title: Internalization of modified lipids by CD36 and SR-A leads to hepatic inflammation and lysosomal cholesterol storage in Kupffer cells.
abstract: OBJECTIVE
  Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation, which can further progress into fibrosis and cirrhosis. Recently, we demonstrated that combined deletion of the two main scavenger receptors, CD36 and macrophage scavenger receptor 1 (MSR1), which are important for modified cholesterol-rich lipoprotein uptake, reduced NASH. The individual contributions of these receptors to NASH and the intracellular mechanisms by which they contribute to inflammation have not been established. We hypothesize that CD36 and MSR1 contribute independently to the onset of inflammation in NASH, by affecting intracellular cholesterol distribution inside Kupffer cells (KCs).
  
  
  RESULTS
  Ldlr(-/-) mice were transplanted with wild-type (Wt), Cd36(-/-) or Msr1(-/-) bone marrow and fed a Western diet for 3 months. Cd36(-/-)- and Msr1(-/-)- transplanted (tp) mice showed a similar reduction in hepatic inflammation compared to Wt-tp mice. While the total amount of cholesterol inside KCs was similar in all groups, KCs of Cd36(-/-)- and Msr1(-/-)-tp mice showed increased cytoplasmic cholesterol accumulation, while Wt-tp mice showed increased lysosomal cholesterol accumulation.
  
  
  CONCLUSIONS
  CD36 and MSR1 contribute similarly and independently to the progression of inflammation in NASH. One possible explanation for the inflammatory response related to expression of these receptors could be abnormal cholesterol trafficking in KCs. These data provide a new basis for prevention and treatment of NASH.
authors.affiliation: Department of Molecular Genetics, Electron Microscopy Unit of Molecular Cell Biology, and Pathology, Nutrition and Toxicology Research (NUTRIM) Institute of Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Veerle
authors.initials: V
authors.lastname: Bieghs
authors.forename: Fons
authors.initials: F
authors.lastname: Verheyen
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van Gorp
authors.forename: Tim
authors.initials: T
authors.lastname: Hendrikx
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Wouters
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Marion J J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005260:Female; D007249:Inflammation / Q000473:pathology; D007728:Kupffer Cells / Q000378:metabolism* / Q000473:pathology*; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; D008055:Lipids; C495140:Msr1 protein, mouse; D011973:Receptors, LDL; D051117:Scavenger Receptors, Class A; D002784:Cholesterol