title: Differential hepatotoxicity of dietary and DNL-derived palmitate in the methionine-choline-deficient model of steatohepatitis.
abstract: BACKGROUND
  Saturated fatty acids are toxic to liver cells and are believed to play a central role in the pathogenesis of non-alcoholic steatohepatitis. In experimental steatohepatitis induced by feeding mice a methionine-choline-deficient (MCD) diet, the degree of liver damage is related to dietary sugar content, which drives de novo lipogenesis and promotes the hepatic accumulation of saturated fatty acids. The objective of this study was to determine whether dietary palmitate exerts the same toxicity as carbohydrate-derived palmitate in the MCD model of fatty liver disease.
  
  
  METHODS
  We fed mice custom MCS and MCD formulas containing 4 different carbohydrate-fat combinations: starch-oleate, starch-palmitate, sucrose-oleate and sucrose-palmitate.  After 3 wk, we compared their metabolic and disease outcomes.
  
  
  RESULTS
  Mice fed the custom MCD formulas developed varying degrees of hepatic steatosis and steatohepatitis, in the order starch-oleate < starch-palmitate < sucrose-oleate < sucrose-palmitate. Liver injury correlated positively with the degree of hepatic lipid accumulation. Liver injury also correlated positively with the amount of palmitate in the liver, but the relationship was weak. Importantly, mice fed MCD starch-palmitate accumulated as much hepatic palmitate as mice fed MCD sucrose-oleate, yet their degree of liver injury was much lower. By contrast, mice fed MCD sucrose-palmitate developed severe liver injury, worse than that predicted by an additive influence of the two nutrients.
  
  
  CONCLUSIONS
  In the MCD model of steatohepatitis, carbohydrate-derived palmitate in the liver is more hepatotoxic than dietary palmitate. Dietary palmitate becomes toxic when combined with dietary sugar in the MCD model, presumably by enhancing hepatic de novo lipogenesis.
authors.affiliation: Liver Center Laboratory, San Francisco General Hospital, University of California San Francisco, 1001 Potrero Avenue, Building 40, Room 4102, 94110, San Francisco, CA, USA. Andrew.Pierce@ucsf.edu.|Department of Medicine, University of California San Francisco, San Francisco, USA. Andrew.Pierce@ucsf.edu.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pierce
authors.affiliation: Liver Center Laboratory, San Francisco General Hospital, University of California San Francisco, 1001 Potrero Avenue, Building 40, Room 4102, 94110, San Francisco, CA, USA. Michael.Pickens@ucsf.edu.|Department of Pediatrics, University of California San Francisco, San Francisco, USA. Michael.Pickens@ucsf.edu.|Present address: Mary Bridge Children's Health Center, 311 S. L Street, 98405, Tacoma, WA, USA. Michael.Pickens@ucsf.edu.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Pickens
authors.affiliation: Liver Center Laboratory, San Francisco General Hospital, University of California San Francisco, 1001 Potrero Avenue, Building 40, Room 4102, 94110, San Francisco, CA, USA. kevinsiao1@gmail.com.|Department of Medicine, University of California San Francisco, San Francisco, USA. kevinsiao1@gmail.com.
authors.forename: Kevin
authors.initials: K
authors.lastname: Siao
authors.affiliation: Liver Center Laboratory, San Francisco General Hospital, University of California San Francisco, 1001 Potrero Avenue, Building 40, Room 4102, 94110, San Francisco, CA, USA. James.Grenert@ucsf.edu.|Department of Pathology, University of California San Francisco, San Francisco, USA. James.Grenert@ucsf.edu.
authors.forename: James P
authors.initials: JP
authors.lastname: Grenert
authors.affiliation: Liver Center Laboratory, San Francisco General Hospital, University of California San Francisco, 1001 Potrero Avenue, Building 40, Room 4102, 94110, San Francisco, CA, USA. Jacquelyn.Maher@ucsf.edu.|Department of Medicine, University of California San Francisco, San Francisco, USA. Jacquelyn.Maher@ucsf.edu.
authors.forename: Jacquelyn J
authors.initials: JJ
authors.lastname: Maher
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D002796:Choline Deficiency / Q000150:complications*; D004032:Diet / Q000009:adverse effects; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004195:Disease Models, Animal; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008809:Mice, Inbred C3H; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology*; D019301:Oleic Acid / Q000633:toxicity; D010168:Palmitates / Q000633:toxicity*; D013395:Sucrose / Q000008:administration & dosage
chemical_list: D004040:Dietary Carbohydrates; D010168:Palmitates; D019301:Oleic Acid; D013395:Sucrose; D008715:Methionine