PPAR-delta Agonist MBX-8025 Abolishes Lipotoxicity andReverses NASH in Diabetic Obese Mice
Date
2016
Authors
Haczeyni, Fahrettin
Wang, Hans
Barn, Vanessa
Mridha, Auvro
Yeh, Matthew
Haigh, W Geoffrey
Ioannou, George
Choi, Yun Jung
McWerther, Charles
Teoh, Narcissus
Journal Title
Journal ISSN
Volume Title
Publisher
John Wiley & Sons Inc.
Abstract
Background: Lipotoxicity associated with insulin resistance
and diabetes is central to the pathogenesis of non-alcoholic
steatohepatitis (NASH), and resultant liver fibrosis and
cirrhosis. To date, only weight loss, which improves insulin
sensitivity, reverses NASH fibrosis; pharmacological agents
have limited efficacy. The mixed peroxisome proliferator-activated
receptor-alpha/delta (PPAR-α/δ) agonist, GFT505, has
demonstrated some efficacy in NASH. MBX-8025 is a selective
PPAR-δ agonist that improves atherogenic dyslipidemia
in rodents and humans. We tested whether MBX-8025 could
reverse lipotoxicity and NASH in a diabetic mouse model.
Methods: From 4 weeks of age, female Alms1 mutant (foz/
foz) and wildtype (Wt) mice were fed an atherogenic diet for
16 weeks, after which groups (8-12 mice) were randomized
to receive MBX-8025 (10mg/kg) or vehicle (1% methylcellulose)
by gavage for 8 weeks. We performed intraperitoneal
glucose tolerance testing (IpGTT) at Week 27, and sacrifice at
28 weeks. Results: MBX-8025 had minimal effect on body or
liver weight, but normalized hyperglycemia, hypercholesterolaemia,
hyperinsulinemia and glucose disposal (by IpGTT) in
foz/foz mice. After 16 weeks of atherogenic dietary intake,
serum ALT ranged from 300-600 U/L in vehicle-treated foz/
foz mice; MBX-8025 reduced this by ~50% (P<0.05). In foz/
foz mice, hepatic lipid fractions showed increased free cholesterol,
diacylglycerol, saturated fatty acid and triglyceride
content. MBX-8025 normalized serum lipids, and corrected
all hepatic lipid pools. This was associated with abolition of
hepatocyte ballooning, substantial reduction of steatosis, and
reduced liver inflammation with a striking decrease in the number
of macrophage crown-like structures; the resultant non-alcoholic
fatty liver disease (NAFLD) Activity Score (NAS) was 6.9
(range 6-7) indicated all vehicle-treated foz/foz mice (8/8)
showed definite NASH. MBX-8025 reversed NASH in all foz/
foz mice (NAS 3.13; P<0.05), with only residual simple steatosis
being present. MBX-8025 also repressed development of
liver fibrosis, quantified by collagen densitometry and mRNA
analyses. Conclusions: The selective PPAR-δ agonist MBX-8025
improves glucose tolerance and reverses diabetes, atherogenic
dyslipidemia, hepatic lipid storage (including lipotoxic lipids),
and NASH pathology in atherogenic diet-fed diabetic mice.
MBX-8025 acts independently of weight reduction, appears to
counter lipotoxicity related to insulin resistance, with accompanying
reductions in liver inflammation and fibrosis. MBX-8025
provides a novel mechanism-based therapeutic agent to treat
NASH.
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Source
Hepatology
Type
Conference paper
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Restricted until
2099-12-31