Hepatic Lamp2a Deficiency Promotes inflammation of Murine Autoimmune Cholangitis via Affecting Bile Acid Metabolism
Primary Biliary Cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by positive-antimitochondrial antibodies and abnormal liver function. The breaking of immune tolerance in PBC patients is closely associated with the disorders of bile acid metabolism, while the mechanism underlying remains unclear. Our previous study found that the absence of Lamp2 exacerbated the cholestasis and elevated serum ALP in the rat BDL model, which are also important clinical features of PBC, suggesting that Lamp2 may play an important role in the PBC progression. However, the specific role of Lamp2a in disease progression and its mechanism are still unclear. In this study, we showed that hepatic-specific Lamp2a deficiency could aggravate the inflammatory phenotype of murine autoimmune cholangitis, which can be abolished by the rescue of Lamp2a. Mechanistically, the loss of Lamp2a in hepatocytes contributed to the abnormal accumulation of the bile acid metabolism enzyme Acot8, thus altered the bile acid components of the liver, thereby enhancing the lymphocyte activities, and ultimately promoting the inflammatory phenotype of model mice. Moreover, we also found that through artificial intervention, Acot8 knockdown could alleviate the liver inflammation caused by Lamp2a deficiency, which marks the possibility of Acot8 as a new target for the treatment of PBC disease. Altogether, our findings explored the effect of Lamp2a deficiency on the murine autoimmune cholangitis by the perspective of bile acid metabolism, providing a theoretical and experimental basis for in-depth understanding the nature of PBC and the development of novel therapeutic targets for the disease treatment.