PPARs, RXRs, and Drug-Metabolizing Enzymes

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This special issue of PPAR Research is dedicated to " PPARs, RXRs and Drug Metabolizing Enzymes ". Knowledge of PPAR biology, over the past five years, has dramatically increased our understanding of the potential therapeutic usefulness of these receptors in metabolic alterations associated with disease process of alcoholic and non-alcoholic fatty liver disease and metabolic syndrome. In addition, the utility of PPAR agonist in the treatment of liver disease by normalizing hypertriglyceridemia, dyslipidemia, and the toxic effects of bile acids has a sound scientific basis in the ability of PPAR receptors to control lipid oxidation and disposal as well as regulators of hepatic inflammation. Further insight into both the indirect and direct effects of dual and pan PPAR agonist may potentiate the development of new therapeutic modalities to treat fatty acid oxidation disorders, dyslipidemia, inflammation, and bile acid accumulation associated with several liver diseases and metabolic syndrome. Articles included in this special issue highlight the importance of PPARs and RXR in drug metabolism and hepatic diseases associated with metabolic disorders. Alterations in drug metabolizing gene expression in different disease states due to the differential expression of PPAR isoforms highlights the importance of PPAR in disease progression and as therapeutic target in the amelioration of disease progression. The first review summarizes past and new developments in alcoholic fatty liver disease (ALD) and how PPAR/RXR regulates phase I enzymes in alcohol metabolism and the redox balance of cells. The direct impairment of PPAR by acetaldehyde results in reduction of NAD+ pool leading to alterations in lipid metabolism, increased oxidative stress, and increased pro-inflammatory cytokines, chemokines and acute phase proteins, which may be central in the onset and perpetuation of mechanism in the clinical progression of alcoholic liver disease (ALD). A second review focuses on the role of PPAR isoforms in the regulation of bile acid and cholesterol metabolism, with specific insight into how PPARα regulates bile acid synthesis, conjugation, and transport by phase II and III enzymes. This review also provides an updated report on how PPARs regulate cholesterol synthesis, absorption, and reverse cholesterol transport, and how PPAR agonist may be used to treat cholestatic liver disease. This review also raises important questions concerning the use of PPAR agonist in treating bile …