Unlocking the therapeutic potential of canagliflozin in NAFLD: Insights into AMPK/SIRT1-mediated lipophagy.

: Nonalcoholic fatty liver disease (NAFLD) is a rising global health problem. The antidiabetic canagliflozin (CANA) has been proposed to ameliorate the metabolic abnormalities in NAFLD.

Objective: This study aimed to explore the possible anti-NAFLD effects of CANA in rats and HepG2 cells, focusing on AMPK/SIRT1-mediated lipophagy.

Methods: Wistar rats were assigned to four groups: control group, NAFLD group, NAFLD+CANA group, and NAFLD+CANA+chloroquine (CQ) group, where CQ served as autophagy inhibitor. HepG2 cells were also divided into four groups: control group, NAFLD group, NAFLD+CANA group, and NAFLD+CANA+compound C (Comp C) group, where Comp C served as AMPK inhibitor.

Results: The histopathological examination showed that CANA alleviated hepatic and intracellular lipid deposition in rats and HepG2 cells. CANA induced lipophagy by increasing LC3-II levels and lowering both p62 and perilipin 2 levels in rats and HepG2 cells, in addition to decreasing mTOR protein expression in rats' livers. These outcomes were associated with upregulation of the lipophagy regulator Rab7 and downregulation of the ER stress-related protein CHOP. CANA enhanced autophagic engulfment of lipid droplets while decreased ER stress and mitochondrial damage in rats' livers, as demonstrated by TEM. In rats, CANA improved hyperglycemia, hyperinsulinemia, dyslipidemia, and obesity. In HepG2 cells, CANA's effects were linked to increased phosphorylated AMPK level and enhanced SIRT1 level and expression. However, blocking lipophagy in rats and AMPK in HepG2 cells markedly weakened CANA's protective effects against NAFLD.

Conclusions: CANA ameliorated NAFLD via enhancing AMPK/SIRT1-mediated lipophagy, suggesting its potential as a therapeutic intervention for this metabolic disorder.