Correction to: Putting genome-wide sequencing in neonates into perspective

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article

Anacetrapib reduces (V)LDL-cholesterol by inhibition of CETP activity and reduction of plasma PCSK9

Recently, we showed in APOE*3-Leiden.CETP mice that anacetrapib attenuated atherosclerosis development by reducing (V)LDL-C rather than by raising HDL-C. Here, we investigated the mechanism by which anacetrapib reduces (V)LDL-C and whether this effect was dependent on the inhibition of CETP. APOE*3-Leiden.CETP mice were fed a Western type diet alone or supplemented with anacetrapib (30 mg/kg body weight/d). Microarray analyses of livers revealed down-regulation of the cholesterol biosynthesis pathway (P<0.001) and predicted down regulation of sterol regulatory element-binding protein-1 and -2 controlled pathways (z-score -2.56 and z-score -2.90, respectively; both P<0.001). These data suggest increased supply of cholesterol to the liver. We found that hepatic proprotein convertase subtilisin/kexin type 9 (Pcsk9) expression was decreased (-28%, P<0.01) accompanied by decreased plasma PCSK9 levels (-47%, P<0.001), and increased hepatic LDL receptor protein content (+64%, P<0.01). Consistent with this, anacetrapib increased the clearance and hepatic uptake (+25%, P<0.001) of [14C]cholesteryl oleate-labeled VLDL-mimicking particles. In APOE*3-Leiden mice that do not express CETP, anacetrapib still decreased (V)LDL-C and plasma PCSK9 levels, indicating that these effects were independent of CETP inhibition. Anacetrapib reduces (V)LDL-C by two mechanisms: 1) inhibition of CETP activity, resulting in remodelled VLDL that are more susceptible to hepatic uptake and 2) a CETP-independent reduction of plasma PCSK9 levels that has the potential to increase LDL receptor mediated hepatic remnant clearance

Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration

BACKGROUND AND PURPOSE: The aetiology of inflammation in the liver and vessel wall, leading to non-alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored. Here, we tested the hypothesis that exendin-4 reduces inflammation in both the liver and vessel wall, and investigated the common underlying mechanism. EXPERIMENTAL APPROACH: Female APOE*3-Leiden.CETP mice, a model with human-like lipoprotein metabolism, were fed a cholesterol-containing Western-type diet for 5 weeks to induce atherosclerosis and subsequently treated for 4 weeks with exendin-4. KEY RESULTS: Exendin-4 modestly improved dyslipidaemia, but markedly decreased atherosclerotic lesion severity and area (-33%), accompanied by a reduction in monocyte adhesion to the vessel wall (-42%) and macrophage content in the plaque (-44%). Furthermore, exendin-4 reduced hepatic lipid content and inflammation as well as hepatic CD68(+) (-18%) and F4/80(+) (-25%) macrophage content. This was accompanied by less monocyte recruitment from the circulation as the Mac-1(+) macrophage content was decreased (-36%). Finally, exendin-4 reduced hepatic chemokine expression in vivo and suppressed oxidized low-density lipoprotein accumulation in peritoneal macrophages in vitro, effects dependent on the GLP-1 receptor. CONCLUSIONS AND IMPLICATIONS: Exendin-4 reduces inflammation in both the liver and vessel wall by reducing macrophage recruitment and activation. These data suggest that exendin-4 could be a valuable strategy to treat NASH and atherosclerosis simultaneously

Putting genome-wide sequencing in neonates into perspective

Genetics of disease, diagnosis and treatmen

Putting genome-wide sequencing in neonates into perspective (vol 24, pg 1074, 2019)

Genetics of disease, diagnosis and treatmen

Duodenal adenomas and cancer in MUTYH-associated polyposis: an international cohort study

Hereditary cancer genetic