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-κB and AP-1, thus constituting one of the major mechanisms for the progression of steatosis to steatohepatitis. 1. Introduction 1.1. Epidemiologic Aspects Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome (MetS) and has emerged as the most frequent cause of chronic liver disease worldwide, becoming the third most common indication for liver transplantation in order to rescue patients with end-stage liver disease [1, 2]. NAFLD encompasses a wide disease spectrum ranging from simple triacylglycerol (TAG) accumulation in hepatocytes (hepatic steatosis), which is defined by accumulation of liver fat (>5% per liver weight) in the presence of <20？g of daily alcohol consumption, to steatosis with inflammation (nonalcoholic steatohepatitis, NASH), fibrosis, and cirrhosis [2, 3]. Liver biopsy is the gold standard for diagnosis and has the additional benefit of distinguishing between NASH and simple steatosis, thus allowing for the staging of the degree of fibrosis [4]. NAFLD affects 17 to 33% in the general populations, whereas that of NASH affects 2% to 3% of the population [2, 5]. In obese subjects, NAFLD incidence reaches 60% to 90% and for NASH and hepatic cirrhosis 20% to 25% and 2% to 8%, respectively. In subjects with MetS, the prevalence of NAFLD is increased fourfold compared with those without the disease, and 30% of NAFLD subjects have MetS [6,
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