Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea.
Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Int J Mol Sci. 2019 Apr 10;20(7):1782. doi: 10.3390/ijms20071782.
Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression through adiponectin receptor (AdipoR)1 and AdipoR2, respectively, which in turn activate PPAR gamma coactivator 1 alpha (PGC-1α), increase the phosphorylation of acyl CoA oxidase, and upregulate the uncoupling proteins involved in energy consumption. Moreover, adiponectin potently stimulates ceramidase activity associated with its two receptors and enhances ceramide catabolism and the formation of its anti-apoptotic metabolite, sphingosine 1 phosphate (S1P), independently of AMPK. Low circulating adiponectin levels in obese patients with a risk of insulin resistance, type 2 diabetes, and cardiovascular diseases, and increased adiponectin expression in the state of albuminuria suggest a protective and compensatory role for adiponectin in mitigating further renal injury during the development of overt diabetic kidney disease (DKD). We propose AdipoRon, an orally active synthetic adiponectin receptor agonist as a promising drug for restoration of DKD without inducing systemic adverse effects. Its renoprotective role against lipotoxicity and oxidative stress by enhancing the AMPK/PPARα pathway and ceramidase activity through AdipoRs is revealed here.
脂联素是一种由脂肪细胞分泌的脂肪因子，通过其抗炎、抗纤维化和抗氧化作用，在糖尿病和代谢综合征的环境中发挥有益作用。它通过诱导 AMP 激活蛋白激酶 (AMPK) 磷酸化和分别通过脂联素受体 (AdipoR)1 和 AdipoR2 增加过氧化物酶体增殖物激活受体 (PPAR)-α 的表达来介导脂肪酸代谢，这反过来又激活 PPARγ共激活因子 1α (PGC-1α)，增加酰基辅酶 A 氧化酶的磷酸化，并上调与能量消耗相关的解偶联蛋白。此外，脂联素强烈刺激与其两个受体相关的 ceramidase 活性，并增强神经酰胺代谢和其抗凋亡代谢物神经鞘氨醇 1 磷酸 (S1P) 的形成，而不依赖于 AMPK。肥胖患者循环脂联素水平低，存在胰岛素抵抗、2 型糖尿病和心血管疾病的风险，白蛋白尿状态下脂联素表达增加，表明脂联素在减轻显性糖尿病肾病 (DKD) 发展过程中进一步肾损伤方面具有保护和代偿作用。我们提出了 AdipoRon，一种口服活性的合成脂联素受体激动剂，作为一种有前途的药物，可恢复 DKD，而不会引起全身不良反应。它通过增强 AMPK/PPARα 通路和通过 AdipoRs 增加 ceramidase 活性来发挥抗脂毒性和抗氧化应激的肾保护作用。
