Division of Functional Structure, Department of Morphological Biology, Fukuoka Dental College, Fukuoka, 814-0193, Japan.
OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, 812-8582, Japan.
Adv Biol Regul. 2020 Dec;78:100752. doi: 10.1016/j.jbior.2020.100752. Epub 2020 Sep 10.
Bone provides skeletal support and functions as an endocrine organ by producing osteocalcin, whose uncarboxylated form (GluOC) increases the metabolism of glucose and lipid by activating its putative G protein-coupled receptor (family C group 6 subtype A). Low doses (≤10 ng/ml) of GluOC induce the expression of adiponectin, adipose triglyceride lipase and peroxisome proliferator-activated receptor γ, and promote active phosphorylation of lipolytic enzymes such as perilipin and hormone-sensitive lipase via the cAMP-PKA-Src-Rap1-ERK-CREB signaling axis in 3T3-L1 adipocytes. Administration of high-dose (≥20 ng/ml) GluOC induces programmed necrosis (necroptosis) through a juxtacrine mechanism triggered by the binding of Fas ligand, whose expression is induced by forkhead box O1, to Fas that is expressed in adjacent adipocytes. Furthermore, expression of adiponectin and adipose triglyceride lipase in adipocytes is triggered in the same manner as following low-dose GluOC stimulation; these effects protect mice from diet-induced accumulation of triglycerides in hepatocytes and consequent liver injury through the upregulation of nuclear translocation of nuclear factor-E2-related factor-2, expression of antioxidant enzymes, and inhibition of the c-Jun N-terminal kinase pathway. Evaluation of these molecular mechanisms leads us to consider that GluOC might have potential as a treatment for lipid metabolism disorders. Indeed, there have been many reports demonstrating the negative correlation between serum osteocalcin levels and obesity or non-alcoholic fatty liver disease, a common risk factor for which is dyslipidemia in humans. The present review summarizes the effects of GluOC on lipid metabolism as well as its possible therapeutic application for metabolic diseases including obesity and dyslipidemia.
骨通过产生骨钙素提供骨骼支持并发挥内分泌器官的功能，其未羧化形式（GluOC）通过激活其假定的 G 蛋白偶联受体（家族 C 组 6 亚型 A）增加葡萄糖和脂质的代谢。低剂量（≤10ng/ml）的 GluOC 诱导脂联素、脂肪甘油三酯脂肪酶和过氧化物酶体增殖物激活受体 γ 的表达，并通过 cAMP-PKA-Src-Rap1-ERK-CREB 信号通路促进脂肪分解酶如 perilipin 和激素敏感脂肪酶的活性磷酸化，在 3T3-L1 脂肪细胞中。高剂量（≥20ng/ml）GluOC 通过 Fas 配体结合触发的旁分泌机制诱导程序性细胞坏死（坏死），Fas 配体的表达受叉头框 O1 诱导，而 Fas 在相邻脂肪细胞中表达。此外，脂肪细胞中脂联素和脂肪甘油三酯脂肪酶的表达也以与低剂量 GluOC 刺激相同的方式被触发；这些作用通过上调核因子-E2 相关因子-2 的核转位、抗氧化酶的表达和抑制 c-Jun N-末端激酶途径来保护小鼠免受饮食诱导的肝细胞内甘油三酯积累和随之发生的肝损伤。对这些分子机制的评估使我们认为 GluOC 可能具有作为治疗脂质代谢紊乱的潜力。事实上，已经有许多报道表明血清骨钙素水平与肥胖或非酒精性脂肪肝之间存在负相关，后者的常见危险因素是人类的血脂异常。本综述总结了 GluOC 对脂质代谢的影响及其在包括肥胖和血脂异常在内的代谢性疾病中的潜在治疗应用。
