title: Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis.
abstract: The majority of patients with nonalcoholic fatty liver disease (NAFLD) have "simple steatosis," which is defined by hepatic steatosis in the absence of substantial inflammation or fibrosis and is considered to be benign. However, 10%-30% of patients with NAFLD progress to fibrosing nonalcoholic steatohepatitis (NASH), which is characterized by varying degrees of hepatic inflammation and fibrosis, in addition to hepatic steatosis, and can lead to cirrhosis. The cause(s) of progression to fibrosing steatohepatitis are unclear. We aimed to test the relative contributions of dietary fat and dietary cholesterol and their interaction on the development of NASH. We assigned C57BL/6J mice to four diets for 30 weeks: control (4% fat and 0% cholesterol); high cholesterol (HC; 4% fat and 1% cholesterol); high fat (HF; 15% fat and 0% cholesterol); and high fat, high cholesterol (HFHC; 15% fat and 1% cholesterol). The HF and HC diets led to increased hepatic fat deposition with little inflammation and no fibrosis (i.e., simple hepatic steatosis). However, the HFHC diet led to significantly more profound hepatic steatosis, substantial inflammation, and perisinusoidal fibrosis (i.e., steatohepatitis), associated with adipose tissue inflammation and a reduction in plasma adiponectin levels. In addition, the HFHC diet led to other features of human NASH, including hypercholesterolemia and obesity. Hepatic and metabolic effects induced by dietary fat and cholesterol together were more than twice as great as the sum of the separate effects of each dietary component alone, demonstrating significant positive interaction.
  
  
  CONCLUSIONS
  Dietary fat and dietary cholesterol interact synergistically to induce the metabolic and hepatic features of NASH, whereas neither factor alone is sufficient to cause NASH in mice.
authors.affiliation: Research Enhancement Award Program, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Savard
authors.forename: Erica V
authors.initials: EV
authors.lastname: Tartaglione
authors.forename: Rahul
authors.initials: R
authors.lastname: Kuver
authors.forename: W Geoffrey
authors.initials: WG
authors.lastname: Haigh
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Farrell
authors.forename: Savitha
authors.initials: S
authors.lastname: Subramanian
authors.forename: Alan
authors.initials: A
authors.lastname: Chait
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: Lebris S
authors.initials: LS
authors.lastname: Quinn
authors.forename: George N
authors.initials: GN
authors.lastname: Ioannou
mesh_terms: D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000276:immunology; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008079:Lipoproteins, VLDL / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D015430:Weight Gain
chemical_list: D052242:Adiponectin; D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D005227:Fatty Acids; D008055:Lipids; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger