The role of GPIHBP1 in regulation of LPL Selleckchem ATM/ATR inhibitor activity is supported by the observations that the pattern of tissue GPIHBP1 expression is similar to that of LPL (high levels in heart, adipose and skeletal muscle), and both GPIHBP1-deficient mice and humans show severe hypertriglyceridemia and diminished heparin-releasable LPL [21]. Moreover, GPIHBP1-expressing CHO cells avidly bind large lipoproteins (d < 1.006 g/ml) from GPIHBP1-deficient mice and exhibit 10- to 20-fold greater LPL

binding capacity than control cells [22]. In a series of earlier studies we found a significant reduction of gene expression, protein abundance and enzymatic activity of LPL, and heparin releasable LPL in adipose tissue, skeletal muscle and myocardium of rats with CKD [14, 15]. In confirmation of the earlier studies, BIIB057 datasheet CRF rats employed in the present study exhibited a significant down-regulation of LPL mRNA and protein expressions selleck in the skeletal muscle, myocardium and visceral as well as subcutaneous fat tissues. Down-regulation of LPL in skeletal muscle and adipose tissue in the CRF animals was accompanied by a significant reduction of GPIHBP1 mRNA abundance in these tissues. This observation suggests that CKD can simultaneously reduce LPL and GPIHBP1 transcript abundance by either suppressing their gene expression of or lowering their mRNA stability. The reduction

of mRNA abundance was accompanied by a parallel reduction of Vorinostat immunostaining for GPIHBP1 protein in the corresponding tissues of the CRF animals. Thus acquired LPL deficiency is compounded by GPIHBP1 deficiency in CKD. LPL and GPIHBP1 deficiencies in CKD result in impaired clearance of triglyceride-rich lipoproteins and diminished availability of lipid fuel to adipocytes for energy storage and to myocytes

for energy production. Together these defects contribute to the CKD-associated hypertriglyceridemia, cachexia, reduced exercise capacity and atherogenic diathesis. The authors wish to note that the mechanism by which CRF down-regulates GPIHBP1 is presently unclear and awaits future investigations. Moreover, while demonstrating a direct association, the data presented are not sufficient to prove causality between LPL and GPIHBP1 deficiencies in CRF animals. Further studies are needed to determine the contribution of down-regulation of GPIHBP1 to LPL deficiency in CRF. Longitudinal studies employing animals with different types and severities of renal insufficiency can help to further define the course and consequences of the CRF-induced GPIHBP1 deficiency. In conclusion, LPL deficiency in CKD is associated with and compounded by GPIHBP1 deficiency. Together these abnormalities contribute to impaired clearance of triglyceride-rich lipoproteins, diminished availability of lipid fuel for energy storage in adipocytes and energy production in myocytes and consequent hypertriglyceridemia, cachexia, muscle weakness and atherosclerosis.