Abstract
Aquaglyceroporins (AQPs) allow the movement of glycerol that is required for triglyceride formation in hepatic stellate cells (HSC), as key cellular source of fibrogenesis in the liver. The genetic polymorphism I148M of the patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with hepatic steatosis and its progression to steatohepatitis (NASH), fibrosis and cancer. We aimed to explore the role of AQP3 for HSC activation and unveil its potential interactions with PNPLA3. HSC were isolated from human liver, experiments were performed in primary HSC and human HSC line LX2. AQP3 was the only aquaglyceroporin present in HSC and its expression decreased during activation. The PPARγ agonist, rosiglitazone, recovered AQP3 expression also in PNPLA3 I148M carrying HSC. When PNPLA3 was silenced, AQP3 expression increased. In liver sections from patients with NASH, the decreased amount of AQP3 was proportional to the severity of fibrosis and presence of the PNPLA3 I148M variant. In PNPLA3 I148M cells, the blockade of JNK pathway upregulated AQP3 in synergism with PPARγ. In conclusion, we demonstrated profound reduction of AQP3 in HSC carrying the PNPLA3 I148M variant in parallel to decreased PPARγ activation, which could be rescued by rosiglitazone and blockade of JNK.
Highlights
Lipid content is a crucial factor in hepatic stellate cells (HSC) pathophysiology[5,6] and lipogenic activity decreases in parallel with vitamin A content during HSC activation[7]
HSCs, categorized according to days (D) in cell culture; AQP3 decreases with time and cells activation, calnexin was used as loading control and α-SMA as a marker for HSC activation. (D) P21 expression increases with cell passage (P), highlighting HSCs senescence (*p < 0.05, **p < 0.01 compared to P0. p values for P5: p = 0.03; P7: p = 0.009); (E) Quantification of flow cytometric indirect staining for AQP3 shows decreased AQP3 expression over time expressed in days (D) in accordance to the western blot results (*p = 0.04); gating depicted in Suppl
We aimed to uncover (i) which AQPs were expressed in primary hepatic stellate cells, (ii) how AQP expression is regulated at the molecular level and (iii) whether patatin-like phospholipase domain-containing 3 (PNPLA3) mutations modulated AQP levels in HSC
Summary
Lipid content is a crucial factor in HSC pathophysiology[5,6] and lipogenic activity decreases in parallel with vitamin A content during HSC activation[7]. In a recent study we showed that primary HSC carrying the human genetic variant of PNPLA3 (adiponutrin), known as PNPLA3 I148M, lack peroxisome proliferator-activated receptor gamma (PPARγ, NR1C3) expression and activity[8], which is closely linked to HSC activation[9]. This PNPLA3 I148M variant has been associated to higher accumulation of fat in liver, steatohepatitis and inflammation, progression to fibrosis/cirrhosis and liver cancer[10,11]. We aimed to uncover (i) which AQPs were expressed in primary hepatic stellate cells, (ii) how AQP expression is regulated at the molecular level and (iii) whether PNPLA3 mutations modulated AQP levels in HSC
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