title: Dysregulation of hepatic fatty acid metabolism in chronic kidney disease.
abstract: 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 (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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Nephrology and Hypertension, University of California, Irvine, Irvine, CA, USA.
authors.forename: Kyubok
authors.initials: K
authors.lastname: Jin
authors.forename: Keith
authors.initials: K
authors.lastname: Norris
authors.forename: Nosratola D
authors.initials: ND
authors.lastname: Vaziri
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D047495:PPAR gamma / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000503:physiopathology*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005227:Fatty Acids; C442825:Mlxipl protein, rat; D047495:PPAR gamma; D014280:Triglycerides; C494883:Dgat1 protein, rat; D051048:Diacylglycerol O-Acyltransferase