Research & Education

Intro to Geranylgeraniol

What is geranylgeraniol? Geranyl-what? Besides being a bit of a tongue-twister, geranylgeraniol (GG) is a compound synthesized endogenously in the human body via the mevalonate pathway—the same biochemical pathway by which cholesterol, heme A, dolichol and ubiquinone (CoQ10) are synthesized. GG also occurs naturally in certain foods (such as flax, sunflower and olive oils, as well as select medicinal herbs), but the majority is synthesized endogenously. GG is an essential building block for the production of CoQ10, vitamin K2 and testosterone, as well as for protein synthesis and modification. Synthesis of GG declines naturally during aging and is inhibited by the use of certain pharmaceutical drugs, namely, statins and bisphosphonates. Repletion of GG stores may help mitigate the damaging side-effects of these drugs.

Effect of statins on synthesis of GG and downstream products

Statin drugs exert their effects early in the mevalonate pathway (via inhibition of the enzyme HMG-CoA reductase), far upstream of where GG and its byproducts are produced. Synthesis of all compounds produced after this step may be reduced, which likely contributes to the neuromyotoxicity and mitochondrial toxicity of statins. Decreased synthesis of CoQ10 may result in depressed cellular energy generation via impaired mitochondrial respiration, and consequences of reduced GG synthesis may include decreased endogenous vitamin K2 production and poor protein synthesis and modification with cascading effects on numerous tissue systems. The exact mechanisms behind the myopathy and myotoxicity many statin users experience are not known for certain but it’s possible they result from inadequate synthesis of GG and, as a result, inadequate CoQ10. Researchers have stated that GG is “the principal target of statin-dependent myotoxicity,” and statin-induced muscle damage “is the result of a geranylgeranylation defect”—potentially due to an inadequate pool of GG.

Heme A and dolichol

Beyond statins’ effect on CoQ10, their role in decreased heme A synthesis may also disturb mitochondrial function. Heme A is an essential component of cytochrome C oxidase, or complex IV of the electron transport chain, one of the major regulatory sites for oxidative phosphorylation and mitochondrial respiration. Deficiency of cytochrome C oxidase enhances mitochondrial apoptosis in response to oxidative stress. In addition to those related to reduced CoQ10 synthesis, some statin side-effects may result from insufficient heme A synthesis disrupting mitochondrial structure and function and therefore, cellular energy generation.

Drugs that impair GG synthesis also may result in decreased production of dolichol, a major lipid component of human endocrine organs. Dolichol plays a crucial role in cell membrane structure and function, influencing membrane fluidity and permeability. Owing to its large volume, muscle tissue synthesizes 50% of total body dolichol, but dolichol is synthesized at high rates in the liver, kidneys and spleen, and has a high concentration in the pancreas, testes, and thyroid, pituitary and adrenal glands. It’s believed that alterations in the amount and structural composition of dolichol derivatives may contribute to the changed cell membrane properties observed in certain diseases.

Can GG help?

Animal models and cell studies show that given in combination with statins, GG increases mitochondrial respiration and restores ubiquinone synthesis without negatively impacting statins’ cholesterol-lowering effects. Administration of GG to statin-treated human neurons decreased expression of inflammatory markers and reduced mitochondrial damage, facilitating maintenance of proper mitochondrial structure and function. In human monocytes and liver cells, GG reversed mevastatin-induced reductions in ubiquinone synthesis and mitochondrial electron transport that typically lead to cell death, again, without impeding the drug’s cholesterol-lowering property for those who benefit from that. (However, it’s worth mentioning that a great deal of controversy exists around whether elevated LDL-cholesterol, independently of other factors, is a risk for cardiovascular disease and whether statins are a wise course of treatment.) Notably, addition of GG was more effective than addition of exogenous CoQ10 for attenuating these adverse effects, leading researchers to state that compared to ubiquinone, “Geranylgeraniol may be a more useful and practical means of limiting the toxicities of statins, without reducing their efficacy as cholesterol-lowering agents.”

Bisphosphonates and GG

Bisphosphonate drugs are another category of pharmaceuticals that interfere with endogenous synthesis of GG through the mevalonate pathway. The enzyme target of these drugs is farnesyl pyrophosphate synthase (FPPS) rather than HMG-CoA reductase, so the precise mechanism is different from that of statins. PPS is involved in the steps immediately preceding GG synthesis. A common result of nitrogen-containing bisphosphonate (NBP) use is osteonecrosis of the jaw (ONJ). Effective treatments for this are lacking, and GG has been identified as a potential preventive and therapeutic agent. Most of the research in this area has been done in rodents and cell cultures but results are promising.

GG was shown to reverse the effects of NBPs on reduced angiogenesis, which is speculated to be one of many mechanisms contributing to ONJ. GG has also been shown to reverse the negative effects of NBPs in human fibroblasts, osteogenic cells and HUVEC cells. Endothelial progenitor cells (EPC) co-treated with NBPs and GG showed significantly increased cell viability, migration ability and increased EPC colony density (decreased apoptosis) compared to non-GG-treated controls, effectively reversing the negative effects of NBPs. Researchers concluded that systemic or local GG treatment could be a therapeutic strategy for ONJ. Similar results have been demonstrated for GG reversing the negative effects of NBP on human alveolar osteoblasts, periodontal ligament fibroblasts and oral keratinocytes. 

It’s ironic that the influence of NBPs on the mevalonate pathway may result in reduced vitamin K2 synthesis. Vitamin K2 is instrumental in supporting bone mass, so these osteoporosis drugs may actually induce the opposite of their intended effect. Vitamin K2-dependent enzymes play essential roles in calcium trafficking, and a deficit of enzyme activity may contribute to reduced bone mineralization and increased risk for vascular and soft tissue calcification. Although vitamin K1 accounts for over 90% of dietary vitamin K, the K2 form menaquinone-4 makes up over 90% of tissue vitamin K stores.

Future articles will explore other biological roles for GG. Evidence indicates it may be helpful for both acute and chronic pain relief, increasing testosterone and progesterone synthesis, and increasing insulin sensitivity, with implications for therapeutic use in type 2 diabetes—particularly in cases of statin-induced diabetes