The balance of protein farnesylation and geranylgeranylation during the progression of nonalcoholic fatty liver disease

Protein prenylation is an essential posttranslational modification and includes protein farnesylation and geranylgeranylation using farnesyl diphosphate (FPP) or geranylgeranyl diphosphate (GGPP) as substrates, respectively. Geranylgeranyl diphosphate synthase (GGPPS) is a branchpoint enzyme in the mevalonate (MVA) pathway that affects the ratio of FPP to GGPP. Abnormal GGPPS expression and activity can therefore disrupt the balance of farnesylation and geranylgeranylation and alter the ratio between farnesylated and geranylgeranylated proteins. This change is associated with the progression of nonalcoholic fatty liver disease (NAFLD), a condition characterized by hepatic fat overload. Of note, differential accumulation of farnesylated and geranylgeranylated proteins has been associated with differential stages of NAFLD and NAFLD-associated liver fibrosis. In this review, we summarize key aspects of protein prenylation as well as advances that have uncovered the regulation of associated metabolic patterns and signaling pathways, such as Ras GTPase signaling, involved in NAFLD progression. Additionally, we discuss unique opportunities for targeting prenylation in NAFLD/hepatocellular carcinoma (HCC) with agents such as statins and bisphosphonates (BPs) to improve clinical outcomes.