The PKA‐SREBP1c Pathway Plays a Key Role in the Protective Effects of Lactobacillus johnsonii JNU3402 Against Diet‐Induced Fatty Liver in Mice

Abstract

ScopeThe present study aims to assess the protective effect of Lactobacillus johnsonii JNU3402 (LJ3402) against diet‐induced non‐alcoholic fatty liver disease (NAFLD) and determine the mechanism underlying its beneficial effect on the liver in mice.Methods and resultsSeven‐week‐old male mice are fed a high‐fat diet (HFD) with or without oral supplementation of LJ3402 for 14 weeks. In mice fed an HFD, LJ3402 administration alleviates liver steatosis, diet‐induced obesity, and insulin resistance with a decreased hepatic expression of sterol‐regulatory element‐binding protein‐1c (SREBP‐1c), fatty acid synthase (FAS) and acetyl‐CoA carboxylase (ACC), and an increased phosphorylation of SREBP‐1c. The mechanistic study shows that LJ3402 inhibits SREBP‐1c transcriptional activity by enhancing protein kinase A (PKA)‐mediated phosphorylation and reduces the expression of its lipogenic target genes in AML12 and HepG2 cells, thereby attenuating hepatic lipid accumulation. Moreover, silencing the PKA α catalytic subunit or the inhibition of PKA activity by H89 abolishes LJ3402 suppression of free fatty acid (FFA)‐induced SREBP‐1c activity in hepatocytes. In addition, LJ3402 administration elevates the plasma lactate levels in mice fed an HFD; this lactate increases PKA‐mediated SREBP‐1c phosphorylation in AML12 cells with a decreased expression of its target genes, reducing hepatic lipid accumulation.ConclusionLJ3402 attenuates HFD‐induced fatty liver in mice through the lactate‐PKA‐SREBP‐1c pathway.

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“…Lactobacillus is essential for maintaining intestinal homeostasis. One study reported that Lactobacillus johnsonii JNU3402 protects against NAFLD via lactate PKA-SREBP-1c pathway ( Hong et al, 2023 ). Lactobacillus consumption may be a viable measure to prevent and treat HF, as suggested by previous research ( Santos et al, 2020 ; Won et al, 2023 ).…”