Dietary Geranylgeranyl Pyrophosphate Counteracts the Benefits of Statin Therapy in Experimental Pulmonary Hypertension.

BACKGROUND: The mevalonate pathway generates endogenous cholesterol and intermediates including geranylgeranyl pyrophosphate (GGPP). By reducing GGPP production, statins exert pleiotropic or cholesterol-independent effects. The potential regulation of GGPP homeostasis through dietary intake and the interaction with concomitant statin therapy is unknown. METHODS: We developed a sensitive high-pressure liquid chromatography technique to quantify dietary GGPP and conducted proteomics, qualitative real-time polymerase chain reaction screening, and Western blot to determine signaling cascades, gene expression, protein-protein interaction, and protein membrane trafficking in wild-type and transgenic rats. RESULTS: GGPP contents were highly variable depending on food source that differentially regulated blood GGPP levels in rats. Diets containing intermediate and high GGPP reduced or abolished the effects of statins in rats with hypoxia- and monocrotaline-induced pulmonary hypertension: this was rescuable by methyl-allylthiosulfinate and methyl-allylthiosulfinate-rich garlic extracts. In human pulmonary artery smooth muscle cells treated with statins, hypoxia activated RhoA in an extracellular GGPP-dependent manner. Hypoxia-induced ROCK2 (Rho associated coiled-coil containing protein kinase 2)/Rab10 (Ras-related protein rab-10) signaling was prevented by statin and recovered by exogenous GGPP. The hypoxia-activated RhoA/ROCK2 pathway in rat and human pulmonary artery smooth muscle cells upregulated the expression of Ca2+-sensing receptor (CaSR) and HIMF (hypoxia-induced mitogenic factor), a mechanism attenuated by statin treatment and regained with exogenous GGPP. Rab10 knockdown almost abrogated hypoxia-promoted CaSR membrane trafficking, a process diminished by statin and resumed by exogenous GGPP. Hypoxia-induced pulmonary hypertension was reduced in rats with CaSR mutated at the binding motif of HIMF and the interaction between dietary GGPP and statin efficiency was abolished. In humans fed a high GGPP diet, blood GGPP levels were increased. This abolished statin-lowering effects on plasma GGPP, and also on hypoxia-enhanced RhoA activity of blood monocytes that was rescued by garlic extracts. CONCLUSIONS: There is important dietary regulation of GGPP levels that interferes with the effects of statin therapy in experimental pulmonary hypertension. These observations rely on a key and central role of RhoA-ROCK2 cascade activation and Rab10-faciliated CaSR membrane trafficking with subsequent overexpression and binding of HIMF to CaSR. These findings warrant clinical investigation for the treatment of pulmonary hypertension and perhaps other diseases by combining statin with garlic-derived methyl-allylthiosulfinate or garlic extracts and thus circumventing dietary GGPP variations.

Aquaporin 7 involved in GINSENOSIDE-RB1-mediated anti-obesity via peroxisome proliferator-activated receptor gamma pathway.

BACKGROUND: Obesity, characterized by the excessive accumulation of triglycerides in adipocytes and their decreased excretion from adipocytes, is closely related to various health problems. Ginsenoside Rb1 (Rb1), the most active component of the traditional Chinese medicine ginseng, has been reported to have positive effects on lipid metabolism. The aim of the present study was to determine the protective effects of Rb1 on glycolipid metabolism under obesity conditions and its mechanisms and to reveal the signaling pathways involved. METHODS: In our study, male C57BL/6 mice with obesity induced by a high-fat diet (HFD) and mature 3 T3-L1 adipocytes were used to investigate the role of Rb1 in lipid accumulation and explore its possible molecular mechanism in vivo and in vitro, respectively. RESULTS: Rb1 reduced the body weight, fat mass, adipocytes size and serum free fatty acid (FFA) concentration of obese mice. In differentiated 3 T3-L1 adipocytes, Rb1 reduced the accumulation of lipid droplets and stimulated output of triglycerides. Additionally, the expression of peroxisome proliferator-activated receptor gamma (PPARγ), phosphorylated PPARγ (Ser112) and aquaporin 7 (AQP7) was upregulated in adipocytes and adipose tissues upon Rb1 treatment. However, intervention of GW9662, PPARγ antagonist, attenuated Rb1-mediated effects on glycolipid metabolism and AQP7 levels. CONCLUSIONS: These data indicated that Rb1 reduced body weight and improved glycolipid metabolism by upregulating PPARγ and AQP7 protein levels. Our study indicated a potential role for Rb1 in the prevention and treatment of obesity.