Revisiting Old Friends
Sortilin-1, Low-Density Lipoprotein Receptor, and Prorenin Receptor as Modulators of Lipoprotein and Energy Metabolism
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Although initially named for its ability to bind renin and prorenin, it is now universally accepted that the prorenin receptor ((P)RR) encoded by the ATP6AP2 gene has a myriad of functions outside of the renal axis, including a role in lipoprotein metabolism. (P)RR knockdown in vitro is known to reduce the levels of 2 low-density lipoprotein (LDL) clearance receptors, the LDL receptor (LDLR) and SORT1 (sortilin-1).1 In this issue, Ren et al2 further explore the role of (P)RR in lipid metabolism and report that antisense-mediated reduction of Atp6ap2 expression in vivo affects plasma cholesterol, plasma triglycerides, LDL clearance, triglyceride secretion, and hepatic lipid content and that some of the effects of Atp6ap2 inhibition depend on genetic background and diet, nominating the (P)RR pathway as an important regulator of lipoprotein metabolism.
Article, see p 730
Ren et al2 used antisense oligonucleotides (ASOs) to decrease Atp6ap2 expression in mouse liver and found that consistent with prior in vitro studies, (P)RR knockdown reduced hepatic LDLR and SORT1 protein levels. Both SORT1 and the LDLR play critical roles in lipid metabolism, with LDLR serving as the primary receptor for LDL clearance and SORT1 serving both as an LDL clearance receptor and as a regulator of hepatic lipoprotein secretion. Atp6ap2 knockdown in wild-type mice fed normal and high-fat diets increased plasma cholesterol and decreased LDL clearance. ASO-mediated hepatic Atp6ap2 knockdown also decreased plasma triglycerides and triglyceride secretion.
In contrast to wild-type mice, in 2 different models of LDLR deficiency, genetically Ldlr-deficient mice and mice injected with an adeno-associated virus encoding a gain-of-function proprotein convertase subtilisin/kexin type 9 mutant (D377Y), ASO-mediated Atp6ap2 knockdown decreased plasma cholesterol and triglycerides. These discordant results may be related to the effect of decreased (P)RR on SORT1 protein levels. Sort1 deficiency is known …