抄録
Non-alcoholic fatty liver disease (NAFLD) has become a worldwide prevalence as it is the most common liver disease in developed countries. NAFLD is linked to increased incidence of obesity and many other metabolic disorders. Studies also support the idea of NAFLD as a hepatic manifestation of metabolic syndrome, a multisystem disease rather than a liver confined pathology. During disease progression, NAFLD is often accompanied by hepatocyte injury and inflammation, a condition referred to as non-alcoholic steatohepatitis (NASH). With continuous collagen deposition and vascular remodeling, cirrhosis may occur. As severe NAFLD can lead to life-threatening conditions such as cirrhosis and hepatocellular carcinoma, understanding the molecular mechanisms is crucial for discovering new targets for prevention and treatment.
Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein first described as a neurotrophic factor in the eye. The role of PEDF in lipid metabolism was established when adipose triglyceride lipase (ATGL), a major triglyceride hydrolase, was characterized as its binding partner. Our data revealed that PEDF expression was decreased in a rat NASH model. We further showed that decreased PEDF levels in hepatocytes resulted in lipid accumulation due to up-regulation of fatty acid translocase (CD36), a major enzyme that facilitates fatty acid uptake. Interestingly, decreased PEDF expression was observed during adipogenic differentiation of rat adipose-derived stem cells (AdSCs) and CD36 was also up-regulated. Knocking down PEDF in differentiated AdSCs resulted in elevated CD36 and C/EBP transcription factors, with a concomitant increase in adipocyte number. We further showed that the increase in CD36 in response to PEDF down-regulation in both cell types was a result of elevated levels of PPARγ, the master regulator in lipid metabolism. Analyzing the promoter region of the PEDF gene, we identified putative response elements of glucocorticoid receptor (GREs). We demonstrated that dexamethasone, a synthetic glucocorticoid widely used for adipogenesis, regulated PEDF expression at the transcriptional level. Taken together, these results suggest that the PEDF-CD36 regulation can be a potential target of interest in developing new therapeutic measures.
