Editors' ChoiceAtherosclerosis

SORT ing Out That Pesky Cholesterol

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Science Translational Medicine  05 Mar 2014:
Vol. 6, Issue 226, pp. 226ec42
DOI: 10.1126/scitranslmed.3008715

According to WebMD, statins are the second most widely prescribed drugs (just behind hydrocodone). But, not all patients on statins see the expected drop in serum levels of low-density lipoprotein cholesterol (LDL-C), and still others report serious adverse events, prompting the search for new lipid-modulating targets for therapies to combat atherosclerosis. Human genetics has pinpointed two potential new targets for LDL-C lowering drugs: proprotein convertase subtilisin/kexin type 9 (PCSK9) and sortilin-1 (SORT1), with ongoing clinical trials for PCSK9 inhibition showing promising results. PCSK9 is believed to regulate LDL-C by targeting the LDL receptor (LDLR) for degradation. However, the mechanism of trafficking PCSK9 out of the liver is not well understood. Now, Gustafsen and colleagues provide evidence that SORT1 regulates PCSK9 activity.

Owing to its similarity to LDLR proteins, the authors began with the hypothesis that SORT1 is a molecular target for PCSK9. They demonstrated that PCSK9 preferentially coimmunoprecipitated with SORT1 from cultured cells and bound to SORT1 in a concentration-dependent manner in vitro. Next, subcellular localization experiments using a liver cell line showed that SORT1 and PCSK9 colocalized with a trans-Golgi marker, suggesting that the SORT1-PCSK9 interaction is established primarily in the secretory pathway. In primary liver cells obtained from SORT1 knockout mice, secretion of PCSK9 was substantially reduced as compared with that in liver cells obtained from wild-type animals. Furthermore, PCSK9 concentrations measured in plasma of the SORT1 knockout mice was also significantly lower and was accompanied by a twofold increase in LDLR levels in liver as compared with that of the wild type. Last, in a population of healthy human subjects, the authors observed a significant positive correlation between plasma concentrations of SORT1 and PCSK9, suggesting that SORT1 expression affects circulating PCSK9 levels. These data suggest a model in which SORT1 acts as a high-affinity receptor for PCSK9, and the two proteins interact in the trans-Golgi network in liver to facilitate the passage of PCSK9 through the late secretory pathway.

The data suggest that both proteins, as well as other putative regulators within this secretion pathway, might serve as therapeutic targets for atherosclerosis drugs. In a broader context, the new work provides further proof that the biology underlying human genetic associations can indeed be SORTed out.

C. Gustafsen et al., The hypercholesterolemia-risk gene SORT1 facilitates PCSK9 secretion. Cell Metab. 19, 310–318 (2014). [Abstract]

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