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

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.

Methotrexate Decreases the Level of PCSK9—A Novel Indicator of the Risk of Proatherogenic Lipid Profile in Psoriasis. The Preliminary Data

“…Elevated PCSK9 is also observed in metabolic syndrome, which affects more than 50% of psoriatic patients [24]. Furthermore, PCSK9 expression can be regulated by agonists adiponectin receptors (AdipoR agonists) through peroxisome proliferator-activated receptor gamma (PPAR-gamma) [32]. Reduction of circulating adiponectin levels and an expression of PPAR-gamma has been proven to be linked with obesity in psoriasis [32,33].…”

“…Furthermore, PCSK9 expression can be regulated by agonists adiponectin receptors (AdipoR agonists) through peroxisome proliferator-activated receptor gamma (PPAR-gamma) [32]. Reduction of circulating adiponectin levels and an expression of PPAR-gamma has been proven to be linked with obesity in psoriasis [32,33]. According to dual mechanisms in lipids metabolism and inflammation, PCSK9 monoclonal inhibitors termed ewolokumab and alirokumab had proven to be highly promising in bringing added cardiovascular benefit in the ODYSSEY LONG TERM trial and the FOURIER trial [34,35].…”

Effect of cilostazol on plasma levels of proprotein convertase subtilisin/kexin type 9

“…The mechanism underlying the effect of cilostazol on PCSK9 concentrations is poorly understood and could only be speculated. Interestingly, the expression of PCSK9 can be regulated not only by SREBP-2 but also by peroxisome proliferator-activated receptor-γ (PPARγ) [ 27 , 28 ]. Furthermore, activation of the adiponectin receptor can upregulate PCSK9 expression through activation of PPARγ and the adenosine monophosphate-activated protein kinase signaling pathway [ 28 ].…”

“…Interestingly, the expression of PCSK9 can be regulated not only by SREBP-2 but also by peroxisome proliferator-activated receptor-γ (PPARγ) [ 27 , 28 ]. Furthermore, activation of the adiponectin receptor can upregulate PCSK9 expression through activation of PPARγ and the adenosine monophosphate-activated protein kinase signaling pathway [ 28 ]. Our previous study revealed that cilostazol could serve as an activator of adenosine monophosphate-activated protein kinase signaling molecules [ 21 ] and adiponectin receptors (unpublished data), and our current study demonstrates that cilostazol treatment can increase plasma adiponectin concentrations.…”

Therapeutic properties of the new phytochemical osmotin for preventing atherosclerosis

“…Several studies have shown that adiponectin and AdipoRon suppress the development of atherosclerotic lesions in apolipoprotein E-deficient (Apoe -/-) mice, an atherogenic mouse model, on a normal or high-fat diet [51][52][53] . Recently, the anti-atherosclerotic effects of osmotin have also been investigated using a variety of animal models in vivo.…”