Non-alcoholic fatty liver disease (
NAFLD) is one of the most common forms of chronic
liver disease, with a prevalence ranging from 10% to 30%. The use of
thyroid hormone receptor (TR) agonists for the treatment of
NAFLD has not been considered viable because
thyroid hormones increase
free fatty acid (FFA) flux from the periphery to the liver, induce hepatic lipogenesis, and therefore could potentially cause steatosis.
MB07811 is an orally active HepDirect
prodrug of
MB07344, a liver-targeted
TR-beta agonist. The purpose of these studies was to assess the effects of
MB07811 on whole body and liver lipid metabolism of normal rodents and rodent models of hepatic steatosis. In the current studies,
MB07811 markedly reduced hepatic steatosis as well as reduced plasma FFA and
triglycerides. In contrast to
MB07811, T(3) induced adipocyte lipolysis in vitro and in vivo and had a diminished ability to decrease hepatic steatosis. This suggests the influx of FFA from the periphery to the liver may partially counteract the antisteatotic activity of T(3). Clearance of liver
lipids by
MB07811 results from accelerated hepatic
fatty acid oxidation, a known consequence of hepatic TR activation, as reflected by increased hepatic mitochondrial respiration rates, changes in hepatic gene expression, and increased plasma acyl-
carnitine levels.
Transaminase levels remained unchanged, or were reduced, and no evidence for
liver fibrosis or other histological liver damage was observed
after treatment with
MB07811 for up to 10 weeks. Additionally,
MB07811, unlike T(3), did not increase heart weight or decrease pituitary
thyroid-stimulating hormone beta (TSHbeta) expression.
CONCLUSION: