Journal
NEPHROLOGY DIALYSIS TRANSPLANTATION
Volume 28, Issue 2, Pages 313-320Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ndt/gfs350
Keywords
carbohydrate-responsive element binding protein; chronic kidney disease; lipid metabolism; PPAR alpha; sterol-responsive element binding protein
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Funding
- NIH [RR026138, MD000182]
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Background. Chronic kidney disease (CKD) results in hypertriglyceridemia which is largely due to impaired clearance of triglyceride-rich lipoproteins occasioned by downregulation of lipoprotein lipase and very low-density lipoprotein (LDL) receptor in the skeletal muscle and adipose tissue and of hepatic lipase and LDL receptor-related protein in the liver. However, data on the effect of CKD on fatty acid metabolism in the liver is limited and was investigated here. Methods. Male Sprague-Dawley rats were randomized to undergo 5/6 nephrectomy (CRF) or sham operation (control) and observed for 12 weeks. The animals were then euthanized and their liver tissue tested for nuclear translocation (activation) of carbohydrate-responsive element binding protein (ChREBP) and sterol-responsive element binding protein-1 (SREBP-1) which independently regulate the expression of key enzyme in fatty acid synthesis, i.e. fatty acid synthase (FAS) and acyl-CoA carboxylase (ACC) as well as nuclear Peroxisome proliferator-activated receptor alpha (PPAR alpha) which regulates the expression of enzymes involved in fatty acid oxidation and transport, i.e. L-FABP and CPT1A. In addition, the expression of ATP synthase alpha, ATP synthase beta, glycogen synthase and diglyceride acyltransferase 1 (DGAT1) and DGAT2 were determined. Results. Compared with controls, the CKD rats exhibited hypertriglyceridemia, elevated plasma and liver tissue free fatty acids, increased nuclear ChREBP and reduced nuclear SREBP-1 and PPAR alpha, upregulation of ACC and FAS and downregulation of L-FABP, CPT1A, ATP synthase alpha, glycogen synthase and DGAT in the liver tissue. Conclusion. Liver in animals with advanced CKD exhibits ChREBP-mediated upregulation of enzymes involved in fatty acid synthesis, downregulation of PPAR alpha-regulated fatty acid oxidation system and reduction of DGAT resulting in reduced fatty acid incorporation in triglyceride.
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