Xanthine-based KMUP-1 improves HDL via PPARγ/SR-B1, LDL via LDLRs and HSL via PKA/PKG for hepatic fat loss.
J Lipid Res. 2015 Sep 8;
Authors: Kuo KK, Wu BN, Liu CP, Yang TY, Kao LP, Wu JR, Lai WT, Chen IJ
The phosphodiesterase inhibitor (PDEI)/endothelial nitric-oxide synthase (eNOS) enhancer KMUP-1, targeting G-protein coupled receptors (GPCRs), improves dyslipidemia. We compared its lipid-lowering effects to simvastatin and explored the hormone sensitive lipase (HSL) translocation in hepatic fat loss. KMUP-1 HCl (1, 2.5, 5 mg/kg/day) and simvastatin (5 mg/kg/day) were administered in C57BL/6J male mice fed a high-fat-diet (HFD) by gavage for 8 weeks. KMUP-1 inhibited HFD-induced plasma/liver TG, total cholesterol and LDL, increased HDL/HMGR/ROCK II/PPARγ/ABCA1 and decreased liver/body weight. KMUP-1 HCl in drinking water (2.5 mg/200 ml tap water) for 1-14 or 8-14 weeks decreased HFD-induced liver/body weight and SR-B1 expression and increased PKA/PKG/LDLRs/HSL expression/immunoreactivity. In HepG2 cells incubated with serum or exogenous mevalonate, KMUP-1 (10-7~10-5 M) reversed HMGR expression by feedback regulation, co-localized ABCA1/ApoA-I/LXRα/PPARγ and exogenous GGPP-/FPP-induced reduction of RhoA/ROCK II expression. A cGMP antagonist reversed KMUP-1-induced ROCK II reduction, indicating cGMP/eNOS involvement. KMUP-1 inceased PKG and LDLRs surrounded by LDL, and restored oxidized LDL-induced PKA. Unlike simvastatin, KMUP-1 could not inhibit 14C mevalonate formation. KMUP-1 could, but simvastatin could not, decrease ROCK II expression by exogenous FPP/CGPP. KMUP-1 improves HDL via PPARγ/LXRα/ABCA1/ApoA-I, increases LDLRs/PKA/PKG and activates HSL, leading to TG hydrolysis for hepatic fat loss and reduction in body-weight.
PMID: 26351364 [PubMed – as supplied by publisher]