Cdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice

Cysteine dioxygenase type 1 (Cdo1) is a key enzyme for cysteine catabolism that is enriched in liver, whose role in NAFLD remains poorly understood. Here, we show that exercise induces the expression of hepatic Cdo1 via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout of Cdo1 (Cdo1LKO) impairs the effect of exercise against NAFLD, whereas hepatocyte-specific overexpression of Cdo1 (Cdo1LTG) and exercise synergistically ameliorates NAFLD in male mice. Mechanistically, Cdo1 facilitates the binding between AMPK and kinase active Camkk2, which activates AMPK signaling. This promotes fatty acid oxidation and mitochondrial biogenesis in hepatocytes to attenuate hepatosteatosis. Therefore, by promoting hepatic Camkk2-AMPK signaling pathway, Cdo1 acts as an important downstream effector of exercise to combat against NAFLD Overall design: Total RNA was obtained from liver of HFD-fed control mice and Cdo1LKO mice.