title: Preservation of hepatocyte nuclear factor-4α contributes to the beneficial effect of dietary medium chain triglyceride on alcohol-induced hepatic lipid dyshomeostasis in rats.
abstract: BACKGROUND
  Alcohol consumption is a major cause of fatty liver, and dietary saturated fats have been shown to protect against alcoholic fatty liver. This study investigated the mechanisms of how dietary saturated fat may modulate alcohol-induced hepatic lipid dyshomeostasis.
  
  
  METHODS
  Male Sprague Dawley rats were pair-fed with 3 isocaloric liquid diets, control, alcohol, and medium chain triglyceride (MCT)/alcohol, respectively, for 8 weeks. The control and alcohol diets were based on the Lieber-DeCarli liquid diet formula with 30% total calories derived from corn oil (rich in unsaturated long chain fatty acids). The corn oil was replaced by MCT, which consists of exclusive saturated fatty acids, in the MCT/alcohol diet. HepG2 cell culture was conducted to test the effects of unsaturated fatty acids on hepatocyte nuclear factor-4α (HNF4α) and the role of HNF4α in regulating hepatocyte lipid homeostasis.
  
  
  RESULTS
  Alcohol feeding caused significant lipid accumulation, which was attenuated by dietary MCT. The major effect of alcohol on hepatic gene expression is the up-regulation of CYP4A1, CD36, and GPAT3, and down-regulation of apolipoprotein B (ApoB). Dietary MCT further up-regulated CYP4A1 gene, normalized ApoB gene, and up-regulated MTTP and SCD1 genes. The protein level of HNF4α, a master transcription factor of the liver, was reduced by alcohol feeding, which was normalized by dietary MCT. Fatty acid profiling demonstrated that alcohol feeding dramatically increased hepatic unsaturated long chain fatty acyl species, particularly linoleic acid and oleic acid, which was attenuated by dietary MCT. Dietary MCT attenuated alcohol-reduced serum triglyceride level and modulated the fatty acid composition of the serum triglycerides. Cell culture study demonstrated polyunsaturated linoleic acid rather than monounsaturated oleic acid inactivated HNF4α in HepG2 cells. Knockdown of HNF4α caused lipid accumulation in HepG2 cells due to dysregulation of very low density lipoprotein secretion.
  
  
  CONCLUSIONS
  Results suggest that dietary MCT prevents alcohol-induced hepatic lipid accumulation, at least partially, through reducing hepatic polyunsaturated long chain fatty acids and preserving HNF4α.
authors.affiliation: Center for Translational Biomedical Research , University of North Carolina at Greensboro, Kannapolis, NC 28081, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.forename: Yunping
authors.initials: Y
authors.lastname: Qiu
authors.forename: Xinqin
authors.initials: X
authors.lastname: Kang
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Sun
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Tan
authors.forename: Yantao
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xinguo
authors.initials: X
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage*; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005227:Fatty Acids / Q000008:administration & dosage; D005235:Fatty Liver, Alcoholic / Q000178:diet therapy* / Q000378:metabolism*; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051536:Hepatocyte Nuclear Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D051557:Hepatocyte Nuclear Factor 4; D051536:Hepatocyte Nuclear Factors; C496594:Hnf4a protein, rat; D000431:Ethanol