Nonalcoholic fatty liver disease (NAFLD) defines a wide spectrum of liver diseases that extend from simple steatosis, that is, increased hepatic lipid content, to nonalcoholic steatohepatitis (NASH), a condition that may progress to cirrhosis with its associated complications. Nuclear hormone receptors act as intracellular lipid sensors that coordinate genetic networks regulating lipid metabolism and energy utilization. This family of transcription factors, in particular peroxisome proliferator-activated receptors (PPARs), represents attractive drug targets for the management of NAFLD and NASH, as well as related conditions such as type 2 diabetes and the metabolic syndrome. The impact on the regulation of lipid metabolism observed for PPARs has led to the hypothesis that genetic variants within the human PPARs genes may be associated with human disease such as NAFLD, the metabolic syndrome, and/or coronary heart disease. Here we review the available evidence on the association between PPARs genetic polymorphism and the susceptibility to NAFLD and NASH, and we provide a meta-analysis of the available evidence. The impact of PPAR variants on the susceptibility to NASH in specific subgroup of patients, and in particular on the response to therapies, especially those targeting PPARs, represents promising new areas of investigation. 1. Introduction Nonalcoholic fatty liver disease (NAFLD), a major cause of progressive liver disease, is defined by an increase in hepatic fat content not related to toxics and has a strong genetic component. As the peroxisome proliferator-activated receptors (PPARs) represent major regulators of lipid metabolism in the liver, a few studies have tested the hypothesis that genetic variants in these hormone receptors may influence the susceptibility to NAFLD, but with controversial results. In this paper, we provide an overview of the published evidence in the field, and a meta-analysis of the available results on the role of the Pro12Ala PPARγ single nucleotide polymorphism (SNP), the most studied genetic variant to date. As PPARs are also the target of several drugs under evaluation for the treatment of NAFLD, this evidence may lay the basis to design pharmacogenetic studies to assess the role of PPARs SNPs in predicting the response to drugs targeting these nuclear receptors. 2. Nonalcoholic Fatty Liver Disease (NAFLD) Liver fat deposition related to systemic insulin resistance (IR) defines NAFLD [1]. The acronym NAFLD defines a wide spectrum of liver disease ranging from simple uncomplicated hepatic fat accumulation in the
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