miR-155-5p promotes hepatic steatosis via PICALM-mediated autophagy in aging hepatocytes

Hepatic steatosis, a lipid disorder characterized by the accumulation of intrahepatic fat, is more prevalent in the elderly population. This study investigates the role of miR-155-5p in the autophagy dysregulation of aging hepatic steatosis.

We established an aging mouse model in vivo and a hepatocellular senescence model induced by low serum and palmitic acid in vitro. The fluctuations of microRNAs were derived from RNA-seq data and confirmed by qPCR in 4- and 18-month-old mouse liver tissues. Hematoxylin-eosin (H&E) staining observed pathological changes. Markers of senescence, autophagy, and lipolysis genes were analyzed using Western blot and qPCR. Bioinformatics analysis predicted miR-155-5p's target gene PICALM, confirmed by dual luciferase reporter assay and transfection of miR-155-5p mimic/inhibitor into senescent hepatocytes.

Senescent markers (p21, p16, and p-P53) and miR-155-5p were up-regulated in aging liver tissues and senescent hepatocytes. Bioinformatics analysis identified PICALM as a target gene of miR-155-5p, a finding further supported by dual luciferase reporter assays. Inhibition of miR-155-5p reduced expression of senescent marker genes (p16, p21, p-P53), improved autophagy (evidenced by increased LC3B-II and ATG5, and decreased P62), and enhanced lipolysis (indicated by increased ATGL and p-HSL) in senescent hepatocytes. Oil red O staining confirmed that miR-155-5p inhibition significantly reduced lipid accumulation in these cells.

This study suggests a potential new therapeutic approach for age-related hepatic steatosis through the inhibition of miR-155-5p to enhance autophagy.