it has become clear that one of the major mechanisms of action of palmitoylethanolamide’s anti-pain and anti-inflammatory actions are mediated via PPAR-alpha.

That is why it is important to review the significance of PPAR alpha and PPAR alpha agonists in a certain medical conditions, because this could lead to new hypothesis related to treatment.

Nan et al. published an interesting paper in ‘Lipids in Health and Disease’ ( 2013, 12:11), title: ‘Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol mediated liver fibrosis in mice’.

In this paper they point out that alcohol metabolism in the liver leads to the release of reactive oxygen species (ROS) and this is followed by the generation of lipid peroxidation products, leading to inflammatory responses and release of proinflammatory and profibrogenic cytokines, such as tumor necrosis factor alpha (TNF-α) and transforming growth factor beta 1 (TGF-β1).

In a previous study the authors showed that Induction of PPARα significantly ameliorated the severity of alcohol induced liver injury by regulating the overexpression of inflammation related genes. In the present study, the effects of PPARα in the pathogenesis of alcohol-induced liver fibrosis were analysed.

In a number of experiments, making use of the PPARα agonist WY14643, the authors showed:

1.a significant reduction of serum ALT and AST levels
2.significant amelioration of the liver injury
3.fibrotic areas of liver sections due to alcohol and CCl4 were significantly blunted

4. restored expression level of PPARα in alcohol plus CCl4 treated mice
5.reduction of the hepatic expression of the proinflammatory factor tumor necrosis factor-alpha (TNF-α)

6.ethanol treatment increased  a number of pro-inflammatory factors, and WY14643  suppressed these (OPN, TGF-β1, visfatin, PI3K, MMP-2 and MMP-9 mRNA)

7. WY14643  enhanced hepatic expression of antifibrotic cytokines

Their conclusion was:

In summary, the present study demonstrated a protective role of PPARα induction in experimental alcoholic liver fibrosis through down-regulating the proinflammatory and profibrogenic factors TNF-α, OPN, TGF-β1, visfatin, PI3K, MMP-2 and MMP-9, and up-regulating the tissue-protective cytokines adiponectin, IL-10 and HO-1. Consequently, PPARα agonist administration might serve as an effective therapeutic strategy for alcoholic liver fibrosis.

WY 14643 is a Peroxisome Proliferator Activated Receptor-α (PPARα) agonist that is under experimental investigation for prevention of severe cardiac dysfunction, cardiomyopathy and heart failure. This compound is a pharmaceutical one still in early development.

Palmitoylethanolamide is a natural  Peroxisome Proliferator Activated Receptor-α (PPARα) agonist, of benefit for a number of pain states and inflammation-related disorders and with a good safety profile.

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