TY - JOUR
T1 - Osteocalcin and Non-Alcoholic Fatty Liver Disease
T2 - Lessons From Two Population-Based Cohorts and Animal Models
AU - Xia, Mingfeng
AU - Rong, Shunxing
AU - Zhu, Xiaopeng
AU - Yan, Hongmei
AU - Chang, Xinxia
AU - Sun, Xiaoyang
AU - Zeng, Hailuan
AU - Li, Xiaoming
AU - Zhang, Linshan
AU - Chen, Lingyan
AU - Wu, Li
AU - Ma, Hui
AU - Hu, Yu
AU - He, Wanyuan
AU - Gao, Jian
AU - Pan, Baishen
AU - Hu, Xiqi
AU - Lin, Huandong
AU - Bian, Hua
AU - Gao, Xin
N1 - Funding Information:
This work was supported by the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01 to XG), the National Key Research Program of China (2017YFC1309800, 2017YFC1309801 to HB), the key basic research grants from Science and Technology Commission of Shanghai Municipality (grant number 16JC1400500 to XG), the National Natural Science Foundation of China (grant number 81873660 to MX), the Shanghai Pujiang Talent Program (grant number 20PJ1402300 to MX), and the Shanghai Municipal Science and Technology Commission Foundation (grant number 16411954800 to XG).
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - BONE–LIVER INTERACTION
KW - HEPATIC DE NOVO LIPOGENESIS
KW - NAFLD
KW - OSTEOCALCIN
KW - SREBP-1C
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U2 - 10.1002/jbmr.4227
DO - 10.1002/jbmr.4227
M3 - Article
C2 - 33270924
AN - SCOPUS:85097820884
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
SN - 0884-0431
ER -