Objective:
Previous studies associated plasma cathepsin D (CTSD) activity with hepatic insulin resistance in overweight and obese humans. Insulin resistance is a major feature of non-alcoholic fatty liver disease (NAFLD) and is one of the multiple hits determining the progression towards non-alcoholic steatohepatitis (NASH). In line, we have previously demonstrated that plasma CTSD levels are elevated in patients with NASH. However, it is not known whether insulin resistance associates with plasma CTSD activity in NAFLD. Investigating the link between plasma CTSD activity to insulin resistance in NAFLD patients will increase our understanding regarding the mechanisms by which insulin resistance mediates NAFLD progression.

Methods:
Fifty-five liver biopsy or MRI-proven NAFLD patients (BMI>25kg/m²), of which 26 are females were included. After overnight fasting, blood samples were collected to measure metabolic parameters, liver enzymes and plasma CTSD activity. Associations between CTSD activity and insulin resistance were analyzed with adjustment for age, sex, BMI and waist.

Results:
The homeostasis model assessment for insulin resistance (HOMA-IR) positively associated with plasma CTSD activity, even after adjustment for age, sex, BMI and waist (standardized coefficient β: 0.412, 95% Cl: 0.142~0.679, p=0.004). Furthermore, fasting plasma insulin levels were also positively associated with plasma CTSD activity, independent of age, sex, BMI and waist (standardized coefficient β: 0.495, 95% Cl: 0. 236~0.758, p=0.000).

Conclusions:
Insulin resistance is associated with plasma CTSD activity in NAFLD patients. Together with previous studies, these data suggest that insulin resistance may contribute to NAFLD progression via elevation of CTSD activity in plasma. As such, these data pave the way for testing CTSD inhibitors as a pharmacological treatment of NAFLD/NASH.