Upregulation of fatty acid synthase gene expression in experimental chronic renal failure

Abstract

Hypertriglyceridemia associated with chronic renal failure (CRF) and elevated plasma concentration of very-low-density lipoprotein (VLDL) are thought to be a consequence of the depressed lipoprotein lipase and hepatic lipase activities and impaired clearance of lipoproteins. However, there is some evidence that the lipoproteins overproduction might also contribute to hypertriglyceridemia in CRF. This study was performed to test the hypothesis that the increased rate of lipogenesis consequent to upregulation of fatty acid synthase (FAS), a key lipogenic enzyme, gene expression could contribute to overproduction of triacylglycerols and to hypertriglyceridemia in CRF. FAS activity, FAS protein mass (Western blot analysis), and FAS mRNA level (Northern blot analysis) in liver and epididymal white adipose tissue (WAT) were measured in male Wistar rats 6 weeks after subtotal (5 of 6) nephrectomy or sham operation. Moreover, the rate of lipogenesis in WAT was determined. The CRF group showed significant increase in FAS gene expression (measured as activity, mRNA, and protein abundance) in both liver and WAT. This was associated with the increase in the lipogenesis rate and with the increase in plasma triacylglycerol and VLDL concentrations. Our results suggest that not only decreased removal, but also an increase of triacylglycerol production could contribute, in part, to the CRF-associated hyperlipidemia. Upregulation of FAS gene expression, shown in this report for the first time, reveals another factor involved in disturbed lipid metabolism in CRF. It seems that elevated plasma insulin and cytokine concentration could play an important role in the mechanism responsible for the increased FAS gene expression in CRF.