Fatty liver disease is one of the main hepatic complications associated with
obesity. To date, there are no effective treatments for this pathology apart from the use of classical
fibrates. In this study, we have characterized the in vivo effects of a novel conjugation of
oleic acid with an
amphetamine derivative (
OLHHA) in an animal model of genetic
obesity. Lean and obese Zucker rats received a daily intraperitoneal administration of
OLHHA (5 mg kg(-1)) for 15 days. Plasma and liver samples were collected for the biochemical and molecular
biological analyses, including both immunohistochemical and histological studies. The expression of key
enzymes and
proteins that are involved in lipid metabolism and energy homeostasis was evaluated in the liver samples. The potential of
OLHHA to produce
adverse drug reactions or toxicity was also evaluated through the monitoring of interactions with hERG channel and liver
cytochrome. We found that
OLHHA is a
drug with a safe pharmacological profile. Treatment for 15 days with
OLHHA reduced the liver fat content and plasma
triglyceride levels, and this was accompanied by a general improvement in the profile of plasma parameters related to liver damage in the obese rats. A decrease in fat accumulation in the liver was confirmed using histological staining. Additionally,
OLHHA was observed to exert anti-apoptotic effects. This hepatoprotective activity in obese rats was associated with an increase in the
mRNA and
protein expression of the
cannabinoid type 1 receptor and a decrease in the expression of the lipogenic
enzymes FAS and HMGCR primarily. However, changes in the
mRNA expression of certain
proteins were not associated with changes in the
protein expression (i.e. L-FABP and INSIG2). The present results demonstrate that
OLHHA is a potential anti-steatotic
drug that ameliorates the
obesity-associated
fatty liver and suggest the potential use of this new
drug for the treatment of
non-alcoholic fatty liver disease.