Aim: Loss of function mutations in ANGPTL3 cause low plasma lipid concentrations. Statins supposedly suppress hepatic ANGPTL3 mRNA expression in healthy subjects (J. Intern. Med. 2011: 269: 333). How statins regulate Angptl3 and whether statins reduce plasma Angptl3 concentrations in patients with elevated LDL cholesterol levels, e.g., familial hypercholesterolemia (FH), is unknown. 
Methods: We measured plasma Angptl3 concentrations in 157 genetically confirmed FH patients (LDL cholesterol concentrations above the 90th percentile for age and sex) and in 129 age and sex matched unaffected relatives. The effect of simvastatin on ANGPTL3 mRNA expression and Angptl3 secretion was assessed in the human hepatoma cell line Huh7. 
Results: Plasma Angptl3 concentrations were 25% lower in statin naïve FH patients than in unaffected relatives (180 ± 52 vs. 238 ± 76 ng/ml, p<0.05). In statin treated FH patients, plasma Angptl3 concentrations were even 13% lower than in statin naïve FH patients (161 ± 60 vs. 180 ± 52 ng/ml, p<0.05). Simvastatin treatment of Huh7 cells resulted in 73% and 42% lower ANGPTL3 mRNA expression and Angptl3 secretion, respectively. The liver X receptor (LXR) agonist T0901317 increased ANGPTL3 mRNA expression 6-fold and Angptl3 secretion 3-fold but blocked the inhibitory effects of simvastatin on these parameters. Treatment with the LXR antagonist GSK2230 attenuated the simvastatin-mediated reduction of ANGPTL3 mRNA expression. 
Conclusions: Plasma Angptl3 concentrations are lower in FH patients than in controls. Statin therapy lowers plasma Angptl3 concentrations due to decreased hepatic ANGPTL3 mRNA expression and Angptl3 secretion, likely caused by interfering with LXR transcriptional activity.

05 - STATINS REDUCE HEPATIC ANGPTL3 EXPRESSION AND SECRETION, LIKELY BY INTERFERING WITH LXR-MEDIATED TRANSCRIPTION