title: Tetradecylthiopropionic acid induces hepatic mitochondrial dysfunction and steatosis, accompanied by increased plasma homocysteine in mice.
abstract: BACKGROUND
  Hepatic mitochondrial dysfunction plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methyl donor supplementation has been shown to alleviate NAFLD, connecting the condition to the one-carbon metabolism. Thus, the objective was to investigate regulation of homocysteine (Hcy) and metabolites along the choline oxidation pathway during induction of hepatic steatosis by the fatty acid analogue tetradecylthiopropionic acid (TTP), an inhibitor of mitochondrial fatty acid oxidation.
  
  
  METHODS
  Mice were fed a control diet, or diets containing 0.3 %, 0.6 %, or 0.9 % (w/w) TTP for 14 days. Blood and liver samples were collected, enzyme activities and gene expression were analyzed in liver, lipid and fatty acid composition in liver and plasma, one-carbon metabolites, B-vitamin status, carnitine and acylcarnitines were analyzed in plasma.
  
  
  RESULTS
  Liver mitochondrial fatty acid oxidation decreased by 40 % and steatosis was induced in a dose dependent manner; total lipids increased 1.6-fold in animals treated with 0.3 % TTP, 2-fold with 0.6 % TTP and 2.1 fold with 0.9 % TTP compared to control. The higher hepatic concentration of fatty acids was associated with shortening of carbon-length. Furthermore, the inhibited fatty acid oxidation led to a 30-fold decrease in plasma carnitine and 9.3-fold decrease in acetylcarnitine at the highest dose of TTP, whereas an accumulation of palmitoylcarnitine resulted. Compared to the control diet, TTP administration was associated with elevated plasma total Hcy (control: 7.2 ± 0.3 umol/L, 0.9 % TTP: 30.5 ± 5.9 umol/L) and 1.4-1.6 fold increase in the one-carbon metabolites betaine, dimethylglycine, sarcosine and glycine, accompanied by changes in gene expression of the different B-vitamin dependent pathways of Hcy and choline metabolism. A positive correlation between total Hcy and hepatic triacylglycerol resulted.
  
  
  CONCLUSIONS
  The TTP-induced inhibition of mitochondrial fatty acid oxidation was not associated with increased hepatic oxidative stress or inflammation. Our data suggest a link between mitochondrial dysfunction and the methylation processes within the one-carbon metabolism in mice.
authors: Department of Clinical Science, University of Bergen, 5020, Bergen, Norway. rolf.berge@uib.no.|Department of Heart Disease, Haukeland University Hospital, 5021, Bergen, Norway. rolf.berge@uib.no.
authors: Rolf K
authors: RK
authors: Berge
authors: Department of Clinical Science, University of Bergen, 5020, Bergen, Norway. bodil.bjorndal@uib.no.
authors: Bodil
authors: B
authors: Bjørndal
authors: Department of Clinical Science, University of Bergen, 5020, Bergen, Norway. elin.strand@uib.no.
authors: Elin
authors: E
authors: Strand
authors: Department of Clinical Science, University of Bergen, 5020, Bergen, Norway. pavol.bohov@uib.no.
authors: Pavol
authors: P
authors: Bohov
authors: Department of Clinical Science, University of Bergen, 5020, Bergen, Norway. carine.lindquist@uib.no.
authors: Carine
authors: C
authors: Lindquist
authors: Department of Clinical Science, University of Bergen, 5020, Bergen, Norway. jan.nordrehaug@uib.no.|Department of Heart Disease, Stavanger University Hospital, 4142, Stavanger, Norway. jan.nordrehaug@uib.no.
authors: Jan Erik
authors: JE
authors: Nordrehaug
authors: Department of Clinical Science, University of Bergen, 5020, Bergen, Norway. asbjorn.svardal@uib.no.
authors: Asbjørn
authors: A
authors: Svardal
authors: Department of Clinical Science, University of Bergen, 5020, Bergen, Norway. jon.skorve@uib.no.
authors: Jon
authors: J
authors: Skorve
authors: Department of Clinical Science, University of Bergen, 5020, Bergen, Norway. ottar.nygard@uib.no.|Department of Heart Disease, Haukeland University Hospital, 5021, Bergen, Norway. ottar.nygard@uib.no.|KG Jebsen Centre for Diabetes Research, University of Bergen, 5020, Bergen, Norway. ottar.nygard@uib.no.
authors: Ottar
authors: O
authors: Nygård
mesh_terms: D000818:Animals; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism; D006710:Homocysteine / Q000097:blood*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D013440:Sulfides / Q000494:pharmacology*
chemical_list: D011422:Propionates; D013440:Sulfides; D006710:Homocysteine; C062077:1-(carboxyethylthio)tetradecane