Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist.
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.


CONCLUSIONS
MB07811 represents a novel class of liver-targeted TR agonists with beneficial low-density lipoprotein cholesterol-lowering properties that may provide additional therapeutic benefit to hyperlipidemic patients with concomitant NAFLD.
Cable
Edward E
EE
Metabasis Therapeutics, Inc, La Jolla, CA 92037, USA. edwardc@mbasis.com
Finn
Patricia D
PD
Stebbins
Jeffrey W
JW
Hou
Jinzhao
J
Ito
Bruce R
BR
van Poelje
Paul D
PD
Linemeyer
David L
DL
Erion
Mark D
MD
D000085:Acetates / Q000627:therapeutic use; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004822:Epididymis; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy*; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D010636:Phenols / Q000627:therapeutic use; D010647:Phenyl Ethers / Q000627:therapeutic use; D010648:Phenylacetates / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000819:agonists*
D000085:Acetates; D005230:Fatty Acids, Nonesterified; C413355:GC 1 compound; C478108:KB 141; D010636:Phenols; D010647:Phenyl Ethers; D010648:Phenylacetates; D011988:Receptors, Thyroid Hormone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human