Quercetin Reduces Lipid Accumulation in a Cell Model of NAFLD by Inhibiting De Novo Fatty Acid Synthesis through the Acetyl-CoA Carboxylase 1/AMPK/PP2A Axis.

Abstract

Dysregulation of de novo lipogenesis (DNL) has recently gained strong attention as being one of the critical factors that contribute to the assessment of non-alcoholic fatty liver disease (NAFLD). NAFLD is often diagnosed in patients with dyslipidemias and type 2 diabetes; thus, an interesting correlation can be deduced between high hematic free fatty acids and glucose excess in the DNL dysregulation. In the present study, we report that, in a cellular model of NAFLD, the coexistence of elevated glucose and FFA conditions caused the highest cellular lipid accumulation. Deepening the molecular mechanisms of the DNL dysregulation-RT-qPCR and immunoblot analysis demonstrated increased expression of mitochondrial citrate carrier (CiC), cytosolic acetyl-CoA carboxylase 1 (ACACA), and diacylglycerol acyltransferase 2 (DGAT2) involved in fatty acids and triglycerides synthesis, respectively. XBP-1, an endoplasmic reticulum stress marker, and SREBP-1 were the transcription factors connected to the DNL activation. Quercetin (Que), a flavonoid with strong antioxidant properties, and noticeably reduced the lipid accumulation and the expression of SREBP-1 and XBP-1, as well as of their lipogenic gene targets in steatotic cells. The anti-lipogenic action of Que mainly occurs through a strong phosphorylation of ACACA, which catalyzes the committing step in the DNL pathway. The high level of ACACA phosphorylation in Que-treated cells was explained by the intervention of AMPK together with the reduction of enzymatic activity of PP2A phosphatase. Overall, our findings highlight a direct anti-lipogenic effect of Que exerted through inhibition of the DNL pathway by acting on ACACA/AMPK/PP2A axis; thus, suggesting this flavonoid as a promising molecule for the NAFLD treatment.

• Authors: Antonio Gnoni, Benedetta Di Chiara Stanca, Laura Giannotti, Gabriele Vincenzo Gnoni, Luisa Siculella, Fabrizio Damiano
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 3 (Jan 18 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35162967 (Publication Type: Journal Article)

Chemical References

• Fatty Acids
• Quercetin
• AMP-Activated Protein Kinases
• Protein Phosphatase 2
• ACACA protein, human
• Acetyl-CoA Carboxylase

Topics

• AMP-Activated Protein Kinases (metabolism)
• Acetyl-CoA Carboxylase (genetics, metabolism)
• Fatty Acids (metabolism)
• Gene Expression Profiling
• Hep G2 Cells
• Humans
• Lipogenesis
• Models, Biological
• Non-alcoholic Fatty Liver Disease (drug therapy, genetics, metabolism)
• Phosphorylation
• Protein Phosphatase 2 (metabolism)
• Quercetin (pharmacology)
• Signal Transduction