Apolipoprotein A5 is an inflammatory responsive gene down-regulated by
tumor necrosis factor alpha and interleukin-1
Several epidemiological studies have established that elevated plasma triglyceride concentrations constitute an independent risk factor for cardiovascular diseases. In addition, systemic inflammation is associated with severe hypertriglyceridemia and previous studies have demonstrated that cytokines such as tumor necrosis factor alpha (TNFalpha;) and interleukin-1 (IL-1) can elevate plasma triglyceride levels. Recently, we identified a new apolipoprotein, APOA5, selectively expressed in the liver and showed that this gene is a crucial determinant of plasma triglyceride levels. In this study, we sought to determine whether inflammatory cytokines regulate APOA5 and consequently influence plasma triglyceride levels. We found initially that treatment of human hepatocytes with TNFalpha; or IL-1 reduced the expression of APOA5 mRNA. Subsequent, we demonstrated through transient transfection experiments that both TNFalpha; and IL-1 down-regulate human APOA5 at the transcriptional level. Further deletion analyses of the APOA5 promoter and binding assays revealed the presence of a promoter sequence, containing a PPARalpha; Response Element, responsive to cytokine stimulation. In vivo, treatment of hAPOA5 transgenic mice with TNFalpha; down-regulated the hAPOA5 gene expression in hepatocytes. In patients displaying systemic inflammation, plasma concentrations of triglycerides and ApoAV were inversely correlated. These findings demonstrate that APOA5 is an inflammatory responsive gene and constitutes a link between inflammation and triglyceride-associated cardiovascular risk.