Caveolin-1 protects against liver damage exacerbated by acetaminophen in non-alcoholic fatty liver disease by inhibiting the ERK/HIF-1α pathway.

Acetaminophen (APAP) is a common antipyretic and analgesic drug that can cause long-term liver damage after an overdose. Non-alcoholic fatty liver disease (NAFLD) increases susceptibility to APAP. In NAFLD, excessive accumulation of lipids leads to an abnormal increase in hypoxia-inducible factor-1α (HIF-1α). Caveolin-1 (CAV1) may protect against NAFLD by inhibiting HIF-1α. This research aimed to determine whether CAV1 could attenuate APAP-exacerbated liver injury in NAFLD by inhibiting oxidative stress involving HIF-1α. In this study, 7-week-old C57BL/6 mice were fed a high-fat diet (HFD) for eight weeks, followed by the instillation of APAP. Levels of oxidative stress and liver lipid deposition were determined, and p-ERK1/2 and HIF-1α protein expression were measured by the Western blot (WB) method. In the APAP-treated group, the level of CAV1 was decreased, while the levels of HIF-1α and reactive oxygen species (ROS) were significantly increased. AML12 cells were treated with a mixture of palmitic acid (PA) and oleic acid (OA) (1:2 mix) for 48 h, and APAP was added for the last 24 h. Overexpression of CAV1 in AML12 cells significantly inhibited the expression of ROS and HIF-1α. And the results of immunofluorescence after treatment with CAV1-SiRNA showed that the HIF-1α levels were significantly increased in mitochondria. In conclusion, our experimental results suggest that CAV1 has a protective function in the fatty liver based on preventing oxidative stress, which involves HIF-1α. Thus, upregulation of CAV1 may attenuate APAP-exacerbated liver injury in NAFLD.