title: Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis.
abstract: Nonalcoholic steatohepatitis (NASH) involves liver lipid accumulation (steatosis) combined with hepatic inflammation. The transition towards hepatic inflammation represents a key step in pathogenesis, because it will set the stage for further liver damage, culminating in hepatic fibrosis, cirrhosis, and liver cancer. The actual risk factors that drive hepatic inflammation during the progression to NASH remain largely unknown. The role of steatosis and dietary cholesterol in the etiology of diet-induced NASH was investigated using hyperlipidemic mouse models fed a Western diet. Livers of male and female hyperlipidemic (low-density lipoprotein receptor-deficient [ldlr(-/-)] and apolipoprotein E2 knock-in [APOE2ki]) mouse models were compared with livers of normolipidemic wild-type (WT) C57BL/6J mice after short-term feeding with a high-fat diet with cholesterol (HFC) and without cholesterol. Whereas WT mice displayed only steatosis after a short-term HFC diet, female ldlr(-/-) and APOE2ki mice showed steatosis with severe inflammation characterized by infiltration of macrophages and increased nuclear factor kappaB (NF-kappaB) signaling. Remarkably, male ldlr(-/-) and APOE2ki mice developed severe hepatic inflammation in the absence of steatosis after 7 days on an HFC diet compared with WT animals. An HFC diet induced bloated, "foamy" Kupffer cells in male and female ldlr(-/-) and APOE2ki mice. Hepatic inflammation was found to be linked to increased plasma very low-density lipoprotein (VLDL) cholesterol levels. Omitting cholesterol from the HFC diet lowered plasma VLDL cholesterol and prevented the development of inflammation and hepatic foam cells.
  
  
  CONCLUSIONS
  These findings indicate that dietary cholesterol, possibly in the form of modified plasma lipoproteins, is an important risk factor for the progression to hepatic inflammation in diet-induced NASH.
authors.affiliation: Department of Molecular Genetics, Physiology and Electron Microscopy Unit, Nutrition and Toxicology Research and Cardiovascular Research, Institutes of Maastricht University, Maastricht, The Netherlands.
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Wouters
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van Gorp
authors.forename: Veerle
authors.initials: V
authors.lastname: Bieghs
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Hans
authors.initials: H
authors.lastname: Duimel
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Anja
authors.initials: A
authors.lastname: Kerksiek
authors.forename: Roger
authors.initials: R
authors.lastname: van Kruchten
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Marc
authors.initials: M
authors.lastname: van Bilsen
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
mesh_terms: D000818:Animals; D053329:Apolipoprotein E2 / Q000378:metabolism; D002791:Cholesterol, Dietary; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications; D005260:Female; D005487:Foam Cells / Q000473:pathology; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D006505:Hepatitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006949:Hyperlipidemias / Q000097:blood / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency; D015398:Signal Transduction
chemical_list: D053329:Apolipoprotein E2; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D008055:Lipids; D008079:Lipoproteins, VLDL; D016328:NF-kappa B; D011973:Receptors, LDL