Inhibition of Lysosomal LAMTOR1 Increases Autophagy by Suppressing the MTORC1 Pathway to Ameliorate Lipid Accumulations in MAFLD

ABSTRACT: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a serious metabolic disorder characterized by fat accumulation in the liver, which can trigger liver inflammation and fibrosis, potentially leading to cirrhosis or liver cancer. Despite many studies on MAFLD over the past decades, the development of effective treatment mechanisms for MAFLD remains unclear due to its complex etiology. Given these limitations, we have focused on the discovery of therapeutic agents and molecular targets for the treatment of MAFLD treatment. In this study, we demonstrated that the natural compound acacetin alleviates MAFLD by regulating autophagy in a rapidly induced steatohepatitis a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) mouse model. In addition, acacetin inhibited lipid accumulation in 3T3-L1 adipocytes through autophagy. To identify the target contributing to the autophagy activity of acacetin, we performed Drug Affinity Responsive Target Stability (DARTS) combined with Liquid Chromatography with Tandem Mass Spectrometry (LC-MS/MS) proteomic analysis, which led to the identification of late endosomal/lysosomal adapter and MAPK and MTOR activator (LAMTOR1), a lysosomal membrane adaptor protein. Binding of acacetin to LAMTOR1 induces the release from the LAMTOR complex, leading to inhibition of mammalian target of rapamycin complex 1 (MTORC1), thereby increasing autophagy and ameliorating metabolic disorders through modulation of the MTORC1/AMPK axis. Furthermore, genetic knockdown of LAMTOR1 induced lysosomal activity and reduced lipid accumulation in cells, confirming that acacetin targets LAMTOR1. Taken together, this study identifies LAMTOR1 as a key protein target of acacetin, a natural anti-MAFLD compound, providing a novel therapeutic approach for the treatment of MAFLD by targeting LAMTOR1.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Ho Jeong Kwon  

PROVIDER: MSV000096568 | MassIVE | Mon Dec 02 06:34:00 GMT 2024

SECONDARY ACCESSION(S): PXD058477

REPOSITORIES: MassIVE