Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse.
Conjugated linoleic acids (CLA) are a class of positional, geometric, conjugated dienoic isomers of linoleic acid (LA). Dietary CLA supplementation results in a dramatic decrease in body fat mass in mice, but also causes considerable liver steatosis. However, little is known of the molecular mechanisms leading to hepatomegaly. Although c9,t11- and t10,c12-CLA isomers are found in similar proportions in commercial preparations, the respective roles of these two molecules in liver enlargement has not been studied. We show here that mice fed a diet enriched in t10,c12-CLA (0.4% w/w) for 4 weeks developed lipoatrophy, hyperinsulinemia, and fatty liver, whereas diets enriched in c9,t11-CLA and LA had no significant effect. In the liver, dietary t10,c12-CLA triggered the ectopic production of peroxisome proliferator-activated receptor gamma (PPARgamma), adipocyte lipid-binding protein and fatty acid transporter mRNAs and induced expression of the sterol responsive element-binding protein-1a and fatty acid synthase genes. In vitro transactivation assays demonstrated that t10,c12- and c9,t11-CLA were equally efficient at activating PPARalpha, beta/delta, and gamma and inhibiting liver-X-receptor. Thus, the specific effect of t10,c12-CLA is unlikely to result from direct interaction with these nuclear receptors. Instead, t10,c12-CLA-induced hyperinsulinemia may trigger liver steatosis, by inducing both fatty acid uptake and lipogenesis.
Clément
Lionel
L
Physiologie de la Nutrition, Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation (ENSBANA) FRE2328 CNRS-CESG/Université de Bourgogne F-21000, Dijon, France.
Poirier
Hélène
H
Niot
Isabelle
I
Bocher
Virginie
V
Guerre-Millo
Michèle
M
Krief
Stéphane
S
Staels
Bart
B
Besnard
Philippe
P
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004268:DNA-Binding Proteins; D004041:Dietary Fats / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D005234:Fatty Liver / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006946:Hyperinsulinism / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D007328:Insulin / Q000097:blood; D007536:Isomerism; D019787:Linoleic Acid / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D004041:Dietary Fats; D007328:Insulin; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019787:Linoleic Acid