Miltefosine Suppresses Hepatic Steatosis By Activating AMPK Signal Pathway

Adenosine monophosphate-activated protein kinase(AMPK),a heterotrimeric enzyme consisting with catalytic a subunits and regulatory β and γ subunits,is a cellular energy sensor implicated in the regulation of lipid and glucose homeostasis.Phosphorylation of Thr172 in a subunit leads to AMPK activation which is catalyzed by liver kinase B1(LKB1),a tumor suppressor protein kinase,and calmodulin-dependent protein kinase kinase β(CaMKK β).Liver AMPK promotes fatty acid oxidation by phosphorylating and inactivating acetyl-CoA carboxylase(ACC)and carnitinepalmitoyltransferase 1A(CPT1A).It also inhibits hepatic fatty acid synthesis by suppressing sterol regulatory element-binding protein 1C(SREBP1C)and fatty acid synthase(FAS).It has been accepted that AMPK activation exhibits many beneficial effects on glucolipid metabolism.Lysophosphatidylcholine(LPC)is an important lysophospholipid associated with many metabolic processes in the human body.It is an important lysophospholipid which can improve blood glucose levels in diabetic mice and attenuate inflammation by activating AMPK signal pathway in macrophages.However,application of LPC to the human being is limited by its very short half-life period and instability in vivo.Synthetic alkylphospholipids(ALPs),such as miltefosine,is used as an alternate of LPC for the clinical application.It is an antitumor agent and has been used for effective treatment of leishmaniasis.Here,we investigated whether miltefosine could have an impact on hepatic steatosis and related metabolic disorders.Mice were fed with a high fat diet(HFD)for 16 weeks to generate an obese model.Next,the non-obese and obese mice were randomly divided into three groups:saline-treated and miltefosine-treated(2.5 or 5 mg/kg’d)groups.When miltefosine was intraperitoneally administrated into mice,it substantially improved glucose metabolism,prevented hepatic lipid accumulation,and inhibited liver inflammation in high fat diet-fed mice by activating AMPK signal pathway.In vitro,miltefosine stimulated AMPKa phosphorylation both in time and dose dependent manner and decreased lipid accumulation in liver cells.Next,we used a specific AMPK inhibitor compound C to verify these effects.We found that the lipid lowering effects of miltefosine on HFD-induced mouse were abolished when compound C was treated.Here we demonstrated that miltefosine might be a new activator of AMPK signal pathway in vivo and in vitro and be useful for treatment of hepatic steatosis and related metabolic disorders.