Abstract
Background and PurposeIt has been accepted that AMPK (Adenosine monophosphate–activated protein kinase) activation exhibits many beneficial effects on glucolipid metabolism. Lysophosphatidylcholine (LPC) is an important lysophospholipid which can improve blood glucose levels in diabetic mice and attenuate inflammation by activating AMPK signal pathway in macrophages. Synthetic alkylphospholipids (ALPs), such as miltefosine, is used as an alternate of LPC for the clinical application. Here, we investigated whether miltefosine could have an impact on hepatic steatosis and related metabolic disorders.Experimental ApproachMice were fed with high fat diet (HFD) for 16 weeks to generate an obese model. Next, the obese mice were randomly divided into three groups: saline-treated and miltefosine-treated (2.5 or 5 mg/kg/d) groups. Miltefosine was intraperitoneally administrated into mice for additional 4 weeks plus HFD treatment.Key ResultsIt was shown that miltefosine treatment could substantially improve glucose metabolism, prevented hepatic lipid accumulation, and inhibited liver inflammation in HFD-fed mice by activating AMPK signal pathway. In vitro, miltefosine stimulated AMPKα phosphorylation both in time and dose dependent manner and decreased lipid accumulation in liver cells. When a specific AMPK inhibitor compound C was used to treat mice, the antagonistic effects of miltefosine on HFD-induced mouse hyperlipidaemia and liver steatosis were abolished. Treatment with miltefosine also dramatically inhibited the HFD-induced liver inflammation in mice.Conclusions and ImplicationsHere 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.
Highlights
We demonstrated that miltefosine might be a new activator of Adenosine monophosphate–activated protein kinase (AMPK) signal pathway in vivo and in vitro and be useful for treatment of hepatic steatosis and related metabolic disorders
Adenosine monophosphate–activated protein kinase (AMPK), a heterotrimeric enzyme consisting with catalytic α subunits and regulatory β and γ subunits, is a cellular energy sensor implicated in the regulation of lipid and glucose homeostasis [1,2,3,4]
The present study demonstrated that miltefosine could be a useful drug to antagonize high fat diet (HFD)-induced body weight increase, insulin resistance, and hepatic steatosis by activating AMPK signaling in mice
Summary
Adenosine monophosphate–activated protein kinase (AMPK), a heterotrimeric enzyme consisting with catalytic α subunits and regulatory β and γ subunits, is a cellular energy sensor implicated in the regulation of lipid and glucose homeostasis [1,2,3,4]. Liver AMPK promotes fatty acid oxidation by phosphorylating and inactivating acetylCoA carboxylase (ACC) which leads to increased carnitinepalmitoyltransferase 1A (CPT1A) expression and fatty acid transport into the mitochondria for beta oxidation [8,9,10]. It inhibits hepatic fatty acid synthesis by suppression of sterol regulatory element-binding protein 1C (SREBP1C) and fatty acid synthase (FAS) [11,12,13]. Miltefosine was intraperitoneally administrated into mice for additional 4 weeks plus HFD treatment
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