Geranylgeranyl Diphosphate Synthase Modulates Fetal Lung Branching Morphogenesis Possibly through Controlling K-Ras Prenylation.

G proteins play essential roles in regulating fetal lung development, and any defects in their expression or function (eg, activation or posttranslational modification) can lead to lung developmental malformation. Geranylgeranyl diphosphate synthase (GGPPS) can modulate protein prenylation that is required for protein membrane-anchoring and activation. Here, we report that GGPPS regulates fetal lung branching morphogenesis possibly through controlling K-Ras prenylation during fetal lung development. GGPPS was continuously expressed in lung epithelium throughout whole fetal lung development. Specific deletion of geranylgeranyl diphosphate synthase 1 (Ggps1) in lung epithelium during fetal lung development resulted in neonatal respiratory distress syndrome-like disease. The knockout mice died at postnatal day 1 of respiratory failure, and the lungs showed compensatory pneumonectasis, pulmonary atelectasis, and hyaline membranes. Subsequently, we proved that lung malformations in Ggps1-deficient mice resulted from the failure of fetal lung branching morphogenesis. Further investigation revealed Ggps1 deletion blocked K-Ras geranylgeranylation and extracellular signal-related kinase 1 or 2/mitogen-activated protein kinase signaling, which in turn disturbed fibroblast growth factor 10 regulation on fetal lung branching morphogenesis. Collectively, our data suggest that GGPPS is essential for maintaining fetal lung branching morphogenesis, which is possibly through regulating K-Ras prenylation.

Cholesterol metabolic enzyme Ggpps regulates epicardium development and ventricular wall architecture integrity in mice.

During embryonic heart development, the progenitor cells in the epicardium would migrate and differentiate into noncardiomyocytes in myocardium and affect the integrity of ventricular wall, but the underlying mechanism has not been well studied. We have found that myocardium geranylgeranyl diphosphate synthase (Ggpps), a metabolic enzyme for cholesterol biosynthesis, is critical for cardiac cytoarchitecture remodelling during heart development. Here, we further reveal that epicardial Ggpps could also regulate ventricular wall architecture integrity. Epicardium-specific deletion of Ggpps before embryonic day 10.5 (E10.5) is embryonic lethal, whereas after E13.5 is survival but with defects in the epicardium and ventricular wall structure. Ggpps deficiency in the epicardium enhances the proliferation of epicardial cells and disrupts cell‒cell contact, which makes epicardial cells easier to invade into ventricular wall. Thus, the fibroblast proliferation and coronary formation in myocardium were found enhanced that might disturb the coronary vasculature remodelling and ventricular wall integrity. These processes might be associated with the activation of YAP signalling, whose nuclear distribution is blocked by Ggpps deletion. In conclusion, our findings reveal a potential link between the cholesterol metabolism and heart epicardium and myocardium development in mammals, which might provide a new view of the cause for congenital heart diseases and potential therapeutic target in pathological cardiac conditions.

Conditional loss of geranylgeranyl diphosphate synthase alleviates acute obstructive cholestatic liver injury by regulating hepatic bile acid metabolism.

Previous studies have suggested that metabolites in the mevalonate pathway are involved in hepatic bile acid metabolism, yet the details of this relationship remain unknown. In this study, we found that the hepatic farnesyl pyrophosphate (FPP) level and the ratio of FPP to geranylgeranyl pyrophosphate (GGPP) were increased in mice with acute obstructive cholestasis compared with mice that underwent a sham operation. In addition, the livers of the mice with acute obstructive cholestasis showed lower expression of geranylgeranyl diphosphate synthase (GGPPS), which synthesizes GGPP from FPP. When Ggps1 was conditionally deleted in the liver, amelioration of liver injury, as shown by downregulation of the hepatic inflammatory response and decreased hepatocellular apoptosis, was found after ligation of the common bile duct and cholecystectomy (BDLC). Subsequently, liquid chromatography/mass spectrometry analysis showed that knocking out Ggps1 decreased the levels of hepatic bile acids, including hydrophobic bile acids. Mechanistically, the disruption of Ggps1 increased the levels of hepatic FPP and its metabolite farnesol, thereby resulting in farnesoid X receptor (FXR) activation, which modulated hepatic bile acid metabolism and reduced hepatic bile acids. It was consistently indicated that digeranyl bisphosphonate, a specific inhibitor of GGPPS, and GW4064, an agonist of FXR, could also alleviate acute obstructive cholestatic liver injury in vivo. In general, GGPPS is critical for modulating acute obstructive cholestatic liver injury, and the inhibition of GGPPS ameliorates acute obstructive cholestatic liver injury by decreasing hepatic bile acids, which is possibly achieved through the activation of FXR-induced bile acid metabolism.

Reduced triglyceride accumulation due to overactivation of farnesoid X receptor signaling contributes to impaired liver regeneration following 50% hepatectomy in extra­cholestatic liver tissue.

The aim of the present study was to investigate the role of triglyceride metabolism in the effect of obstructive cholestasis on liver regeneration following 50% partial hepatectomy (PH). Obstructive cholestatic rat models were achieved via ligation of the common bile duct (BDL). Following comparisons between hepatic pathological alterations with patients with perihilar cholangiocarcinoma, rats in the 7 day post­BDL group were selected as the BDL model for subsequent experiments. Liver weight restoration, proliferating cell nuclear antigen labeling index, cytokine and growth factor expression levels, and hepatic triglyceride content were evaluated to analyze liver regeneration post­PH within BDL and control group rats. The results of the present study revealed that obstructive cholestasis impaired liver mass restoration, which occurred via inhibition of early stage hepatocyte proliferation. In addition, reduced triglyceride content and inhibited expression of fatty acid ß­oxidation­associated genes, peroxisome proliferator activated receptor α and carnitine palmitoyltransferase, were associated with an insufficient energy supply within the BDL group post­PH. Notably, the expression levels of fatty acid synthesis­associated genes, including sterol­regulatory element­binding protein­1c, acetyl­coA carboxylase 1 and fatty acid synthase were also reduced within the BDL group, which accounted for the reduced triglyceride content and fatty acid utilization. Further investigation revealed that overactivated farnesoid X receptor (FXR) signaling may inhibit fatty acid synthesis within BDL group rats. Collectively, the role of triglycerides in liver regeneration following PH in extra­cholestatic livers was identified in the present study. Additionally, the results indicated that overactivated FXR signaling­induced triglyceride reduction is associated with insufficient energy supply and therefore contributes to the extent of impairment of liver regeneration following PH within extra­cholestatic livers.