511-P: Serum Tsukushi Is Associated with HDL Dysfunction in Type 2 Diabetes and Nonalcoholic Fatty Liver Disease

Introduction & Objective: Tsukushi (TSK) is a recently identified hepatokine and animal studies have suggested that TSK can affect systemic cholesterol homeostasis. Gain- and loss-of-function experiments in mice showed that TSK reduced circulating HDL-cholesterol (HDL-C). We therefore investigated whether TSK was associated with HDL-C and HDL function in type 2 diabetes with co-existing non-alcoholic fatty liver disease (NAFLD).

Methods: Vibration‑controlled transient elastography was performed in 565 subjects with type 2 diabetes. The degree of hepatic steatosis and fibrosis was reflected by controlled attenuation parameter (CAP) and liver stiffness (LS) respectively, and the presence of NAFLD was defined as CAP ≥248 dB/m. Serum TSK was measured by ELISA. Cholesterol efflux capacity (CEC), an indicator of HDL function, was determined by measuring the efflux of [3H]-cholesterol from RAW264.7 macrophages to apolipoprotein B-depleted serum.

Results: NAFLD was present in 430 subjects (76%). The age, proportion of male subjects and duration of diabetes were comparable between those with and without NAFLD. However, individuals with NAFLD had higher BMI (p<0.01) and serum TSK levels [97.0 ng/ml (63.8 - 136.3) versus 81.5 ng/ml (57.8 - 119.4) respectively, p<0.01], lower HDL-C (p<0.01) and CEC (18.0 ± 4.9% versus 19.1 ± 5.9% respectively, p<0.05) than those without NAFLD. Serum TSK correlated with HDL-C (r = -0.19, p<0.01) and with CEC (r = -0.16, p<0.01). Linear regression analysis showed that TSK, HDL-C and the use of thiazolidinediones were significant and independent determinants of CEC, in a model also consisting of age, sex, smoking, BMI, and the use of various anti-diabetic agents and lipid lowering therapy.

Conclusion: elevated TSK level was associated with reduced HDL-C, and HDL dysfunction with impaired CEC in type 2 diabetes and co-existing NAFLD.