We read with interest the article by Qin et al.1 and the editorial comments by Andrews et al.2 regarding an elegantly revealed novel mechanism by which peroxisome proliferator-activated receptor-δ (PPARδ) regulates lipogenesis and suggesting its potential therapeutic use in liver steatosis or more appropriately non-alcoholic fatty liver disease. The authors strongly demonstrated that treatment with GW0742, the PPARδ agonist, or PPARδ overexpression markedly reduced intracellular lipid accumulation in the hepatocytes. The mechanism offered by them is that PPARδ acts by suppressing sterol regulatory element-binding protein-1 (SREBP-1) activity and by inducing the expression of insulin-induced gene-1 (Insig-1).1 The up-regulation of Insig-1 reduces lipid synthesis by preventing SREBPs from entering the Golgi apparatus for proteolytic generation of their transcriptionally active forms, thereby limiting the induction of SREBP target genes and hence lipid synthesis.
The role of PPARδ agonists in reducing body fat has been studied by various investigators. In a study by Choi et al.,3 it was shown that in the visceral adipose tissue of PPARδ agonist (L-165041)–treated rats, visfatin and adiponectin messenger RNA levels are significantly increased, suggesting that the PPARδ agonist has regulatory effects on a variety of adipokines. Similarly, another PPARδ agonist, GW501516, has been envisioned as a useful strategy against human metabolic syndrome and related diseases.4
Although in this study the authors have shown interesting observations, as clinicians, in our opinion, data from basic research studies needs to be transformed into clinical practice with caution. First, the cause–effect relationship of fatty liver and insulin resistance has been a matter of debate.5 Second, the metabolic syndrome is the outcome of a complex interaction between numerous hereditary and environmental factors.6, 7 Hence, a molecule that targets not only fatty liver but other metabolic abnormalities such as dyslipidemia, hypertension, and diabetes is needed to treat it holistically. Third, studies have shown that expression of Insig-1 also might be regulated by other PPAR isoforms8, 9; therefore, the molecule targeting a single gene (for example, PPARδ) has its own limitations. Fourth, the numerous differences between mouse and human PPAR isoforms makes it imperative to further the research using human hepatic cell lines from patients with fatty liver. This will help the scientists, researchers, and clinicians to select a few important drugs of great consequence for fatty liver from the vast armamentarium with significant therapeutic potential. Last, we think that a spirited and indomitable search for a potential therapy to treat all the correlated metabolic diseases based on the concept of the polypill should be made.10, 11