Misregulation of PPAR functioning and its pathogenic consequences associated with nonalcoholic fatty liver disease in human obesity

Nonalcoholic fatty liver disease in human obesity is characterized by the multifactorial nature of the underlying pathogenic mechanisms,which include misregulation of ppars signaling. liver ppar-α downregulation with parallel ppar-γ and srebp-1c up-regulation may trigger major metabolic disturbances between de novo lipogenesis and fatty acid oxidation favouring the former,in association with the onset of steatosis in obesity-induced oxidative stress and related long-chain polyunsaturated fatty acid n-3 (lcpufa n-3) depletion,insulin resistance,hypoadiponectinemia,and endoplasmic reticulum stress. considering that antisteatotic strategies targeting ppar-α revealed that fibrates have poor effectiveness,thiazolidinediones have weight gain limitations,and dual ppar-α/γ agonists have safety concerns,supplementation with lcpufa n-3 appears as a promising alternative,which achieves both significant reduction in liver steatosis scores and a positive anti-inflammatory outcome. this latter aspect is of importance as ppar-α downregulation associated with lcpufa n-3 depletion may play a role in increasing the dna binding capacity of proinflammatory factors,nf-b and ap-1,thus constituting one of the major mechanisms for the progression of steatosis to steatohepatitis. © 2012 luis a. videla and paulina pettinelli.