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Dysregulation of hepatic fatty acid metabolism in chronic kidney disease.

AbstractBACKGROUND:
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 (PPARα) 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 α, ATP synthase β, 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 PPARα, upregulation of ACC and FAS and downregulation of L-FABP, CPT1A, ATP synthase α, 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 PPARα-regulated fatty acid oxidation system and reduction of DGAT resulting in reduced fatty acid incorporation in triglyceride.
AuthorsKyubok Jin, Keith Norris, Nosratola D Vaziri
JournalNephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 28 Issue 2 Pg. 313-20 (Feb 2013) ISSN: 1460-2385 [Electronic] England
PMID23045433 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Fatty Acids
  • Mlxipl protein, rat
  • PPAR gamma
  • Triglycerides
  • Dgat1 protein, rat
  • Diacylglycerol O-Acyltransferase
Topics
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (metabolism)
  • Diacylglycerol O-Acyltransferase (metabolism)
  • Disease Models, Animal
  • Fatty Acids (metabolism)
  • Liver (metabolism)
  • Male
  • PPAR gamma (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Renal Insufficiency, Chronic (metabolism, physiopathology)
  • Triglycerides (metabolism)

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