Osteocalcin and non‐alcoholic fatty liver disease:​ lessons from two population‐based cohorts and animal models

Xia, Mingfeng; Rong, Shunxing; Zhu, Xiaopeng; Yan, Hongmei; Chang, Xinxia; Sun, Xiaoyang; Zeng, Hailuan; Li, Xiaoming; Zhang, Linshan; Chen, Lingyan; Wu, Li; Ma, Hui; Hu, Yu; He, Wanyuan; Gao, Jian; Pan, Baishen; Hu, Xiqi; Lin, Huandong; Bian, Hua; Gao, Xin

Affiliations

¹Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China

²Fudan Institute for Metabolic Diseases, Shanghai, China

³Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA

⁴Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China

⁵Department of Ultrasonography, Zhongshan Hospital, Fudan University, Shanghai, China

⁶Center of Clinical Epidemiology and EBM of Fudan University, Shanghai, China

⁷Department of Nutrition, Zhongshan Hospital of Fudan University, Shanghai, China

⁸Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China

⁹Department of Pathology, Medical College, Fudan University, Shanghai, China

Abstract and keywords

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.

Keywords: OSTEOCALCIN; NAFLD; BONE–LIVER INTERACTION; SREBP‐1C; HEPATIC DE NOVO LIPOGENESIS

Links

DOI: 10.1002/jbmr.4227

PubMed: 33270924

WoS: 000600534000001

History

Received: 2020-05-19

Revised: 2020-11-22

Accepted: 2020-11-27

Online: 2020-12-21

Cited Works (1)

Year	Entry
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