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. 2017 Jul;37(7):1290-1300.
doi: 10.1161/ATVBAHA.117.309630. Epub 2017 May 25.

Activation of Adiponectin Receptor Regulates Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Inhibits Lesions in ApoE-Deficient Mice

Lei Sun  1 , Xiaoxiao Yang  1 , Qi Li  1 , Peng Zeng  1 , Ying Liu  1 , Lipei Liu  1 , Yuanli Chen  1 , Miao Yu  1 , Chuanrui Ma  1 , Xiaoju Li  1 , Yan Li  1 , Rongxin Zhang  1 , Yan Zhu  1 , Qing Robert Miao  1 , Jihong Han  2 , Yajun Duan  2
Affiliations

Activation of Adiponectin Receptor Regulates Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Inhibits Lesions in ApoE-Deficient Mice

Lei Sun et al. Arterioscler Thromb Vasc Biol. 2017 Jul.

Abstract

Objective: The reduced adiponectin levels are associated with atherosclerosis. Adiponectin exerts its functions by activating adiponectin receptor (AdipoR). Proprotein convertase subtilisin kexin type 9 (PCSK9) degrades LDLR protein (low-density lipoprotein receptor) to increase serum LDL-cholesterol levels. PCSK9 expression can be regulated by PPARγ (peroxisome proliferator-activated receptor γ) or SREBP2 (sterol regulatory element-binding protein 2). The effects of AdipoR agonists on PCSK9 and LDLR expression, serum lipid profiles, and atherosclerosis remain unknown.

Approach and results: At cellular levels, AdipoR agonists (ADP355 and AdipoRon) induced PCSK9 transcription/expression that solely depended on activation of PPAR-responsive element in the PCSK9 promoter. AdipoR agonists induced PPARγ expression; thus, the AdipoR agonist-activated PCSK9 expression/production was impaired in PPARγ deficient hepatocytes. Meanwhile, AdipoR agonists transcriptionally activated LDLR expression by activating SRE in the LDLR promoter. Moreover, AMP-activated protein kinase α (AMPKα) was involved in AdipoR agonist-activated PCSK9 expression. In wild-type mice, ADP355 increased PCSK9 and LDLR expression and serum PCSK9 levels, which was associated with activation of PPARγ, AMPKα and SREBP2 and reduction of LDL-cholesterol levels. In contrast, ADP355 reduced PCSK9 expression/secretion in apoE-deficient (apoE-/-) mice, but it still activated hepatic LDLR, PPARγ, AMPKα, and SREBP2. More importantly, ADP355 inhibited lesions in en face aortas and sinus lesions in aortic root in apoE-/- mice with amelioration of lipid profiles.

Conclusions: Our study demonstrates that AdipoR activation by agonists regulated PCSK9 expression differently in wild-type and apoE-/- mice. However, ADP355 activated hepatic LDLR expression and ameliorated lipid metabolism in both types of mice and inhibited atherosclerosis in apoE-/- mice.

Keywords: AMP-activated protein kinases; adiponectin; adiponectin receptors; atherosclerosis; peroxisome proliferator-activated receptors.

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