title: Increased dietary fat contributes to dysregulation of the LKB1/AMPK pathway and increased damage in a mouse model of early-stage ethanol-mediated steatosis.
abstract: OBJECTIVE
  The objective of the study was to examine the interaction of moderate and high dietary fat and ethanol with respect to formation of steatosis and regulation of the AMP-activated protein kinase (AMPK) pathway in a mouse model of chronic ethanol consumption.
  
  
  METHODS
  Male C57BL/6J mice were pair-fed a modified Lieber-DeCarli diet composed of either moderate fat [30% fat-derived calories (MF)] or high fat [45% fat-derived calories (HF)] combined with increasing concentrations of ethanol (2%-6%) for 6 weeks.
  
  
  RESULTS
  Chronic ethanol consumption resulted in significant increases in plasma alanine aminotransferase in MF (1.84-fold) and HF mice (2.33-fold), yet liver triglycerides only increased significantly in the HF model (1.62-fold). Ethanol addition significantly increased plasma adiponectin under conditions of MF but not HF. In combination with MF, the addition of ethanol significantly decreased total and hepatic pThr(172)AMPKα and acetyl CoA Carboxylase (ACC). HF plus ethanol decreased pSer(108)AMPKβ, yet a marked 1.5-fold increase in pThr(172)AMPKα occurred. No change was evident in pSer(79)ACC under conditions of ethanol and HF ingestion. In both models, nuclear levels of sterol response element binding protein 1c and carbohydrate response element binding protein were decreased. Surprisingly, MF plus ethanol significantly elevated protein expression of medium-chain acyl-CoA dehydrogenase (MCAD), long-chain acyl-CoA dehydrogenase (LCAD) and very long chain acyl-CoA dehydrogenase but did not significantly affect mRNA expression of other proteins involved in β-oxidation and fatty acid synthesis. HF plus ethanol significantly reduced mRNA expression of both stearoyl CoA desaturase 1 and fatty acid elongase 5, but did not have an effect on MCAD or LCAD.
  
  
  CONCLUSIONS
  These data suggest that, when co-ingested with ethanol, dietary fat differentially contributes to dysregulation of adiponectin-dependent activation of the AMPK pathway in the liver of mice.
authors: Department of Pharmaceutical Sciences, University of Colorado Denver Anchutz Medical Campus, Aurora, CO 80045, USA.
authors: Colin T
authors: CT
authors: Shearn
authors: Rebecca L
authors: RL
authors: Smathers
authors: Hua
authors: H
authors: Jiang
authors: David J
authors: DJ
authors: Orlicky
authors: Kenneth N
authors: KN
authors: Maclean
authors: Dennis R
authors: DR
authors: Petersen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D052242:Adiponectin / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004041:Dietary Fats / Q000008:administration & dosage*; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects*; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D052242:Adiponectin; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004041:Dietary Fats; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D000431:Ethanol; D000410:Alanine Transaminase; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase
keywords: ACC; ACLY; ALD; ALT; AMP-activated protein kinase; AMPK; ATP citrate lyase; Alcohol; CYP2E1; ChREBP; Dietary fat; ELOVL5; ELOVL6; FASN; Hepatic steatosis; LCAD; LKB1; MCAD; ME; PP2A; SCAD; SCD-1; SREBP; VLCAD; acetyl CoA carboxylase; alanine aminotransferase; alcoholic liver disease; carbohydrate response element binding protein; cytochrome p450 2E1; fatty acid elongase 5; fatty acid elongase 6; fatty acid synthase; liver kinase B1; long-chain acyl-CoA dehydrogenase; malic enzyme; medium-chain acyl-CoA dehydrogenase; protein phosphatase 2A; short-chain acyl-CoA dehydrogenase; stearoyl CoA desaturase 1; sterol response element binding protein 1; very long chain acyl CoA dehydrogenase