Abstract Background and Purpose: The autophagic degradation of lipid
droplets (LDs), termed lipophagy, is the main mechanism contributing to
lipid consumption in hepatocytes. The identification of effective and
safe natural compounds that target lipophagy to eliminate excess lipids
may be a potential therapeutic strategy for non-alcoholic fatty liver
disease (NAFLD). Here, we investigated the effects of naringin on NAFLD
and the underlying mechanism. Experimental Approach: The role of
naringin was investigated in mice fed a high-fat diet (HFD) to induce
NAFLD, as well as in AML12 cells and primary hepatocytes stimulated by
palmitate (PA). Transcription factor EB (TFEB)-knockdown AML12 cells and
hepatocyte-specific TFEB-knockout mice were also used for the mechanism
study. In vivo and in vitro studies were conducted using transmission
electron microscopy, immunofluorescence techniques and western blot
analysis. Key Results: We found that naringin treatment effectively
relieved HFD-induced hepatic steatosis in mice and inhibited palmitate
(PA)-induced lipid accumulation in hepatocytes. The increased p62 and
LC3-II levels observed with excess lipid-support autophagosome
accumulation and impaired autophagic flux. Treatment with naringin
restored TFEB-mediated lysosomal biogenesis, thereby promoting the
fusion of autophagosomes and lysosomes, restoring impaired autophagic
flux and further inducing lipophagy. However, the knockdown of TFEB in
hepatocytes or the hepatocyte-specific knockout of TFEB in mice
abrogated naringin-induced lipophagy, which eliminated the therapeutic
effect of naringin on hepatic steatosis. Conclusion and Implications:
These results demonstrate that TFEB-mediated lysosomal biogenesis and
subsequent lipophagy play essential roles in the ability of naringin to
mitigate hepatic steatosis and suggest that naringin is a promising drug
for treating or relieving NAFLD.
Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease