Xanthine-based KMUP-1 improves HDL via PPARγ/SR-B1, LDL via LDLRs, and HSL via PKA/PKG for hepatic fat loss.
The phosphodiesterase inhibitor (PDEI)/eNOS enhancer KMUP-1, targeting G-protein coupled receptors (GPCRs), improves dyslipidemia. We compared its lipid-lowering effects with simvastatin and explored hormone-sensitive lipase (HSL) translocation in hepatic fat loss. KMUP-1 HCl (1, 2.5, and 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/3-hydroxy-3-methylglutaryl-CoA reductase (HMGR)/Rho kinase II (ROCK II)/PPARγ/ABCA1; and decreased liver and 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 and body weight and scavenger receptor class B type I expression and increased protein kinase A (PKA)/PKG/LDLRs/HSL expression and immunoreactivity. In HepG2 cells incubated with serum or exogenous mevalonate, KMUP-1 (10(-7)∼10(-5) M) reversed HMGR expression by feedback regulation, colocalized expression of ABCA1/apolipoprotein A-I/LXRα/PPARγ, and reduced exogenous geranylgeranyl pyrophosphate/farnesyl pyrophosphate (FPP)-induced RhoA/ROCK II expression. A guanosine 3',5'-cyclic monophosphate (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 expresion. Unlike simvastatin, KMUP-1 could not inhibit (14)C 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/Apo-I expression and increases LDLRs/PKA/PKG/HSL expression and immunoreactivity, leading to TG hydrolysis to lower hepatic fat and body weight.
Division of Hepatobiliopancreatic Surgery, Kaohsiung Medical University Hospital.
Kung-Kai
KK
Kuo
Department of Pharmacology, School of Medicine, College of Medicine.
Bin-Nan
BN
Wu
Department of Cardiology, Yuan's General Hospital, Kaohsiung, Taiwan.
Chung-Pin
CP
Liu
Department of Pharmacology, School of Medicine, College of Medicine.
Tzu-Yang
TY
Yang
Department of Pharmacology, School of Medicine, College of Medicine.
Li-Pin
LP
Kao
Department of Pedatrics, Kaohsiung Medical University Hospital.
Jiunn-Ren
JR
Wu
Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Wen-Ter
WT
Lai
Department of Pharmacology, School of Medicine, College of Medicine.
Ing-Jun
IJ
Chen
D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D056945:Hep G2 Cells; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006951:Hyperlipoproteinemias / Q000188:drug therapy* / Q000209:etiology; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000502:physiology; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011973:Receptors, LDL / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D015290:Second Messenger Systems; D002787:Sterol Esterase / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology* / Q000627:therapeutic use
D064286:ATP Binding Cassette Transporter 1; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D006903:Hydroxymethylglutaryl CoA Reductases; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008798:Mevalonic Acid; D047495:PPAR gamma; D010880:Piperidines; D011973:Receptors, LDL; D051122:Scavenger Receptors, Class B; D002787:Sterol Esterase; D014970:Xanthines; C577833:Abca1 protein, mouse; C454739:Scarb1 protein, mouse; C439304:KMUP 1
3-hydroxy-3-methylglutaryl-CoA reductase; endothelial nitric-oxide synthase/RhoA/Rho kinase II; low density lipoprotein/high density lipoprotein; protein kinase A/G; scavenger receptor class B type I/peroxisome proliferator activated receptor γ