Puerarin protects against high‐fat high‐sucrose diet‐induced non‐alcoholic fatty liver disease by modulating PARP‐1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis

Abstract

As yet, there was no effective pharmacological therapy approved for non‐alcoholic fatty liver disease (NAFLD). Here, we aimed to evaluate the therapeutic potential of puerarin against NAFLD and explored the underlying mechanisms. C57BL/6J mice were fed with a high‐fat high‐sucrose (HFHS) diet with or without puerarin coadministration intragastrically. The levels of hepatocellular injury, steatosis, fibrosis, and mitochondrial and metabolism alteration were detected. First, puerarin ameliorated histopathologic abnormalities due to HFHS. We observed a marked increase in hepatic lipid content, inflammation, and fibrosis level, which were attenuated by puerarin. Possible mechanisms were related to puerarin‐mediated activation of PI3K/AKT pathway and further improvement in fatty acid metabolism. Puerarin restored the NAD+ content and beneficially affected the hepatic mitochondrial function, which attenuated HFHS‐induced steatosis and metabolic disturbances. Finally, hepatic PARP‐1 was activated due to excessive fat intake. Puerarin attenuated the PARP‐1 expression in HFHS‐fed mice, and PJ34, the PARP inhibitor, could mimic these protections of puerarin. However, pharmacological inhibition of PI3K disabled the protection of puerarin or PJ34 toward NAD+ refilling and mitochondrial homeostasis. In conclusion, our findings indicated that puerarin could be a promising and practical therapeutic strategy in NAFLD through modulating PARP‐1/PI3K/AKT signaling pathway and further facilitating mitochondrial function.

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

“…A decrease of 50%-60% in the activity and assembly of all OXPHOS complexes has been observed with the progression of NAFLD to NASH [202], which may be justified by a marked reduction in OXPHOS subunit expression, particularly in mitochondrial DNA-encoded subunits. Interestingly, this process is correlated with some findings describing a decrease in mtDNA in the liver of mice fed a HF diet supplemented with sucrose [203,204]. However, it should be highlighted that other diets lacking sucrose and mostly composed of lard did not show the same pattern regarding the depletion of mtDNA levels in steatotic mice and rats [199,201].…”

“…Nigro et al observed a decrease in Complex I activity using a HF diet supplemented with fructose [196]. Similar findings were observed when fructose was replaced by sucrose as a supplement to a HF diet [203]. Fructose may act as an inducer of a more aggressive NAFLD phenotype compared to the effect of a HF diet alone [196].…”

“…High fat [202] High fat (lard; soybean oil) (45% saturated fatty acids (FAs)) [196] Choline deficient diet [198] High fat (61% saturated FAs) and sucrose [203] Maintenance High fat (lard) [199] Induction High fat (lard; soybean oil) [191] High fructose [196] Mitochondrial ATP production…”

“…High fat (61% saturated FAs) and sucrose [203] High fat (coconut and soybean oil) and sucrose [204] Maintenance High fat (lard) [199]…”

Puerarin Relieved Compression-Induced Apoptosis and Mitochondrial Dysfunction in Human Nucleus Pulposus Mesenchymal Stem Cells via the PI3K/Akt Pathway

“…Mitochondrial biogenesis in hepatocytes required functional class 3 PI3K, which controls PPARα transcriptional activity and harmonizes energy demand with mitochondrial content [54]. Inhibition of PI3K was also found to disable the effect of PUR on mitochondrial homeostasis in nonalcoholic fatty liver disease [55]. Consisting with those findings, blocking of PI3K/Akt signaling pathway significantly diminished the effects of PUR on antioxidation and mitochondrial maintenance.…”