Nonalcoholic fatty liver disease (NAFLD), is associated with metabolic disease and estimated to affect 25% of adults. NAFLD can progress to nonalcoholic steatohepatitis (NASH) which may lead to cirrhosis and hepatocellular carcinoma. There is no current treatment or cure for NASH.
AMPK (5’AMP-activated protein kinase) activators have shown potential for treating NAFLD/NASH due to their effects on fatty acid inhibition and cholesterol synthesis. To evaluate this potential, an AMPK activator (herein known as C455) was selected for a preclinical NASH study. C455 demonstrated potent and selective activation of AMPK (cellular EC50= 85 nM). X-ray crystallography showed the compound binds at the ADaM site, and pharmacokinetics determined a bioavailability of 45% and half-life of 3h.
Mice (male ob/ob on Amylin-NASH diet for 14-weeks or low-fat control) were dosed orally with vehicle or C455 at 3 or 30mg/kg daily. After 6 weeks of treatment, plasma ALT and terminal liver weight were decreased 32% and 22% respectively in mice treated with 30mg/kg C455 vs. vehicle. This dose also decreased liver lipid from 33% to 23%. Fibrosis via collagen staining did not improve with treatment, but significant decreases in mRNA transcripts for Col1a1(62%), Col1a2(59%), Col4a1(56%), and Timp1(55%) were seen with the high dose. Histology showed dose dependent increases in heart weight relative to body weight, and increased expression of genes associated with cardiac hypertrophy. Mice given 30mg/kg C455 also had increased cardiac glycogen storage compared to vehicle treated or LFD control mice.
Our study results show that systemic activation of AMPK in a diet-induced mouse model of NASH reduces plasma ALT, decreases liver lipid, and suppressed hepatic collagen gene expression but shows no histological improvement in fibrosis. Coupled with increased heart weight and glycogen storage, the data suggests that current small molecule activators of AMPK may not be viable therapies for the treatment of NASH-related fibrotic disease.
K.M. Mather: None. M.L. Boland: None. E. Rivers: None. A. Srivastava: None. M. Schimpl: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Robinson: None. P.T.C. Wan: None. J.L. Hansen: None. J.A. Read: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J.L. Trevaskis: Employee; Self; Gilead Sciences, Inc. D.M. Smith: Employee; Self; AstraZeneca.