Lipid overload results in lipid redistribution among metabolic organs such as liver, adipose, and muscle; therefore, the interplay between liver and other organs is important to maintain lipid homeostasis. Here, we show that liver responds to lipid overload first and sends hepatocyte-derived extracellular vesicles (EVs) targeting adipocytes to regulate adipogenesis and lipogenesis. Geranylgeranyl diphosphate synthase (Ggpps) expression in liver is enhanced by lipid overload and regulates EV secretion through Rab27A geranylgeranylation. Consistently, liver-specific Ggpps deficient mice have reduced fat adipose deposition. The levels of several EV-derived miRNAs in the plasma of non-alcoholic fatty liver disease (NAFLD) patients are positively correlated with body mass index (BMI), and these miRNAs enhance adipocyte lipid accumulation. Thus, we highlight an inter-organ mechanism whereby the liver senses different metabolic states and sends corresponding signals to remodel adipose tissue to adapt to metabolic changes in response to lipid overload.

We conducted a single-center randomized trial to compare the efficacy of 8 mm Fluency covered stent and bare stent in transjugular intrahepatic portosystemic shunt (TIPS) for cirrhotic portal hypertension. From January 2006 to December 2010, the covered (experimental group) or bare stent (control group) was used in 131 and 127 patients, respectively. The recurrence rates of gastrointestinal bleeding (18.3% vs. 33.9%, P = 0.004) and refractory hydrothorax/ascites (6.9% vs. 16.5%, P = 0.019) in the experimental group were significantly lower than those in the control group. The cumulative restenosis rates in 1, 2, 3, 4, and 5-years in the experimental group (6.9%, 11.5%, 19.1%, 26.0%, and 35.9%, respectively) were significantly lower (P < 0.001) than those in the control group (27.6%, 37.0%, 49.6%, 59.8%, 74.8%, respectively). Importantly, the 4 and 5-year survival rates in the experimental group (83.2% and 76.3%, respectively) were significantly higher (P = 0.001 and 0.02) than those in the control group (71.7% and 62.2%, respectively). The rate of secondary interventional therapy in the experimental group was significantly lower than that in the control group (20.6% vs. 49.6%; P < 0.001). Therefore, Fluency covered stent has advantages over the bare stent in terms of reducing the restenosis, recurrence, and secondary interventional therapy, whereas improving the long-term survival for post-TIPS patients.

Protein prenylation is an essential posttranslational modification and includes protein farnesylation and geranylgeranylation using farnesyl diphosphate or geranylgeranyl diphosphate as substrates, respectively. Geranylgeranyl diphosphate synthase is a branch point enzyme in the mevalonate pathway that affects the ratio of farnesyl diphosphate to geranylgeranyl diphosphate. Abnormal geranylgeranyl diphosphate synthase 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 with agents such as statins and bisphosphonates to improve clinical outcomes.