Abstract
The adipocytokine adiponectin and its structural homologs, the C1q/TNF-related proteins (CTRPs), increase insulin sensitivity, fatty acid oxidation and mitochondrial biogenesis. Adiponectin- and CTRP-induced signal transduction has been described to involve the adiponectin receptors and a number of co-receptors including the Low density lipoprotein receptor-related protein 1 (LRP1). LRP1 is another target of the proprotein convertase subtilisin/kexin-9 (PCSK9) in addition to the LDL-receptor (LDL-R). Here, we investigated the influence of PCSK9 on the metabolic effects of CTRP9, the CTRP with the highest homology to adiponectin. Knockdown of LRP1 in H9C2 cardiomyoblasts blunts the effects of CTRP9 on signal transduction and mitochondrial biogenesis, suggesting its involvement in CTRP9-induced cellular effects. Treatment of adult rat cardiomyocytes with recombinant PCSK9 but not knockdown of endogenous PCSK9 by siRNA results in a strong reduction in LRP1 protein expression and subsequently reduces the mitochondrial biogenic effect of CTRP9. PCSK9 treatment (24 h) blunts the effects of CTRP9-induced signaling cascade activation (AMP-dependent protein kinase, protein kinase B). In addition, the stimulating effects of CTRP9 on cardiomyocyte mitochondrial biogenesis and glucose metabolism (GLUT-4 translocation, glucose uptake) are largely blunted. Basal fatty acid (FA) uptake is strongly reduced by exogenous PCSK9, although protein expression of the PCSK9 target CD36, the key regulator of FA transport in cardiomyocytes, is not altered. In addition, only minor effects of PCSK9 were observed on CTRP9-induced FA uptake or the expression of genes involved in FA metabolism or uptake. Finally, this CTRP9-induced increase in CD36 expression occurs independent from LRP1 and LDL-R. In conclusion, PCSK9 treatment influences LRP1-mediated signaling pathways in cardiomyocytes. Thus, therapeutic PCSK9 inhibition may provide an additional benefit through stimulation of glucose metabolism and mitochondrial biogenesis in addition to the known lipid-lowering effects. This could be an important beneficial side effect in situations with impaired mitochondrial function and reduced metabolic flexibility thereby influencing cardiac function.
Highlights
Adipose tissue is an important endocrine organ, secreting various adipose-derived cytokines, so called adipokines, which regulate metabolic and non-metabolic functions in our body
MtDNA content and citrate synthase (CS) activity were increased in mock transfected, C1q/TNFrelated protein 9 (CTRP9)-treated cells H9C2 cells but not after lipoprotein receptor-related protein 1 (LRP1) knockdown (Figure 1C), suggesting that LRP1 is involved in mediating these CTRP9 effects
Unlike LRP1 protein, which was highly expressed in left ventricular (LV) tissue and in adult rat cardiomyocytes (Supplementary Figures 2A,B), proprotein convertase subtilisin/kexin-9 (PCSK9) protein expression was low in the LV (Supplementary Figure 2C)
Summary
Adipose tissue is an important endocrine organ, secreting various adipose-derived cytokines, so called adipokines, which regulate metabolic and non-metabolic functions in our body. Among these adipokines, acrp (adiponectin) was shown to increase glucose uptake, insulin sensitivity, fatty acid (FA) uptake and oxidation as well as mitochondrial biogenesis in cardiomyocytes. CTRP9 shares the highest degree of amino acid identity (51%) with the globular domain of adiponectin (Wong et al, 2009) and has been shown to mediate multiple cardioprotective effects (Kambara et al, 2012; Su et al, 2013; Sun et al, 2013; Zhao et al, 2018; Niemann et al, 2020; Zuo et al, 2020). The heart was identified as the organ expressing highest CTRP9 tissue levels, even exceeding adipose tissue where CTRP9 was originally discovered (Wong et al, 2009; Su et al, 2013)
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