Osteocalcin and Non-Alcoholic Fatty Liver Disease: Lessons From Two Population-Based Cohorts and Animal Models

Abstract

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).

Non-Alcoholic Steatohepatitis (NASH) and Organokines: What Is Now and What Will Be in the Future

“…Therefore, OCN stimulates the consumption of glucose and FFAs by promoting the expression of fatty acid transporters, stimulating B-oxidation and translocation of GLUT4 to the plasma membrane. This scenario generates an anti-inflammatory environment, contributing to reducing visceral fat and reducing NASH [ 75 , 84 , 87 ]. Figure 5 shows the main organokines involved in the pathophysiology of NASH.…”

DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing

“…Human study and approval A total of 30 adults who underwent liver biopsy for suspected NASH were enrolled for analysis. The inclusion and exclusion criteria were the same as those in our previous study (Xia et al, 2021). Briefly, we excluded individuals with excessive alcohol intake (R140 g per week for men or R70 g per week for women) (Farrell et al, 2007) or other liver diseases (such as hepatitis B, hepatitis C, or autoimmune hepatitis et al) and those who used hepatic protectants.…”

Type 2 Diabetes Is Causally Associated With Reduced Serum Osteocalcin: A Genomewide Association and Mendelian Randomization Study

“…However, in our recently published study, serum total OCN was highly correlated with uncarboxylated OCN (r = 0.528, p < 0.001). (58) Lastly, the present study was conducted in East Asian populations, and the findings may not be applicable to other ethnicities. In addition, we were not able to perform MR analyses on other traits including 25OHD, PTH, BMD, and fat distribution because of a paucity of large GWAS results in East Asian population.…”