Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates.
OBJECTIVE
The molecular mechanisms leading to Non-Alcoholic Steatohepatitis (NASH) are not fully understood. In mice, NASH can be inhibited by fenofibrate, a synthetic agonist for the nuclear receptor peroxisome proliferator activated receptor alpha, which regulates hepatic triglyceride metabolism. This study aimed to elucidate the relation between steatosis and inflammation in NASH in a human-like hyperlipidemic mouse model.


METHODS
Liver phenotype and gene expression were assessed in APOE2 knock-in mice that were fed a western-type high fat diet with or without co-administration of fenofibrate.


RESULTS
In response to a western diet, APOE2 knock-in mice developed NASH characterized by steatosis and inflammation. Strikingly, macrophage accumulation in the liver preceded the steatosis during progression of the disease. This phenotype was in line with gene expression patterns, which showed regulation of two major groups of genes, i.e. inflammatory and lipid genes. Fenofibrate treatment decreased hepatic macrophage accumulation and abolished steatosis. Moreover, a marked reduction in the expression of inflammatory genes occurred immediately after fenofibrate treatment.


CONCLUSIONS
These data indicate that inflammation might play an instrumental role during the development of NASH in this mouse model. Inhibition of NASH by fenofibrate may be due, at least in part, to its inhibitory effect on pro-inflammatory genes.
Shiri-Sverdlov
Ronit
R
Department of Molecular Genetics, University Maastricht, UNS40/11 P.O. Box 16, 6200 MD, Maastricht, The Netherlands.
Wouters
Kristiaan
K
van Gorp
Patrick J
PJ
Gijbels
Marion J
MJ
Noel
Benoit
B
Buffat
Laurent
L
Staels
Bart
B
Maeda
Nobuyo
N
van Bilsen
Marc
M
Hofker
Marten H
MH
D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000235:genetics; D000818:Animals; D053329:Apolipoprotein E2; D001057:Apolipoproteins E / Q000235:genetics* / Q000502:physiology; D002995:Clofibric Acid / Q000494:pharmacology / Q000627:therapeutic use*; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D006949:Hyperlipidemias / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D010741:Phospholipases A / Q000032:analysis / Q000235:genetics; D000077153:Progranulins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000032:analysis / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D053329:Apolipoprotein E2; D001057:Apolipoproteins E; D004041:Dietary Fats; D000960:Hypolipidemic Agents; D036341:Intercellular Signaling Peptides and Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D000077153:Progranulins; D019010:Vascular Cell Adhesion Molecule-1; D002995:Clofibric Acid; D013230:Stearoyl-CoA Desaturase; D010741:Phospholipases A; D011345:Fenofibrate