Lysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis through degradating CDC42

Abstract Non-alcoholic steatohepatitis (NASH) has received great attention due to its extremely high incidence. Our team screened LAPTM5 associated with NASH progression through extensive bioinformatics analysis. We found protein LAPTM5 markedly decreased in response to lipotoxicity both in liver tissues from human and mouse NASH groups, and protein level of LAPTM5 was negatively correlated with NAS score. Then, we found LAPTM5 degradation was mediated through its ubiquitination modification by the E3 ubquitin ligase NEDD4L. Hepatocyte specific depleting LAPTM5 exacerbated hepatic steatosis, inflammation and fibrosis in mouse NASH models. In contrast, LAPTM5 overexpression in hepatocyte exerted opposite effects. Mechanistically, LAPTM5 interacted with CDC42 and promoted its degradation through a lysosomal dependent manner, thus inhibited activation of the mitogen-activated protein kinase signaling pathway. Finally, adenovirus-mediated hepatic LAPTM5 overexpression ameliorated above symptoms in NASH models. These findings proved LAPTM5 as effective treatment in NASH and a potential biological marker for detecting NASH progression.