Role of scavenger receptor A and CD36 in diet-induced nonalcoholic steatohepatitis in hyperlipidemic mice.
OBJECTIVE
Nonalcoholic steatohepatitis (NASH) is a disorder that consists of steatosis and hepatic inflammation. It is not known why only some people with steatosis develop NASH. Recently, we identified dietary cholesterol as a factor that directly leads to hepatic inflammation and hepatic foam cell formation. We propose a mechanism by which Kupffer cells (KCs) take up modified cholesterol-rich lipoproteins via scavenger receptors (SRs). KCs thereby accumulate cholesterol, become activated, and may then trigger an inflammatory reaction. Scavenging of modified lipoproteins mainly depends on CD36 and macrophage scavenger receptor 1.


METHODS
To evaluate the involvement of SR-mediated uptake of modified lipoproteins by KCs in the development of diet-induced NASH, female low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice were lethally irradiated and transplanted with bone marrow from Msr1(+/+)/Cd36(+/+)or Msr1(-/-)/Cd36(-/-) mice and fed a Western diet.


RESULTS
Macrophage and neutrophil infiltration revealed that hepatic inflammation was substantially reduced by approximately 30% in Msr1(-/-)/Cd36(-/-)-transplanted mice compared with control mice. Consistent with this, the expression levels of well-known inflammatory mediators were reduced. Apoptotis and fibrosis were less pronounced in Msr1(-/-)/Cd36(-/-)-transplanted mice, in addition to the protective phenotype of natural antibodies against oxidized low-density lipoprotein in the plasma. Surprisingly, the effect on hepatic inflammation was independent of foam cell formation.


CONCLUSIONS
Targeted inactivation of SR pathways reduces the hepatic inflammation and tissue destruction associated with NASH, independent of hepatic foam cell formation.
Bieghs
Veerle
V
Department of Molecular Genetics, Pathology and Physiology, Nutrition and Toxicology Research and Cardiovascular Research Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands.
Wouters
Kristiaan
K
van Gorp
Patrick J
PJ
Gijbels
Marion J J
MJ
de Winther
Menno P J
MP
Binder
Christoph J
CJ
Lütjohann
Dieter
D
Febbraio
Maria
M
Moore
Kathryn J
KJ
van Bilsen
Marc
M
Hofker
Marten H
MH
Shiri-Sverdlov
Ronit
R
D000818:Animals; D017209:Apoptosis; D018955:CD36 Antigens / Q000502:physiology*; D005234:Fatty Liver / Q000209:etiology*; D005260:Female; D005487:Foam Cells / Q000473:pathology; D006505:Hepatitis / Q000209:etiology; D006949:Hyperlipidemias / Q000150:complications*; D015603:Keratinocytes / Q000378:metabolism; D007728:Kupffer Cells; D015227:Lipid Peroxidation; D008106:Liver Cirrhosis, Experimental / Q000209:etiology; D016031:Liver Transplantation; D051379:Mice; D051117:Scavenger Receptors, Class A / Q000502:physiology*
D018955:CD36 Antigens; C495139:MSR1 protein, human; D051117:Scavenger Receptors, Class A