Hepatocyte-derived Fetuin-A promotes alcohol-associated liver disease in mice by inhibiting autophagy-lysosome degradation of TLR and M2 macrophage polarization

Alcohol-associated liver disease (ALD) is one of the most common chronic liver diseases worldwide. Fetuin-A (FetA) is a plasma glycoprotein closely related to fat accumulation in the liver. However, the role of FetA in ALD remains unclear. Both National Institute on Alcohol Abuse and Alcoholism (NIAAA) model and ethanol (EtOH) treated cell were used in this study. The effect of FetA deficiency on the progression of ALD was analyzed and the underlying mechanism was explored. The expression of FetA was upregulated in the liver tissues of ethanol-fed mice and ALD patients, as well as in AML12 cells treated with ethanol. FetA deletion reduced hepatic steatosis, oxidative stress, and inflammation in ALD mice. Interestingly, the absence of FetA led to a reduction of TLR4 protein level in liver tissue of EtOH-fed mice, without a corresponding change of its mRNA level. Conversely, the administration of recombinant FetA elevated TLR4 protein level in ethanol-treated RAW264.7 cells. FetA knockout significantly impeded the polarization of M1 macrophage in vivo or in vitro. Mechanistically, FetA deficiency drived the autophagy-lysosomal degradation of TLR4, subsequently inhibiting the activation of NF-kB/NLRP3 inflammasome pathway. Furthermore, knockdown of FetA using an adeno-associated virus 8 (AAV8)-shRNA can effectively prevent the progression of ALD in mice. Our results indicate that inhibition of FetA reverses the progression of ALD in mice, implying that FetA can serve as a therapeutic target for the treatment of ALD.