Treatment of preestablished diet-induced fatty liver by oral fatty acid-bile acid conjugates in rodents.
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in industrialized countries. It has no accepted medical therapy. Fatty acid-bile acid conjugates (FABACs) were proven to prevent diet-induced NAFLD in rodents.


OBJECTIVE
This study was undertaken to test whether oral FABACs are also effective in reducing liver fat in preestablished diet-induced NAFLD.


METHODS
NAFLD was induced in mice and rats by a high-fat diet and maintained by various proportions thereof. The FABACs used were conjugates of cholic acid with either arachidic or stearic acids.


RESULTS
FABAC therapy reduced liver fat in all four series of experiments. The rapidity of the effect was inversely proportional to the concentration of fat in the maintenance diet. In mice on a 25% maintenance diet FABACs decreased total liver lipids by about 30% in 4 weeks (P<0.03). Diglycerides (P<0.003) and triglycerides (P<0.01) were the main neutral liver lipids that decreased during FABAC therapy. Both FABACs tested reduced liver fat in NAFLD at doses of 25 and 150 mg/kg/day. High-fat diet increased, whereas FABAC therapy decreased plasma 16 : 1/(16 : 0+16 : 1) fatty acid ratio - a marker of stearoyl CoA desaturase activity. In HepG2 cells FABACs decreased de-novo fatty acid synthesis dose dependently.


CONCLUSIONS
Oral FABAC therapy decreased liver fat in preestablished NAFLD in mice and rats. Inhibition of stearoyl CoA desaturase activity and fatty acid synthesis are mechanisms that may contribute to this decrease. FABACs may be potential therapeutic agents for human NAFLD.
Leikin-Frenkel
Alicia
A
Minerva Center for Cholesterol Gallstones and Lipid Metabolism in the Liver, Tel-Aviv University, Tel-Aviv, Israel.
Goldiner
Ilana
I
Leikin-Gobbi
Diana
D
Rosenberg
Ruth
R
Bonen
Hamutal
H
Litvak
Alex
A
Bernheim
Joelle
J
Konikoff
Fred M
FM
Gilat
Tuvia
T
D000818:Animals; D001647:Bile Acids and Salts / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D002793:Cholic Acids / Q000627:therapeutic use; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005227:Fatty Acids / Q000096:biosynthesis / Q000627:therapeutic use*; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051381:Rats; D011916:Rats, Inbred F344; D013230:Stearoyl-CoA Desaturase / Q000097:blood; D015430:Weight Gain
D001647:Bile Acids and Salts; D001786:Blood Glucose; D002793:Cholic Acids; D004041:Dietary Fats; D005227:Fatty Acids; D013230:Stearoyl-CoA Desaturase; C455117:aramchol