Osteocalcin and Non-Alcoholic Fatty Liver Disease: Lessons From Two Population-Based Cohorts and Animal Models
Osteocalcin and Non-Alcoholic Fatty Liver Disease: Lessons From Two Population-Based Cohorts and Animal Models
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骨钙素和非酒精性脂肪肝：两个基于人群的队列和动物模型的教训
DOI：
10.1002/jbmr.4227
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发表时间：
2021
影响因子：
6.2
通讯作者：
Xin Gao
中科院分区：
文献类型：
--
作者：
Mingfeng Xia;Shunxing Rong;Xiaopeng Zhu;Hongmei Yan;Xinxia Chang;Xiaoyang Sun;Hailuan Zeng;Xiaoming Li;Linshan Zhang;Lingyan Chen;Li Wu;Hui Ma;Yu Hu;Wanyuan He;Jian Gao;Baishen Pan;Xiqi Hu;Hu;ong Lin;Hua Bian;Xin Gao
骨钙素以一种活性的低羧化/非羧化形式调节能量代谢。然而，其在非酒精性脂肪性肝病(NAFLD)发生发展中的作用仍存在争议。在本研究中，我们在两个人群中调查了循环骨钙素与NAFLD的因果关系，并通过动物模型研究了未羧化骨钙素对肝脏脂质代谢的影响。我们在196名参与者的肝活检队列中分析了血清总/未羧化骨钙素与肝脏脂肪变性/纤维化的相关性，并在上海长丰研究的2055名前瞻性社区队列中分析了血清骨钙素与NAFLD发生/缓解的因果关系。血清总骨钙素与未羧化骨钙素呈正相关(r=0.528，p <； .001)。在男性和女性参与者中，总的和未羧化的骨钙素四分位数与肝脏脂肪变性、炎症、气球膨胀和纤维化分级呈负相关(趋势分析均P；0.05)。在调整了混杂的血糖、血脂和骨代谢参数后，骨钙素水平最低四分位的男性和女性参与者仍有更严重的肝脏脂肪变性，多变量调整后的优势比(OR)分别为7.25(1.07-49.30)和4.44(1.01-19.41)。在前瞻性社区队列中，经过中位数4.2年的随访后，女性而不是男性参与者的骨钙素水平在基线水平处于最低四分位数时，患非酒精性脂肪肝的风险较高(风险比[HR]= 1.90；95%可信区间[CI]1.14-3.16)，缓解的几率较低(HR=0.56；95%可信区间0.31-1.00)。在喂食西方饮食的野生型小鼠中，骨钙素治疗减轻了肝脏脂肪变性，并减少了肝脏SREBP-1及其下游蛋白的表达。在短期应用骨钙素的小鼠中，肝脏SREBP-1的表达减少，而血糖水平或胰岛素敏感性没有变化。当SREBP-1c在人SREBP-1c转基因大鼠模型中稳定表达时，骨钙素诱导的脂肪生成减少被消除。总而言之，循环中的骨钙素与NAFLD呈负相关。骨钙素通过减少SREBP-1c的表达来减少肝脏脂肪生成。©2020美国骨与矿物研究学会(ASBMR)。
Osteocalcin regulates energy metabolism in an active undercarboxylated/uncarboxylated form. However, its role on the development of non‐alcoholic fatty liver disease (NAFLD) is still controversial. In the current study, we investigated the causal relationship of circulating osteocalcin with NAFLD in two human cohorts and studied the effect of uncarboxylated osteocalcin on liver lipid metabolism through animal models. We analyzed the correlations of serum total/uncarboxylated osteocalcin with liver steatosis/fibrosis in a liver biopsy cohort of 196 participants, and the causal relationship between serum osteocalcin and the incidence/remission of NAFLD in a prospective community cohort of 2055 subjects from Shanghai Changfeng Study. Serum total osteocalcin was positively correlated with uncarboxylated osteocalcin (r = 0.528, p < .001). Total and uncarboxylated osteocalcin quartiles were inversely associated with liver steatosis, inflammation, ballooning, and fibrosis grades in both male and female participants (all p for trend <.05). After adjustment for confounding glucose, lipid, and bone metabolism parameters, the male and female participants with lowest quartile of osteocalcin still had more severe liver steatosis, with multivariate‐adjusted odds ratios (ORs) of 7.25 (1.07–49.30) and 4.44 (1.01–19.41), respectively. In the prospective community cohort, after a median of 4.2‐year follow‐up, the female but not male participants with lowest quartile of osteocalcin at baseline had higher risk to develop NAFLD (hazard ratio [HR] = 1.90; 95% confidence interval [CI] 1.14–3.16) and lower chance to achieve NAFLD remission (HR = 0.56; 95% CI 0.31–1.00). In wild‐type mice fed a Western diet, osteocalcin treatment alleviated hepatic steatosis and reduced hepatic SREBP‐1 and its downstream proteins expression. In mice treated with osteocalcin for a short term, hepatic SREBP‐1 expression was decreased without changes of glucose level or insulin sensitivity. When SREBP‐1c was stably expressed in a human SREBP‐1c transgenic rat model, the reduction of lipogenesis induced by osteocalcin treatment was abolished. In conclusion, circulating osteocalcin was inversely associated with NAFLD. Osteocalcin reduces liver lipogenesis via decreasing SREBP‐1c expression. © 2020 American Society for Bone and Mineral Research (ASBMR).